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Relaxation Response Reviews
(46 References)
Stefano, G. B., T. Esch, et al. (2003). "Endocannabinoids as autoregulatory signaling molecules: coupling to nitric oxide and a possible association with the relaxation response." Med Sci Monit 9(4): RA63-75.
Endocannabinoid signaling processes are present in diverse organisms and in organisms 500 million years divergent in evolution. Cannabinoid receptor-1 expression (CB1), anandamide, and anandamide amidase have been found in invertebrates. Furthermore, this signaling system is coupled to constitutive nitric oxide synthase (cNOS)-derived nitric oxide (NO) release in both vertebrates and invertebrates, thereby regulating neural, immune, and vascular-like functions in these divergent organisms. In human endothelial cells from various blood vessels, CB1 immunoreactive components are present as is its coupling to anandamide-stimulated cNOS-derived NO production, which exerts an autoregulatory role on cNOS release. The modulation of vascular diameter and vascular tone represents a crucial point of interest in these pathways, and interactions between NO and the sympathetic nerve system are of importance, i.e, norepinephrine. Here, a possible association of NO and endocannabinoid signaling with the relaxation response, a physiological counterpart of the stress response, may exist.
Saul, L. and M. Shatzer (2003). "B-type natriuretic peptide testing for detection of heart failure." Crit Care Nurs Q 26(1): 35-9.
The incidence of heart failure (HF) is on the increase with the aging population. Heart failure can manifest as either systolic or diastolic dysfunction. Systolic dysfunction causes impaired ventricular contractility with an ejection fraction of less than 45%. In contrast, diastolic dysfunction is evidenced by impaired ventricular relaxation and an ejection fraction greater than 45%. The diagnosis of HF is challenging with patients who present with acute dyspnea and a history of chronic obstructive pulmonary disease or pneumonia. The pathophysiology of HF and the resulting compensatory mechanisms involve a complex neuroendocrine response that includes a release of natriuretic peptides including B-type natriuretic peptides (BNPs). Elevation of BNP is in response to ventricular wall stress and volume overload from HF. BNP promotes natriuresis, diuresis, and vasodilitation and therefore counteracts some of the deleterious effects of the neuroendocrine response in HF Recently, a new laboratory test for BNP has been developed to assist in rapid identification of patients with HF. Research studies have shown that BNP testing assists in differentiating between cardiac and pulmonary causes of acute dyspnea and could be used to evaluate effectiveness of therapy and as a predictor for length of stay and readmission.
Munarriz, R., S. W. Kim, et al. (2003). "A review of the physiology and pharmacology of peripheral (vaginal and clitoral) female genital arousal in the animal model." J Urol 170(2 Pt 2): S40-4; discussion S44-5.
PURPOSE: We review contemporary scientific data concerning the physiology and pharmacology of peripheral female genital arousal responses in the animal (rabbit and rat) model. MATERIALS AND METHODS: We reviewed the contemporary literature and our research studies concerning physiology and pharmacology of peripheral genital arousal from 3 experimental animal models, including genital smooth muscle cell culture, genital strip organ bath and in vivo animal model studies. RESULTS: Nitric oxide (NO) appears to be a key pathway mediating clitoral smooth muscle relaxation. In the vagina NO appeared to have a more controversial role in mediating vaginal muscularis smooth muscle relaxation. Vasoactive intestinal polypeptide induced vaginal smooth muscle relaxation. Functional alpha-adrenergic receptors were expressed in the clitoris and vagina, and mediated norepinephrine induced genital smooth muscle contraction. Androgens and estrogens modulated distinct physiological responses in vagina, and androgens facilitated vaginal smooth muscle relaxation. Papaverine hydrochloride, a smooth muscle relaxant, and phentolamine mesylate, an alpha-blocker, administered into the vaginal spongy muscularis layer increased vaginal wall pressure and vaginal blood flow. Sildenafil caused significant increases in genital (clitoral and vaginal) blood flow and vaginal lubrication in intact and ovariectomized animals. This response was more pronounced in animals treated with estradiol, suggesting that the NO cyclic guanosine monophosphate pathway is involved in the physiological mechanism of female genital arousal and that sildenafil facilitates this response in an in vivo animal model. CONCLUSIONS: To achieve improved understanding of the biological aspects of female sexual function, further research is needed in the physiology and pharmacology of peripheral (clitoral and vaginal) genital arousal in the animal model.
Mebazaa, A. and L. Erhardt (2003). "Levosimendan: a new dual-action drug in the treatment of acute heart failure." Int J Clin Pract 57(5): 410-6.
Levosimendan is a new agent for the treatment of acute heart failure. Levosimendan acts via complementary mechanisms; it enhances contractility by sensitising cardiac myofilaments to calcium and dilates blood vessels by opening ATP-dependent potassium channels. In contrast to traditional inotropes (beta-agonists or phosphodiesterase inhibitors), levosimendan does not raise myocyte calcium levels and is therefore less likely to elicit arrhythmias or to impair diastolic relaxation. The clinical efficacy of levosimendan is supported by four key clinical studies, including more than 900 patients hospitalised for cardiac decompensation due to acutely worsened chronic heart failure or to heart failure following myocardial infarction. When given as short-term therapy, levosimendan enhances cardiac output, reduces systemic vascular resistance and lowers pulmonary capillary wedge pressure. At 31 days post-treatment, mortality rates were halved in decompensated chronic heart failure patients who received levosimendan, compared with those on dobutamine--an advantage sustained at 180 days. Similar survival gains were observed among acute failure patients treated with levosimendan following myocardial infarction. With its substantial haemodynamic and survival benefits, levosimendan is well suited to be part of routine management for patients with acutely decompensated heart failure.
Matz, R. L. and R. Andriantsitohaina (2003). "Age-related endothelial dysfunction : potential implications for pharmacotherapy." Drugs Aging 20(7): 527-50.
Aging per se is associated with abnormalities of the vascular wall linked to both structural and functional changes that can take place at the level of the extracellular matrix, the vascular smooth muscle and the endothelium of blood vessels. Endothelial dysfunction is generally defined as a decrease in the capacity of the endothelium to dilate blood vessels in response to physical and chemical stimuli. It is one of the characteristic changes that occur with age, independently of other known cardiovascular risk factors. This may account in part for the increased incidence of cardiovascular events in elderly people that can be reversed by restoring endothelial function. A better understanding of the mechanisms involved and the aetiopathogenesis of this process will help in the search for new therapeutic agents.Age-dependent alteration of endothelium-dependent relaxation seems to be a widespread phenomenon both in conductance and resistance arteries from several species. In the course of aging, there is an alteration in the equilibrium between relaxing and contracting factors released by the endothelium. Hence, there is a progressive reduction in the participation of nitric oxide and endothelium-derived hyperpolarising factor associated with increased participation of oxygen-derived free radicals and cyclo-oxygenase-derived prostanoids. Also, the endothelin-1 and angiotensin II pathways may play a role in age-related endothelial dysfunction. The use of drugs acting at different levels of these signalling cascades, including antioxidant therapy, lipid-lowering drugs and estrogens, seems to be promising.
Jensen, M. D. (2003). "Fate of fatty acids at rest and during exercise: regulatory mechanisms." Acta Physiol Scand 178(4): 385-90.
Fatty acids are a major fuel source for humans both at rest and during exercise. Plasma free fatty acids (FFA), although present only in micromolar concentrations, are the major circulating lipid fuel. FFA availability can increase two- to four-fold with moderate intensity exercise. Other potential sources of fatty acids include circulating very low-density lipoprotein (VLDL) triglycerides (TGs) ( approximately 1/5 the fuel availability of FFA) and intramyocellular TGs ( approximately 2 mmol kg-1 muscle). At rest approximately 40% of systemic FFA uptake occurs in the splanchnic bed and uptake in legs is approximately 15-20%. During leg exercise the uptake of FFA in leg tissue increases to 30-60% of systemic uptake and splanchnic uptake decreases to 15%. The fate of VLDL TG fatty acids has not been adequately studied. Intramyocellular TG hydrolysis increases during exercise, but the factors that regulate this response are not clear. The fact that contraction of isolated muscles can stimulate the hydrolysis and oxidation of intramyocellular TGs (in the absence of hormonal or neural input) suggests an intracellular regulation of this process. Additional regulation from changes in catecholamines and insulin may also occur. During moderate intensity exercise circulating FFA and intramyocellular TG provide roughly equal portions of fatty acids for oxidation. In addition to endurance training, dietary factors have been shown to modulate the fatty acid oxidation response to exercise. Much remains to be learned about fatty acid trafficking during exercise. What role do VLDL TG play? How is the oxidation of intramyocellular TGs regulated? Techniques to address these questions in humans are only now becoming available.
Graves, P. R. and T. A. Haystead (2003). "A functional proteomics approach to signal transduction." Recent Prog Horm Res 58: 1-24.
The purpose of this review is to highlight how proteomics techniques can be used to answer specific questions related to signal transduction in a wide variety of systems. In our laboratory, we utilize proteomic technologies to elucidate signal transduction pathways involved in smooth muscle contraction and relaxation, cell growth and tumorigenesis, and the pathogenesis of malaria. We see the real application of this technology as a tool to enhance the power of existing approaches such as classical yeast and mouse genetics, tissue culture, protein expression systems, and site-directed mutagenesis. Our basic approach is to examine only those proteins that differ by some variable from the control sample. In this way, the number of proteins to be processed by electrophoresis, Edman degradation, or mass spectrometry is greatly reduced. In addition, since only those proteins that change in response to a given biological treatment are analyzed, the experimental outcome provides information about specific signaling pathways. Examples of typical experiments in our laboratory are measurement of changes in protein phosphorylation in response to treatment of cells with growth factors or specific drugs, characterization of proteins associated with a bait protein in a "pull-down" experiment, or measurement of changes in protein expression. Frequently, in these experiments, it is necessary to define complex protein mixtures. To achieve this goal, we utilize a variety of techniques to isolate specific types of proteins or "subproteomes" for further analysis. In this review, we discuss strategies used in our laboratory for studying signaling pathways, including subproteome isolation, proteome mining, and analysis of the phosphoproteome.
Fowler, D. E., S. Yang, et al. (2003). "Adrenomedullin and adrenomedullin binding protein-1: their role in the septic response." J Surg Res 109(2): 175-81.
Adrenomedullin (AM) is a recently discovered, potent vasodilatory peptide with activities including maintenance of cardiovascular and renal homeostasis. Studies have indicated that AM is important in initiating the hyperdynamic response during the early stage of sepsis, and reduction of the vascular effects of AM marks the transition from the initial hyperdynamic phase to the late hypodynamic phase in experimental sepsis. The decreased AM responsiveness in late sepsis may be related to alterations in the AM receptor binding characteristics and/or signaling pathways. Genetic experiments have provided useful information by enhancing AM gene expression. Moreover, a plasma protein which binds AM, adrenomedullin binding protein-1 (AMBP-1), was reported very recently and is just beginning to be investigated as an important modulator in the biphasic septic response. In this regard, our recent results have demonstrated that AMBP-1 synergistically enhanced AM-induced vascular relaxation in both sham and septic animals. It appears that decreased levels of AMBP-1 play a critical role in producing vascular AM hyporesponsiveness during the late stage of sepsis. Furthermore, administration of AM and AMBP-1 in combination prevented the transition from the hyperdynamic to hypodynamic response during the progression of polymicrobial sepsis. Thus, modulation of vascular responsiveness to AM by AMBP-1 may provide a novel approach for the management of sepsis.
Esch, T., G. L. Fricchione, et al. (2003). "The therapeutic use of the relaxation response in stress-related diseases." Med Sci Monit 9(2): RA23-34.
The objective of this work was to investigate a possible (therapeutic) connection between the relaxation response (RR) and stress-related diseases. Further, common underlying molecular mechanisms and autoregulatory pathways were examined. For the question of (patho)physiology and significance of RR techniques in the treatment of stress-related diseases, we analyzed peer-reviewed references only. The RR has been shown to be an appropriate and relevant therapeutic tool to counteract several stress-related disease processes and certain health-restrictions, particularly in certain immunological, cardiovascular, and neurodegenerative diseases/mental disorders. Further, common underlying molecular mechanisms may exist that represent a connection between the stress response, pathophysiological findings in stress-related diseases, and physiological changes/autoregulatory pathways described in the RR. Here, constitutive or low-output nitric oxide (NO) production may be involved in a protective or ameliorating context, whereas inducible, high-output NO release may facilitate detrimental disease processes. In mild or early disease states, a high degree of biological and physiological flexibility may still be possible (dynamic balance). Here, the therapeutic use of RR techniques may be considered particularly relevant, and the observable (beneficial) effects may be exerted via activation of constitutive NO pathways. RR techniques, regularly part of professional stress management or mind/body medical settings, represent an important tool to be added to therapeutic strategies dealing with stress-related diseases. Moreover, as part of 'healthy' life-style modifications, they may serve primary (or secondary) prevention. Further studies are necessary to elucidate the complex physiology underlying the RR and its impact upon stress-related disease states.
Casadei, B. and C. E. Sears (2003). "Nitric-oxide-mediated regulation of cardiac contractility and stretch responses." Prog Biophys Mol Biol 82(1-3): 67-80.
In the heart, nitric oxide (NO) is constitutively produced by the vascular and endocardial endothelium, the cardiomyocytes and the autonomic nerves. Whereas stimulation of NO release from the vascular endothelium has consistently been shown to quicken the onset of left ventricular (LV) relaxation and cause a small reduction in peak contraction, the role of myocardial NO production in regulating cardiac function appears to be more complex and controversial. Some studies have shown that non-isoform-specific inhibition of NO synthesis with L-arginine analogues has no effect on basal contraction in LV myocytes. However, others have demonstrated that stimulation of myocardial NO production can offset the increase in contraction in response to a rise in intracellular Ca(2+).Cardiac NO production is also activated by stretch and under these conditions NO has been shown to facilitate the Frank-Starling response and to contribute to the increase in intracellular Ca(2+) transients that mediates the slow increase in contraction in response to stretch (i.e., the Anrep effect).These findings suggest that NO can mediate diverse and even contrasting actions within the myocardium, a notion that is difficult to reconcile with the early description of NO as a highly reactive and diffusible molecule possessing minimal specificity in its interactions. The purpose of this short review is to revisit some of the 'controversial' aspects of NO-mediated regulation of myocardial function, taking into account our current understanding of how mammalian cells may target and regulate the synthesis of NO in such a way that NO can serve diverse physiological functions.
Yallampalli, C., M. Chauhan, et al. (2002). "Calcitonin gene-related peptide in pregnancy and its emerging receptor heterogeneity." Trends Endocrinol Metab 13(6): 263-9.
Calcitonin gene-related peptide (CGRP) is the most potent vasodilator, and there is a growing body of evidence that this peptide might have multiple other functions. During pregnancy, circulating CGRP levels in rats increase up to the time of delivery, followed by a sharp decline at term and postpartum. In addition, the sensitivity of various vascular beds to CGRP in rats appears to increase with advancing pregnancy. This increased sensitivity might be involved in regulating uteroplacental blood flow, in addition to other vascular adaptations that occur during normal pregnancy. Furthermore, the uterine relaxation response to CGRP is elevated during pregnancy and decreased at term. Sex steroid hormones, estrogens and progesterone, regulate CGRP synthesis and its effects on both myometrial and uterine vascular tissues. These changes in smooth muscle relaxation sensitivity to CGRP appear to be a consequence of changes in CGRP-receptor levels in these tissues. There appear to be two receptors for CGRP: the CGRP-A receptor, a well-characterized receptor consisting of calcitonin receptor-like receptor and receptor activity modifying protein 1, and the CGRP-B receptor. The CGRP system might play a role in the maintenance of normal pregnancy, and a defect in this system might lead to complications.
Tiruppathi, C., R. D. Minshall, et al. (2002). "Role of Ca2+ signaling in the regulation of endothelial permeability." Vascul Pharmacol 39(4-5): 173-85.
The vascular endothelial cell forms a semipermeable barrier between blood and interstitium. Inflammatory mediators such as thrombin and histamine induce vascular leakage defined as increased endothelial permeability to plasma proteins and other solutes. Increased endothelial permeability is the hallmark of inflammatory vascular edema. Inflammatory mediators that bind to heptahelical G protein-coupled receptors (GPCR) trigger increased endothelial permeability by increasing the intracellular Ca(2+) concentration ([Ca(2+)](i)). The rise in [Ca(2+)](i) activates key signaling pathways, which mediate cytoskeletal reorganization (through myosin light chain (MLC)-dependent contraction) and disassembly of VE-cadherin at the adherens junctions. The Ca(2+)-dependent protein kinase C (PKC) isoform, PKC-alpha, plays a critical role in initiating endothelial cell contraction and disassembly of VE-cadherin junctions. The increase in [Ca(2+)](i) induced by a variety of agonists is achieved by the generation of inositol 1,4,5-trisphosphate (IP3), activation of IP3 receptors (IP3R), release of stored intracellular Ca(2+), and Ca(2+) entry through plasma membrane channels. Recent findings demonstrate that IP3-sensitive Ca(2+) store depletion activates plasma membrane cation channels (i.e., store-operated cation channels (SOC) or Ca(2+) release activated channels) to cause Ca(2+) influx in endothelial cells. This mode of Ca(2+) influx is also known as capacitative Ca(2+) entry (CCE). Store-operated Ca(2+) influx signals increase in permeability and nitric oxide (NO) production and provokes changes in gene expression in endothelial cells. Recent studies have established that the Drosophila transient receptor potential (TRP) gene family of channels expressed in endothelial cells can function as SOC. Deletion of one of the TRP homologues, TRPC4, in mouse caused impairment in store-operated Ca(2+) current and Ca(2+) store release activated Ca(2+) influx in aortic and lung endothelial cells (LEC). In TRPC4 knockout (TRPC4(-/-)) mice, acetylcholine-induced endothelium-dependent smooth muscle relaxation was drastically reduced. In addition, TRPC4(-/-) mice LEC exhibited lack of actin stress fiber formation and cell retraction in response to thrombin activation of proteinase-activated receptor-1 (PAR-1) in endothelial cells. The increase in lung microvascular permeability in response to thrombin receptor activation was inhibited in TRPC4(-/-) mice. These results indicate that endothelial TRP channels such as TRPC1 and TRPC4 play an important role in signaling the increase in endothelial permeability.
Tay, F. R. and D. H. Pashley (2002). "Dental adhesives of the future." J Adhes Dent 4(2): 91-103.
The current trend in the development of dentin adhesives attempts to simplify bonding steps and make them more user-friendly. However, optimizing speed and efficiency should be accomplished without major tradeoffs in the quality or durability of resin bonds. Although dentin adhesives have improved tremendously over the past decade, postoperative sensitivity, incomplete marginal seal, premature bond degradation, biocompatibility, and compromised bonding to abnormal substrates are still considered potential problems associated with their use. Advances in different scientific disciplines will enrich the pool from which ideas may be drawn in designing future dentin adhesives. It is probably on the molecular level that we will see the greatest expansion of horizons. With the advances in biomimetics, future dentin adhesive monomers may contain domains derived from protein-based, underwater bioadhesives secreted by aquatic animals such as mussels and barnacles, making them less dependent on the surface energy of the bonding substrates as well as less susceptible to hydrolytic degradation. As adhesive joints produced by contemporary adhesives are brittle in nature, future adhesive design may incorporate biomimetic intermediate-strength domains that can undergo stepwise reversible unfolding in response to varying functional stress levels before ultimate catastrophic failure of the adhesive joint occurs. These domains may also re-establish folded configurations on stress relaxation, making the adhesive both strong and tough. Using the concept of controlled release, future adhesives may contain fluorescent biosensors that can detect pH changes around leaking restorations. They may even have the capacity to heal autonomously, in response to microcracks formed by functional stresses within the adhesive joint. The ability to self-diagnose and self-repair will increase the life expectancy of adhesive restorations. Future dentin adhesives may also assume a more instrumental role in therapeutics apart from caries prevention. These features may include the controlled release of noncollagenous proteins to promote remineralization of collagen matrices in sound and caries affected dentin, and growth factors to induce controlled formation of reparative dentin.
Tapiero, H., G. Mathe, et al. (2002). "I. Arginine." Biomed Pharmacother 56(9): 439-45.
L-Arginine (Arg) is classified as an essential amino acid for birds, carnivores and young mammals and a conditionally essential amino acid for adults. It is converted by arginase to L-ornithine, a precursor of polyamines and urea, which is important in the urea cycle. Arg serves as a precursor for creatine, which plays an essential role in the energy metabolism of muscle, nerve and testis and accounts for Arg catabolism and for the synthesis of agmatine and proteins. Via its ability to increase growth hormone secretion it influences immune function. Depending on nutritional status and developmental stage, normal plasma Arg concentrations in humans and animals range from 95 to 250 micromol/l. Systemic or oral Arg administration has been shown to improve cardiovascular function and reduce myocardial ischemia in coronary artery disease patients. It reduces blood pressure and renal vascular resistance in essential hypertensive patients with normal or insufficient renal function. Although Arg plasma concentrations are not altered in hypercholesterolemic individuals, oral or intravenous Arg administration can reverse endothelial dysfunction in hypercholesterolemic patients and in cigarette smokers. The main importance of Arg is attributed to its role as a precursor for the synthesis of nitric oxide (NO), a free radical molecule that is synthesized in all mammalian cells from L-Arg by NO synthase (NOS). NO appears to be a major form of the endothelium-derived relaxing factor (EDRF). NO and EDRF share similar chemical and pharmacological properties and are derived from the oxidation of a terminal guanidine group of L-Arg. Various mechanisms have been implicated in the defect in vascular relaxation. These include, increased diffusional barrier for NO, L-Arg depletion, altered levels of reactive oxygen, inactivation of NO by superoxide anions (O2-). The independent reactions of O2-, NO and their reaction yielding peroxynitrite are critical in the initiation and maintenance of the atherosclerotic state and contribute to the defect in vasorelaxation. NO also plays a role as a neurotransmitter, mediator of immune response and as signaling molecule. The NO synthesized by iNOS in macrophages contributes to their cytotoxic activity against tumor cells, bacteria and protozoa. Our aim here is to review on some amino acids with high functional priority such as Arg and to define their effective activity in human health and pathologies.
Szelag, A., A. Merwid-Lad, et al. (2002). "[Histamine receptors in the female reproductive system. Part II. The role of histamine in the placenta, histamine receptors and the uterus contractility]." Ginekol Pol 73(7): 636-44.
The presence of the mast cells was confirmed not only in the uterus but also in the placental tissue. Mediators released from the placental mast cells may play a role in regulation of placental blood flow and normal blood pressure. Processes such uptake and clearance of vasoactive mediators may be upset in those women who developed pre-eclampsia. Histamine released from the placental mast cells may be involved in the mechanisms controlling myometrium contractility during the labour at term and preterm delivery. There is a correlation between the level of placental histamine and presence (or not) uterus contractility. Histamine produce a contractile response in isolated myometrial strips, in the majority of mammals, via H1 histamine receptors activation, but in some species e.g. rat, predominant response of uterus is relaxation (via H2 histamine receptors activation). Predominant response of the human uterus to histamine is contraction. Relaxation of human myometrial strips may be evoked after earlier usage of H1 receptors antagonists, although some H2 receptors agonists (e.g. dimaprit) induce the relaxation of human uterus without H1 receptors antagonists. Myometrium contractile activity is under control of sexual hormones. Neither the presence of H3 histamine receptors on the human myometrial smooth cells nor its role in the female reproductive system regulation was proved. Lack of the functional H3 receptors either on the smooth muscle cells or neuronal components of the animals' myometrium was shown in some studies.
Swift, S. (2002). "Current opinion on the classification and definition of genital tract prolapse." Curr Opin Obstet Gynecol 14(5): 503-7.
PURPOSE OF REVIEW: There are few issues in obstetrics and gynecology that seem so readily apparent but are in actuality replete with confusion than the diagnosis of genital tract prolapse. This stems from the difficulties in defining genital tract prolapse and from the long history of turmoil regarding how to classify and describe it. In the past 5-10 years our specialty has begun to make inroads into these issues. Finally, there is an accepted classification system and because of this we are beginning to recognize what represents normal vaginal support versus genital tract prolapse. RECENT FINDINGS: In 1993 the confusion regarding the classification of genital tract prolapse was documented by a very thorough review of the literature; in response, the Pelvic Organ Prolapse Quantification system was developed. Subsequent to this, several articles have begun to define the epidemiology of genital tract prolapse and this is providing a glimpse of what differentiates pathologic genital tract prolapse from normal support. SUMMARY: We can now reliably classify and describe genital tract relaxation and imply what is normal support versus pathological genital tract prolapse. However, we still have not defined genital tract prolapse, determined its prevalence or provided the clinician with a simple and reliable means of testing for its presence or absence.
Schwizer, W., A. Steingotter, et al. (2002). "Non-invasive measurement of gastric accommodation in humans." Gut 51 Suppl 1: i59-62.
Gastric accommodation describes the reduction in gastric tone and increase in compliance that follows ingestion of a meal and involves at least two responses: "receptive relaxation" which allows the stomach to accept a volume load without a significant rise in gastric pressure and "adaptive relaxation" which modulates gastric tone in response to the specific properties of the meal ingested. However, there are considerable technical difficulties in measuring the accommodation process. The current standard barostat studies, and other methods such as conventional and three dimensional ultrasound, or single photon emission computed tomography have significant disadvantages. Preliminary findings from the development and validation of a new magnetic resonance imaging technique that addresses many of the deficiencies of previous methods are presented.
Rosen, R. C. and K. E. McKenna (2002). "PDE-5 inhibition and sexual response: pharmacological mechanisms and clinical outcomes." Annu Rev Sex Res 13: 36-88.
Phosphodiesterase type-5 (PDE-5) inhibitors are a new class of vasoactive drugs that have been developed for treatment of erectile dysfunction (ED). The mechanism of action involves active inhibition of the PDE-5 enzyme and resulting increase in cyclic guanosine monophosphate (cGMP) and smooth muscle relaxation in the penis. Sildenafil citrate (Viagra) is a potent and selective PDE-5 inhibitor, which is the first drug in this class to be approved for treatment of ED. More than 10 million men worldwide have been treated with this drug. Sildenafil has been shown to be generally effective in the treatment of ED, although the degree of efficacy varies according to the etiology and severity of the disorder. The drug is well tolerated, with relatively few contraindications (e.g., nitrates) and safety risks. The cardiovascular effects of sildenafil, in particular, have been extensively investigated. The results of recent studies suggest that sildenafil may have an additional role in the treatment of other male and female sexual disorders, such as premature ejaculation and female sexual arousal disorder, although results to date are inconclusive. Two additional agents in this class (tadalafil [Cialis], vardenafil [Levitra]) have been developed recently and are under regulatory review. Tadalafil is a long-acting PDE-5 inhibitor, which is effective for up to 36 hr in the majority of men. Vardenafil has a similar duration of action to sildenafil, but is more potent and selective biochemically. Both drugs appear to be generally safe and well tolerated, with a similar side-effect profile to sildenafil. There are no controlled comparison studies to date. Despite the overall effectiveness of PDE-5 inhibitors in the treatment of ED, significant psychological and interpersonal issues need to be addressed in their clinical use. The potential impact on societal attitudes toward sexuality and sexual dysfunction also warrants consideration.
Reynaert, H., M. G. Thompson, et al. (2002). "Hepatic stellate cells: role in microcirculation and pathophysiology of portal hypertension." Gut 50(4): 571-81.
Accumulating evidence suggests that stellate cells are involved in the regulation of the liver microcirculation and portal hypertension. Activated hepatic stellate cells have the necessary machinery to contract or relax in response to a number of vasoactive substances. Because stellate cells play a role in both fibrosis and portal hypertension, they are currently regarded as therapeutic targets to prevent and treat the complications of chronic liver disease.
Raj, U. and L. Shimoda (2002). "Oxygen-dependent signaling in pulmonary vascular smooth muscle." Am J Physiol Lung Cell Mol Physiol 283(4): L671-7.
The pulmonary circulation constricts in response to acute hypoxia, which is reversible on reexposure to oxygen. On exposure to chronic hypoxia, in addition to vasoconstriction, the pulmonary vasculature undergoes remodeling, resulting in a sustained increase in pulmonary vascular resistance that is not immediately reversible. Hypoxic pulmonary vasoconstriction is physiological in the fetus, and there are many mechanisms by which the pulmonary vasculature relaxes at birth, principal among which is the acute increase in oxygen. Oxygen-induced signaling mechanisms, which result in pulmonary vascular relaxation at birth, and the mechanisms by which chronic hypoxia results in pulmonary vascular remodeling in the fetus and adult, are being investigated. Here, the roles of cGMP-dependent protein kinase in oxygen-mediated signaling in fetal pulmonary vascular smooth muscle and the effects of chronic hypoxia on ion channel activity and smooth muscle function such as contraction, growth, and gene expression were discussed.
Nehra, A. and H. Kulaksizoglu (2002). "Combination therapy for erectile dysfunction: where we are and what's in the future." Curr Urol Rep 3(6): 467-70.
Penile erection occurs in response to visual, olfactory, imaginative, and tactile stimuli initiated within the brain and/or on the periphery. Responses to these stimuli are mediated by efferent autonomic outflow originating in the sacral spinal cord and transmitted by the cavernosal and penile nerves. A number of neurotransmitters can play an integral role in corpus cavernosum smooth muscle relaxation, in part regulating penile erection through increased smooth muscle synthesis of the secondary messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). In addition to direct-acting agents, there are indirect-acting smooth muscle-relaxing agents. Phosphodiesterase (PDE) inhibitors such as sildenafil act indirectly and require sexual stimulation and endogenous nitric oxide production to activate the cGMP pathway effectively. In contrast, agents such as prostaglandin E(1) (PGE(1)) act directly on the trabecular smooth muscle, binding to specific e-prostanoid receptors and increasing cAMP synthesis. For this reason the direct-acting agents do not require sexual stimulation for efficacy. Combination pharmacotherapy has been used experimentally to treat erectile dysfunction for 25 years, using combinations of cAMP synthesis augmentors, smooth muscle relaxants and PDE inhibitors, and alpha-blockers administered via intracavernosal injection. The present era of oral pharmacotherapy treatment has resulted in significant awareness in the field of sexual dysfunction; however, a single agent may not be ideal to sustain penile rigidity, especially if comorbidities and severity of erectile dysfunction are accounted for. The rationale for and recent reports on combination therapy are presented in this review.
Munarriz, R., N. N. Kim, et al. (2002). "Biology of female sexual function." Urol Clin North Am 29(3): 685-93.
Although the psychosocial and relationship aspects of female sexuality have been extensively investigated, studies concerning the anatomy, physiology and pathophysiology of female sexual function and dysfunction are limited. The paucity of biologic data may be attributed to a lack of reliable experimental models and tools for investigating female sexual function and to limited funding, which is critical for developing experimental approaches. Research efforts by several investigators in different laboratories have been establishing experimental models needed for investigating the physiologic mechanisms involved in the genital arousal response of sexual function. These experimental models have permitted assessment of genital hemodynamics, vaginal lubrication, regulation of genital smooth muscle contractility and signaling pathways, providing preliminary information about the role of neurotransmitters and sex steroid hormones in sexual function. Further research is needed to define the neurotransmitters responsible for vaginal smooth muscle relaxation and the role of sex steroid hormones and their receptors in modulating genital hemodynamics, smooth muscle contractility, and neurotransmitter receptor expression. Finally, a global and integral understanding of the biologic aspects of female sexual function requires investigation of the vascular, neurologic (central and peripheral), and structural components of this extremely complex physiologic process.
Morse, D. and J. Sethi (2002). "Carbon monoxide and human disease." Antioxid Redox Signal 4(2): 331-8.
Carbon monoxide is produced endogenously in humans through the breakdown of hemoglobin by heme oxygenase. Although originally thought to be a superfluous by-product of heme catabolism, carbon monoxide is now known to play a central role in many aspects of human health and disease. The functions of carbon monoxide that have been described to date are myriad, including blood pressure regulation, maintenance of organ-specific vascular tone, neurotransmission, stress response, platelet activation, and smooth muscle relaxation. This review outlines what is known to date about carbon monoxide as it relates to human disease.
Martin, R. J., M. J. Mhanna, et al. (2002). "The role of endogenous and exogenous nitric oxide on airway function." Semin Perinatol 26(6): 432-8.
Coordinated regulation of airway caliber is important for the maintenance of effective ventilation. Therefore, we sought to characterize the role of endogenously released, and exogenously administered, nitric oxide (NO) in mediating airway smooth muscle relaxation during early postnatal life. In both rat pup and piglet models, cholinergically mediated airway contractile responses were diminished by simultaneous release of endogenous NO and cGMP activation in both central airways and peripheral contractile elements. This ability of endogenously released NO to oppose airway constriction may be impaired in response to hyperoxic exposure or in animal models of cystic fibrosis. Additional studies in piglets have shown that exogenously administered NO causes a modest, but significant, reduction in lung resistance, analogous to the decrease in pulmonary vascular resistance induced by inhaled NO. Clinical trials are now underway in preterm infants at risk for chronic neonatal lung injury to determine whether inhaled NO has a beneficial effect on the development of bronchopulmonary dysplasia and whether exogenous NO modulates airway function in such infants.
Maas, M., L. W. Poll, et al. (2002). "Imaging and quantifying skeletal involvement in Gaucher disease." Br J Radiol 75 Suppl 1: A13-24.
Radiological imaging is used in patients with Gaucher disease to estimate the disease burden, to evaluate the presence of specific skeletal complications and to track response to therapy. MRI is currently the best technique for assessing bone marrow involvement in Gaucher disease. Gaucher cell infiltrated bone marrow is characterized by an abnormal low signal intensity on conventional T1- and T2-weighted spin echo sequences, owing to a reduction in fat marrow, which gives a high signal intensity. Enzyme replacement therapy results in a degradation of Gaucher cell deposits with a reconversion of marrow fat and consequently an increased signal on T(1)-weighted images. Conventional MRI also detects other skeletal complications in Gaucher disease, including oedema resulting from acute bone infarction, infection and trauma, avascular necrosis, pathological fractures and vertebral compression. The main drawback of conventional MRI is that it is not quantitative. Quantitative chemical shift imaging is the most sensitive quantitative method for evaluating bone marrow but is not widely available. Alternative MRI-based methods include calculation of the T1 relaxation constant and proton spectroscopy. Scoring of imaging changes detected on conventional MRI may be useful in estimating disease burden and risk of complications. Dual-energy X-ray absorptiometry (DXA) is sensitive to generalized osteopenia and changes in bone mineral density with extended enzyme replacement therapy. However, DXA is insensitive to local changes and cannot yet be used to predict fracture risk in these patients. Until the ideal quantitative technique is developed, conventional MRI will remain the best diagnostic modality for assessing skeletal complications in Gaucher disease and monitoring response to enzyme replacement therapy.
Leach, R. M., H. S. Hill, et al. (2002). "Hypoxia, energy state and pulmonary vasomotor tone." Respir Physiol Neurobiol 132(1): 55-67.
Vasomotor responses to hypoxia constitute a fundamental adaptation to a commonly encountered stress. It has long been suspected that changes in cellular energetics may modulate both hypoxic systemic artery vasodilatation (HSV) and hypoxic pulmonary artery vasoconstriction (HPV). Although limitation of energy has been shown to underlie hypoxic relaxation in some smooth muscles, the response to hypoxia in vascular smooth muscle does not appear to be a simple function of energy stores, but instead may involve perturbations of ATP or energy delivery to mechanisms controlling muscle force, and/or changes associated with anaerobic metabolism. Recent work in pulmonary vascular smooth muscle has demonstrated that energy stores are maintained during hypoxic pulmonary vasoconstriction, and that this is dependent on glucose availability and up-regulation of glycolysis. There is increasing evidence that glycolysis is preferentially coupled to a variety of membrane associated ATP dependent processes, including the Na(+) pump, Ca(2+)-ATPase, and possibly some protein kinases. These and other mechanisms may influence excitation-contraction coupling in both systemic and pulmonary arteries by effects on intracellular Ca(2+) and/or Ca(2+) sensitivity. Hypoxia has also been postulated to have major effects on other cytosolic second messenger systems including phosphatidylinositol pathways, cell redox state and mitochondrial reactive oxygen species production. This review examines the relationship between energy state, anaerobic respiration and hypoxic vasomotor tone, with a particular emphasis on hypoxic pulmonary vasoconstriction.
Lakatta, E. G. and S. J. Sollott (2002). "Perspectives on mammalian cardiovascular aging: humans to molecules." Comp Biochem Physiol A Mol Integr Physiol 132(4): 699-721.
Age-related changes in cardiovascular function and structure in healthy adult volunteer community dwelling subjects (from 20 to 85 years) is remarkable for changes in pump function [impaired left ventricular (LV) ejection reserve capacity manifest by a reduced ejection fraction and accompanied by diminished cardioacceleration, LV dilation at end diastole and an altered diastolic filling pattern] and increased vascular afterloading. There is also evidence for a reduction in the number of cardiac myocytes with advancing age. Subcellular changes with aging (best understood in rodents) include certain regulatory factors of excitation-contraction-relaxation coupling (i.e. calcium handling), modulation by adrenergic receptor (AR) stimulation, and changes in the generation and sensitivity to the damaging effects of ROS. Coordinated changes in gene expression and/or protein function with aging result in a prolonged action potential (AP), Ca(i) transient, and contraction. L-type Ca(2+) current (I(Ca)) inactivates more slowly, and outwardly-directed K(+) currents are reduced, and likely contribute to AP-prolongation. The rate of Ca(2+) sequestration by the sarcoplasmic reticulum (SR) decreases in the senescent myocardium, in part underlying the prolonged Ca(i) transient. An age-associated reduction in transcription of the SERCA2 gene, coding for the SR Ca(2+) pump, accounts in part for a decrease in the SR pump site density. The contractile response to both beta(1)-AR and beta(2)-AR stimulation diminishes with aging due to decreased adrenergic augmentation of I(Ca), and thus the Ca(i) transient, in senescent vs. young hearts. The age-associated reduction in the postsynaptic response of myocardial cells to beta(1)-AR stimulation appears to be due to multiple changes in molecular and biochemical receptor coupling and post-receptor mechanisms. An increased basal production of ROS is paralleled by increased ROS-sensitivity, markers of chronic ROS damage and mitochondrial functional decline. Overall, these changes lead to a diminished (but not necessarily exhausted) capacity of the heart to adapt to physiological or pathological stress with advancing age.
Kimura, H. (2002). "Hydrogen sulfide as a neuromodulator." Mol Neurobiol 26(1): 13-9.
Hydrogen sulfide (H2S) is a well-known toxic gas with the smell of rotten eggs. Since the first description of the toxicity of H2S in 1713, most studies about H2S have been devoted to its toxic effects. Recently, H2S has been proposed as a physiologically active messenger. Three groups discovered that the brain contains relatively high concentrations of endogenous H2S. This discovery accelerated the identification of an H2S-producing enzyme, cystathionine beta-synthase (CBS) in the brain. In addition to the well-known regulators for CBS, S-adenosyl-L-methionine (SAM) and pyridoxal-5'-phosphate, it was recently found that Ca2+/calmodulin-mediated pathways are involved in the regulation of CBS activity. H2S is produced in response to neuronal excitation, and alters hippocampal long-term potentiation (LTP), a synaptic model for memory. can also regulate the release of corticotropin-releasing hormone (CRH) from hypothalamus. Another H2S producing enzyme, cystathionine gamma-lyase (CSE), has been identified in smooth muscle, and H2S relaxes smooth muscle in synergy with nitric oxide (NO). Recent progress in the study of H2S as a novel neuromodulator/transmitter in the brain is briefly reviewed.
Katz, A. M. (2002). "Maladaptive growth in the failing heart: the cardiomyopathy of overload." Cardiovasc Drugs Ther 16(3): 245-9.
The hypertrophic response to overload plays an important role in the progressive deterioration of the failing heart--the "Cardiomyopathy of Overload"--and so contributes to the poor prognosis in patients with heart failure. Although increased myocyte size reduces the load on individual sarcomeres, hypertrophy also has maladaptive features. The latter include molecular changes that weaken and impair relaxation in the overloaded heart, and accelerate cardiac myocyte death. Different types of overload lead to concentric and eccentric hypertrophy; as the latter tends to progress ("remodeling"), dilatation is associated with an especially poor prognosis. Concentric hypertrophy is due largely to cardiac myocyte thickening, while eccentric hypertrophy is caused by cell elongation. These differences, along with evidence that concentric hypertrophy is initiated by increased diastolic stretch while eccentric hypertrophy results from increased systolic stress, indicate that these growth responses are mediated by different signal transudation pathways. The beneficial effects of neurohumoral blockers in patients with heart failure are due partly to their ability to inhibit maladaptive features of overload-induced proliferative signaling. The molecular complexity of the hypertrophic response now being uncovered offers opportunities for the development of new therapy to inhibit remodeling and cell death in the failing heart.
Kaprielian, R., F. del Monte, et al. (2002). "Targeting Ca2+ cycling proteins and the action potential in heart failure by gene transfer." Basic Res Cardiol 97 Suppl 1: I136-45.
Cardiomyocytes isolated from failing human hearts are characterized by contractile dysfunction including prolonged relaxation, reduced systolic force and elevated diastolic force. These contractile abnormalities are paralleled by abnormal Ca2+ homeostasis such as reduced sarcoplasmic reticulum (SR) Ca2+ release, elevated diastolic Ca2+ and reduced rate of Ca2+ removal. In addition, failing human myocardium is characterized by a frequency-dependent decrease in systolic force and Ca2+ as opposed to normal myocardium where an increase in pacing rate results in potentiation of contractility and an increase in SR Ca2+ release. In the failing heart, the decrease in SR Ca2+ load has been linked to a decrease in SR Ca2+ ATPase (SERCA2a) function. We have recently shown that overexpression of SERCA2a by adenoviral gene transfer restores contractile function in cardiac myocytes from failing human hearts. In addition, we have shown that overexpression of SERCA2a in a model of pressure-overload hypertrophy in transition to failure improves contractile function and reserve in these animals. We are currently exploring the effect of long-term expression of SERCA2a in failing animals along with the energy cost of SERCA2a expression using NMR methods. We are also using a different strategy to improve SR Ca2+ ATPase activity which involves decreasing the expression of phospholamban by antisense strategies to enhance SR Ca2+ ATPase activity. The Na/Ca exchanger is also being targeted to enhance calcium removal in failing hearts. Action potential prolongation is attributed to reductions in transient outward current (Ito) density in human heart failure. This prolongation can alter contractility but can also cause afterdepolarization. Using gene transfer of various K channels responsible for Ito, we are investigating the molecular and the ionic basis of action potential prolongation in cardiac hypertrophy and failure and we are examining how intracellular calcium handling changes in response to alterations in action potential duration. Gene transfer, which serves initially as an experimental tool, may provide a novel therapeutic approach.
Johnston, I. A. and G. K. Temple (2002). "Thermal plasticity of skeletal muscle phenotype in ectothermic vertebrates and its significance for locomotory behaviour." J Exp Biol 205(Pt 15): 2305-22.
Seasonal cooling can modify the thermal preferenda of ectothermic vertebrates and elicit a variety of physiological responses ranging from winter dormancy to an acclimation response that partially compensates for the effects of low temperature on activity. Partial compensation of activity levels is particularly common in aquatic species for which seasonal temperature changes provide a stable cue for initiating the response. Thermal plasticity of locomotory performance has evolved independently on numerous occasions, and there is considerable phylogenetic diversity with respect to the mechanisms at the physiological and molecular levels. In teleosts, neuromuscular variables that can be modified include the duration of motor nerve stimulation, muscle activation and relaxation times, maximum force and unloaded shortening velocity (V(max)), although not all are modified in every species. Thermal plasticity in V(max) has been associated with changes in myosin ATPase activity and myosin heavy chain (MyHC) composition and/or with a change in the ratio of myosin light chain isoforms. In common carp (Cyprinus carpio), there are continuous changes in phenotype with acclimation temperature at lower levels of organisation, such as MyHC composition and V(max), but a distinct threshold for an effect in terms of locomotory performance. Thus, there is no simple relationship between whole-animal performance and muscle phenotype. The nature and magnitude of temperature acclimation responses also vary during ontogeny. For example, common carp acquire the ability to modify MyHC composition with changes in acclimation temperature during the juvenile stage. In contrast, the thermal plasticity of swimming performance observed in tadpoles of the frog Limnodynastes peronii is lost in the terrestrial adult stage. Although it is often assumed that the adjustments in locomotory performance associated with temperature acclimation enhance fitness, this has rarely been tested experimentally. Truly integrative studies of temperature acclimation are scarce, and few studies have considered both sensory and motor function in evaluating behavioural responses. Developmental plasticity is a special case of a temperature acclimation response that can lead to temporary or permanent changes in morphology and/or physiological characteristics that affect locomotory performance.
Johnson, G. R. (2002). "Outcome measures of spasticity." Eur J Neurol 9 Suppl 1: 10-6; dicussion 53-61.
Spasticity is characterized by a velocity-dependent increase in muscle resistance, in response to a passive stretch. Whilst clinical scales probably represent the most common approach to its measurement, these are limited by poor reliability and difficulties with some definitions. However, recently, a simple system has been used to provide the clinician with a measure of the force applied during the Ashworth Test. The Wartenberg Pendulum Test has been devised for measuring spasticity at the knee, but has been shown to be unsuitable for measuring more severe spasticity. Powered systems have been used in research studies, but are rarely considered suitable for routine clinical use. However, one method of interest, using a low inertia torque motor to measuring stiffness at the wrist, has been shown to provide rapid measurements which correspond to the degree of spasticity defined by other scales. Clinical gait analysis may have an important role to play in assessing spasticity - since there are clear associations between lower limb spasticity and gait problems - but it does not provide a true measure of the condition. In summary, while scales remain the most common method of measuring spasticity, there is considerable potential in instrumented techniques that can provide greater reliability and precision of measurement.
Johnson, E. N. and K. M. Druey (2002). "Heterotrimeric G protein signaling: role in asthma and allergic inflammation." J Allergy Clin Immunol 109(4): 592-602.
Asthma and rhinitis are pathophysiologic conditions associated with a prototypical allergic response to inhaled allergens consisting of both neuromechanical and inflammatory components. Heptahelical receptors that bind guanosine triphosphate-binding proteins (G proteins), referred to as G protein-coupled receptors (GPCRs), have been intimately linked with asthma and allergic inflammation for many years. G protein signaling mediates responses throughout the immune, nervous, and muscular systems that might contribute to the pathogenesis of allergic processes and asthma. For example, GPCR agonists or antagonists are used as therapies for asthma either by promoting airway smooth muscle relaxation (beta2 adrenergic receptor agonists) or by inhibiting inflammation in the nasal mucosa and airways (cysteinyl leukotriene receptor antagonists). The focus of this review is to explore how downstream signaling cascades elicited by GPCR activation contribute to the allergic phenotype and the mechanism by which pharmaceuticals alter signaling to generate a therapeutic effect. We also discuss physiologic modulators of G protein signaling, such as regulator of G protein signaling proteins and G protein receptor kinases, inasmuch as they represent potential new therapeutic targets in the treatment of atopy and other inflammatory conditions.
Heimberg, R. G. (2002). "Cognitive-behavioral therapy for social anxiety disorder: current status and future directions." Biol Psychiatry 51(1): 101-8.
Cognitive-behavioral therapy (CBT) is the most thoroughly studied nonpharmacologic approach to the treatment of social anxiety disorder, and its efficacy has been demonstrated in a large number of investigations. This article summarizes the data on the efficacy of CBT for the treatment of the symptoms of social anxiety disorder and impaired quality of life. The relative efficacy of various CBT approaches, both in the short-term and over extended follow-up periods, is reviewed. Factors associated with more or less positive response to CBT among patients with social anxiety disorder are examined. Special attention is given to the comparison of CBT with pharmacologic approaches to the treatment of social anxiety disorder and the potential utility of combining these approaches. Future directions in the application of combinations of CBT and pharmacotherapy to the treatment of social anxiety disorder are discussed.
Hartmann, M., S. Heiland, et al. (2002). "[Functional MRI procedures in the diagnosis of brain tumors: Perfusion- and diffusion-weighted imaging]." Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 174(8): 955-64.
Despite the increased diagnostic accuracy of contrast material enhanced MR imaging, specification and grading of brain tumors are still only approximate at best: neither morphology, nor relaxation times or contrast material enhancement reliably predict tumor histology or tumor grade. As histology and tumor grade strongly influence which therapy concept is chosen, a more precise diagnosis is mandatory. With diffusion- and perfusion-weighted MR imaging (DWI, PWI) it is now possible to obtain important information regarding the cellular matrix and the relative regional cerebral blood volume (rrCBV) of brain tumors, which cannot be obtained with standard MR techniques. These dynamic-functional imaging techniques are very useful in the preoperative diagnosis of gliomas, lymphomas, and metastases, as well as in the differentiation of these neoplastic lesions from abscesses, atypical ischemic infarctions, and tumor-like manifestations of demyelinating disease. Additionally, they appear suitable for determining glioma grade and regions of active tumor growth which should be the target of stereotactic biopsy and therapy. After therapy these techniques are helpful to better assess the tumor response to therapy, possible therapy failure and therapy complications such as radiation necrosis.
Esch, T., G. B. Stefano, et al. (2002). "Stress-related diseases -- a potential role for nitric oxide." Med Sci Monit 8(6): RA103-18.
Nitric oxide (NO) is involved in stress physiology and stress-related disease processes. Like stress, NO seems to be capable of principally exerting either beneficial or deleterious effects. The actual distinction depends on a multitude of factors. Moreover, NO counteracts norepinephrine (NE) activity and sympathetic responsivity. Thus, NO and the stress (patho)physiology are closely connected and molecular mechanisms or pathways may be shared under certain conditions. NO is involved in immunological, cardiovascular, and neurodegenerative diseases/ mental disorders. It represents a 'double-edged sword', since small quantities produced by constitutive enzymes may predominantly mediate physiological effects, whereas the expression of inducible NO synthases may lead to larger quantities of NO, a situation that may be associated with cytotoxic and detrimental effects of NO. The key step for normally useful physiological mechanisms becoming pathophysiological may be represented by the loss of balance, the loss of control over the different pathways induced. A failure to terminate or shift originally protective mechanisms may lead to a vicious cycle of disease-supporting pathophysiological pathways.CONCLUSIONS: Profound connections between stress and various disease processes exist. Thereby, common pathophysiological pathways in stress-related diseases have been described, and they involve stress hormone (cortisol, NE) and, in particular, NO activity. Thus, NO has detrimental capacities. However, NO not only exerts deleterious but also strongly ameliorating effects. The balance between both properties is crucial. Yet, nitric oxide involvement in stress-related diseases represents a common pathway, with various pathophysiological analogies, that may be accessible for strategies using stress management and relaxation response techniques.
Dubus, J. C., L. Mely, et al. (2002). "[The beta-2-agonists in asthma in infants and young children]." Arch Pediatr 9 Suppl 3: 384s-389s.
beta 2-agonists, by inducing a fast and long relaxation of the bronchial smooth muscle, are considered as the more potent bronchodilators. beta 2-receptors are present from the 16th gestational week, explaining a possible bronchial response in the youngest children. beta 2-agonists do not induce any bronchodilator response in healthy children. Short-acting beta 2-agonists (salbutamol or albuterol, terbutaline) are indicated for asthma attacks, as needed in chronic asthma, and for prevention of symptoms during effort. They are safe and secure. The more efficient route of administration in preschool children is pressurized metered-dose inhaler used with a spacer device. Therefore, whatever the route of inhalation chosen (inhalation, injection, or continuous nebulization in acute asthma attack), more specified indications and doses are needed in young children. Long-acting beta 2-agonists (formoterol, salmeterol) are not authorized in France in children under 4 to 5 years of age depending on the drug used. Because of new oral formulations and recent considerations about their use in asthma attack, instead of short-acting beta 2-agonists, their indication in preschool asthmatic children might be reconsidered.
D'Eon, T. and B. Braun (2002). "The roles of estrogen and progesterone in regulating carbohydrate and fat utilization at rest and during exercise." J Womens Health Gend Based Med 11(3): 225-37.
OBJECTIVE: Compared with men, women use more fat and less carbohydrate to fuel exercise at the same relative intensity. Circulating levels of estrogen and progesterone are likely to play an important role in explaining this gender difference in exercise substrate utilization. METHODS: Studies, mainly using animal models, have shown that estrogen increases fatty acid availability (lipolysis) and decreases carbohydrate availability and uptake. Studies conducted in humans corroborate the reduction in carbohydrate turnover and oxidation in the presence of estrogen, but the impact on fatty acid availability and utilization is less clear. RESULTS: The effect of circulating estrogen may be mediated, at least in part, by changes in the sensitivity of stored carbohydrate and lipids to mobilization in response to epinephrine. The role of progesterone in metabolic regulation during exercise has not been systematically studied in humans. CONCLUSIONS: Understanding the role of the ovarian hormones in fat and carbohydrate metabolism during exercise may have practical applications in terms of understanding the metabolic consequences of amenorrhea, menopause, and hormone replacement therapy (HRT).
Culpepper, L. (2002). "Generalized anxiety disorder in primary care: emerging issues in management and treatment." J Clin Psychiatry 63 Suppl 8: 35-42.
Generalized anxiety disorder (GAD) is highly prevalent in primary care patients and is a source of major morbidity. The low rate of recognition and diagnosis of GAD is often the result of insufficient knowledge on the part of primary care physicians, time pressures, and competing demands during patients' visits. Patient attribution of symptoms and the stigma related to mental illness also contribute to underrecognition. Other contributing factors include the natural history of GAD, the bimodal age of presentation, a chronic but waxing and waning course, frequent comorbidity with other anxiety and depressive disorders, and the controversy regarding the best diagnostic criteria. However, proper diagnosis is critical to appropriate management. Primary care management of GAD and associated comorbidities includes education about the nature of GAD as a medical disorder that is amenable to treatment and counseling about treatment alternatives and coping strategies. Most patients with GAD suffer from insomnia, and treating insomnia can be of great benefit to them. While cognitive-behavioral therapy and relaxation therapy are effective in treating GAD, most patients in primary care settings are likely to require pharmacologic treatment. Although commonly used, benzodiazepines and their short-term benefits are overshadowed by their decreased long-term effectiveness, their minimal treatment of psychic symptoms, and their degradation of patient performance. The selective serotonin reuptake inhibitor (SSRI) paroxetine is indicated for the short-term treatment of GAD, although adequate data supporting the use of most SSRIs for GAD are not yet available. The serotonin-norepinephrine reuptake inhibitor venlafaxine provides a treatment option resulting in both short- and long-term improvement of symptoms, attaining not only a response but also remission from GAD and prevention of relapse.
Clini, E. and N. Ambrosino (2002). "Nitric oxide and pulmonary circulation." Med Sci Monit 8(8): RA178-82.
The aim of this review is to outline the characteristics of pulmonary circulation in health and disease and to define the value of exhaled NO (eNO) as a means to assess the involvement of pulmonary circulation in pathology. The discovery of the endocrine role of the endothelium has generated great interest in its potential role in regulating the vascular tone of the pulmonary vascular bed. Nitric oxide (NO)-mediated, endothelium-dependent relaxation has been demonstrated in the pulmonary arteries of animals and humans. Changes in the NO pathway in pulmonary hypertension are not completely understood. It is clear that NO has an important role in modulating the response to acute hypoxia, increased flow, and shear stress. The amount of exhaled NO (eNO) in different species may be easily measured, reflecting the overall NO metabolism from the lung (thus including epithelial, endothelial and other cell activity). The development of pulmonary hypertension secondary to systemic (systemic sclerosis, chronic heart failure) or pulmonary (COPD) diseases appears to be associated with a decrease in eNO production both at rest and during exercise. Chronic inhalation of NO appears to protect against pulmonary hypertension in animal models. Exhaled NO is attracting interest for its in vivo ability to represent the features of pulmonary circulation in pathology.
Chess-Williams, R. (2002). "Muscarinic receptors of the urinary bladder: detrusor, urothelial and prejunctional." Auton Autacoid Pharmacol 22(3): 133-45.
1. The parasympathetic nervous system is responsible for maintaining normal bladder function, contracting the bladder smooth muscle (detrusor) and relaxing the bladder outlet during micturition. 2. Contraction of the bladder involves direct contraction via M3 receptors and an indirect 're-contraction' via M2-receptors whereby a reduction in adenylate cyclase activity reverses the relaxation induced by beta-adrenoceptor stimulation. 3. Muscarinic receptors are also located on the epithelial lining of the bladder (urothelium) where they induce the release of a diffusible factor responsible for inhibiting contraction of the underlying detrusor smooth muscle. The factor remains unidentified but is not nitric oxide, a cyclooxygenase product or adenosine triphosphate. 4. Finally, muscarinic receptors are also located prejunctionally in the bladder on cholinergic and adrenergic nerve terminals, where M1-receptors facilitate transmitter release and M2 or M4-receptors inhibit transmitter release. 5. In pathological states, changes may occur in these receptor systems resulting in bladder dysfunction. Muscarinic receptor antagonists are the main therapeutic agents available for treatment of the overactive bladder, but whether their therapeutic effect involves actions at all three locations (detrusor, prejunctional, urothelial) has yet to be established.
Brioni, J. D., M. Nakane, et al. (2002). "Activators of soluble guanylate cyclase for the treatment of male erectile dysfunction." Int J Impot Res 14(1): 8-14.
Soluble guanylate cyclase (sGC) is an important enzyme in corpus cavernosum smooth muscle cells as it is one of the regulators of the synthesis of cGMP. The efficacy of sildenafil (Viagra) in the treatment of male erectile dysfunction indicates the importance of the cGMP system in the erectile response as the increased levels of cGMP induce relaxation of the corpus cavernosum. sGC is physiologically activated by nitric oxide (NO) during sexual stimulation, and its activity can be pharmacologically enhanced by several NO-donors. Agents like YC-1 can also activate sGC after binding to a novel allosteric site in the enzyme, a site different from the NO binding site. YC-1 can relax rabbit cavernosal tissue and it facilitates penile erection in vivo. This review summarizes the enzymology, biochemistry and pharmacology of this novel allosteric site and its relevance for the regulation of penile function. This type of sGC activators represent a new class of compounds with a different pharmacological profile in comparison to the classical NO-donors and they could be beneficial for the treatment of male erectile dysfunction.
Brading, A. F. (2002). "The sarcoplasmic reticulum in disease and smooth muscle dysfunction: therapeutic potential." Novartis Found Symp 246: 244-54; discussion 254-7, 272-6.
The functions of the sarcoplasmic reticulum (SR) in diseased smooth muscle can be investigated by measuring Ca2+ transients in response to agonist application, and through cell homogenization, isolation of microsomes and measurements of Ca-ATPase activity (SERCA). Such measurements have indicated that contractile dysfunction may be associated with degradation of SERCA in some systems, such as hypertrophied bladder smooth muscle. However, the postulated roles of the SR in smooth muscle function vary from one tissue to another and SR may mediate relaxation as well as contraction. Function seems to depend on the precise location of the SR with respect to the plasma membrane and its Ca2+-activated ion channels, the Ca2+ transporters, the cavaeoli, the mitochondria, and the contractile machinery. In diseases characterized by smooth muscle dysfunction, the size of the smooth muscle cells is frequently altered, as occurs in the hypertrophy seen in gut and bladder obstruction and hypertension. This will inevitably lead to alterations in the morphology and the function of the SR. Any therapeutic potential awaits considerable advances in our understanding of the systems in individual smooth muscles and the development of selective drugs.
Bolton, T. B., D. V. Gordienko, et al. (2002). "Calcium release events in excitation-contraction coupling in smooth muscle." Novartis Found Symp 246: 154-68; discussion 168-73, 221-7.
Although smooth muscle cells are not organized in sarcomeres, as are striated muscles, nevertheless Ca2+ for contraction is released from the sarcoplasmic reticulum (SR) at certain preferred sites. These sites commonly discharge packets of Ca2+ spontaneously and have been called frequent discharge sites (FDSs). Each spontaneous release of a Ca2+ packet usually leads to a burst of openings of Ca2+-activated K+ channels in the cell membrane which produces a spontaneous transient outward current (STOC) in smooth muscle cells under voltage clamp. When fluorescent Ca2+ indicators such as Fluo-3 became available, the spontaneous transient increases in [Ca2+]i produced by Ca2+ packets released from the SR were also detected in cardiac muscle as flashes of fluorescence or 'sparks'. Sparks in smooth muscle consist of smaller Ca2+ packets that can give rise to 'microsparks'. In some smooth muscles which have Ca2+-activated Cl- channels, STICs (spontaneous transient inward currents) are also found to be associated with sparks. FDSs have been found to be important initiating sites for a Ca2+ wave in response to an action potential or in response to receptor activation and possibly other stimuli, such as stretch. In both cases Ca2+-induced Ca2+ release seems to be crucially involved.
Belardinelli, R. and G. P. Perna (2002). "Vasomotor reactivity evaluation in cardiac rehabilitation." Monaldi Arch Chest Dis 58(2): 79-86.
Endothelial dysfunction is a generalized phenomenon detectable at various levels in the vasculature, and is evident very early in the atherosclerotic process. These peculiarities have stimulated the introduction of new non-invasive techniques dedicated to evaluate the vasomotor response of arteries or districts in favourable position in the body (forearm, hand) that may reflect the response of inner arteries otherwise requiring invasive procedures (i.e. coronary arteries). Moreover, these techniques can be theoretically used to detect abnormalities of vasomotor response before a clinical adverse event may occur in subjects prone to vascular accidents with risk factors for atherosclerosis. Of physical stimuli inducing e-NOS activation and subsequent nitric oxide synthesis, the shear stress produced by pulsatile blood flow is the most important. This property is actually used in clinical practice to study the flow-mediated vasodilation (FMD) of the brachial artery. Any condition that reduces the ability of endothelial cells to produce nitric oxide causes endothelial dysfunction, which is directly reflected into a depressed FMD. There is evidence that brachial artery flow-mediated dilation is improved after local as well as systemic exercise, suggesting that the improvement in endothelial function is generalized and documentable in different arterial districts with similar results. Aerobic exercise induces e-NOS expression and improves the endothelial-dependent relaxation in normal as well as cardiac patients. The endothelium-independent vasorelaxation is generally unchanged after chronic conditioning, but this result is not evident in all studies. The improved endothelial vasoreactivity is correlated with enhanced functional capacity after moderate aerobic exercise, suggesting an important pathophysiological role of oxygen transport in exercise tolerance. These beneficial effects has been described in patients with stable heart failure in II and III NYHA functional class and in patients with coronary artery disease with programs different for frequency, duration and intensity. The evaluation of vasomotor reactivity gives promising results in explaining the effects of medications and exercise training. The demonstration that flow-mediated dilation may quantify endothelial dysfunction in subjects with a variety of conditions can be used in clinical practice not only to assess the effects of interventions, but also to provide a preliminary screening in apparently healthy subjects who have an underlying silent coronary artery disease. In cardiac rehabilitation, there are promising results from FMD evaluation in selecting patients who take major benefits in terms of functional capacity and endothelium-dependent vasodilation.
Arteaga, G. M., T. Kobayashi, et al. (2002). "Molecular actions of drugs that sensitize cardiac myofilaments to Ca2+." Ann Med 34(4): 248-58.
Ca(2+)-sensitizers are inotropic agents that modify the response of myofilaments to Ca2+, and are potentially valuable drugs in the treatment of heart failure. These agents have diverse chemical structures, and in some cases also have effects as inhibitors of phosphodiesterase activity. Advantages of their actions include vasodilation combined with inotropic effects. Reduction in the amounts of Ca2+ required to activate the myofilaments also lowers the oxygen consumption required for Ca2+ transport, lowers the threat of arrhythmias, and may blunt Ca(2+)-dependent transcriptional and translational mechanisms leading to hypertrophy and failure. Although diastolic abnormalities and impaired relaxation were thought to be potential undesirable effects of Ca(2+)-sensitizers, studies of hearts beating in situ indicate that this may not be a major problem. We focus here on Ca(2+)-sensitizers that act on cardiac troponin C, the Ca2+ receptor that triggers activation of the actin-myosin interaction. Structural studies have identified a unique mode of Ca2+ signaling in cardiac troponin C that should aid in targeting drugs to the heart. Moreover, identification of docking sites of Ca(2+)-sensitizers on troponin C suggest new directions for rational drug design.