cyclic-gmp and Metabolic-Syndrome

Investigations into the mixed muscle-secretory phenotype of cardiomyocytes from the atrial appendages of the heart led to the discovery that these cells produce, in a regulated manner, two polypeptide hormones - the natriuretic peptides - referred to as atrial natriuretic factor or atrial natriuretic peptide (ANP) and brain or B-type natriuretic peptide (BNP), thereby demonstrating an endocrine function for the heart. Studies on the gene encoding ANP (NPPA) initiated the field of modern research into gene regulation in the cardiovascular system. Additionally, ANP and BNP were found to be the natural ligands for cell membrane-bound guanylyl cyclase receptors that mediate the effects of natriuretic peptides through the generation of intracellular cGMP, which interacts with specific enzymes and ion channels. Natriuretic peptides have many physiological actions and participate in numerous pathophysiological processes. Important clinical entities associated with natriuretic peptide research include heart failure, obesity and systemic hypertension. Plasma levels of natriuretic peptides have proven to be powerful diagnostic and prognostic biomarkers of heart disease. Development of pharmacological agents that are based on natriuretic peptides is an area of active research, with vast potential benefits for the treatment of cardiovascular disease.

Topics: Animals; Atrial Appendage; Atrial Fibrillation; Atrial Natriuretic Factor; Atrial Remodeling; Biomarkers; Cyclic GMP; Diabetes Mellitus; Fibrosis; Gene Expression Regulation, Developmental; Heart Atria; Heart Failure; Humans; Hypertension; Lipid Metabolism; Metabolic Syndrome; Mice; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Obesity; Peptide Fragments; Prognosis; Protein Processing, Post-Translational; Pulmonary Arterial Hypertension; Receptors, Guanylate Cyclase-Coupled; Secretory Vesicles; Ventricular Remodeling; Water-Electrolyte Balance

To provide a systematic review of epidemiological data regarding the association between erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) in men.. A research has been conducted on the Medline database using the keywords: ("erectile dysfunction" or "sexual dysfunction") and ("benign prostatic hyperplasia" or "lower urinary tract symptoms"). The eligibility of studies was defined using the PICOS method in accordance with the PRISMA statement. Cross-sectional studies and prospective cohorts assessing the association between LUTS and ED in the primary care setting or in general practice (i.e. exclusion of patients seen in outpatient urology or andrology) were included.. Among 898 reports assessed, seven studies were included in this systematic review (whole cohort: 1,196,393 men). There were five cross-sectional studies and two prospective cohorts. The whole seven studies reported an association between LUTS and ED (range of odds-ratio: 1.52-4.03). Four common pathogenic mechanisms were found in the literature, all of them being somewhat related with metabolic syndrome and cardiovascular risk factors: reduced nitric oxide (NO) pathway signalling, increased RhoA-Rho kinase signalling, autonomic nervous system hyperactivity and pelvic atherosclerosis.. The main limitations of this review were: a possible publication bias, the relatively low number of included studies and the lack of assessment of potential confounders such as factors related to sexual partner.. The close epidemiological and pathogenic links between LUTS and ED have given rise to a new nosological entity: the erectile urogenital dysfunction, which should be assessed globally with special considerations to frequently associated comorbidities such as metabolic syndrome and cardiovascular risk factors.

Topics: Atherosclerosis; Autonomic Nervous System; Cardiovascular Diseases; Comorbidity; Cross-Sectional Studies; Cyclic GMP; Endothelium, Vascular; Erectile Dysfunction; Humans; Impotence, Vasculogenic; Lower Urinary Tract Symptoms; Male; Metabolic Syndrome; Muscle, Smooth; Nitric Acid; Prospective Studies; Prostatic Hyperplasia; rho-Associated Kinases; rhoA GTP-Binding Protein; Risk Factors; Signal Transduction

Natriuretic peptides (NPs) are a group of peptide-hormones mainly secreted from the heart, signaling via c-GMP coupled receptors. NP are well known for their renal and cardiovascular actions, reducing arterial blood pressure as well as sodium reabsorption. Novel physiological functions have been discovered in recent years, including activation of lipolysis, lipid oxidation, and mitochondrial respiration. Together, these responses promote white adipose tissue browning, increase muscular oxidative capacity, particularly during physical exercise, and protect against diet-induced obesity and insulin resistance. Exaggerated NP release is a common finding in congestive heart failure. In contrast, NP deficiency is observed in obesity and in type-2 diabetes, pointing to an involvement of NP in the pathophysiology of metabolic disease. Based upon these findings, the NP system holds the potential to be amenable to therapeutical intervention against pandemic diseases such as obesity, insulin resistance, and arterial hypertension. Various therapeutic approaches are currently under development. This paper reviews the current knowledge on the metabolic effects of the NP system and discusses potential therapeutic applications.

Topics: Animals; Cyclic GMP; Drug Design; Exercise; Humans; Hypertension; Insulin Resistance; Metabolic Syndrome; Natriuretic Peptides; Obesity

Benign prostatic hyperplasia (BPH) is a common disease in older men that can lead to lower urinary tract symptoms (LUTS). Male sexual dysfunction is also an age-related condition. Epidemiological studies have confirmed an association between BPH/LUTS and sexual dysfunction in ageing men that is independent of the effects of age, other co-morbidities and lifestyle factors. Proposed pathophysiological mechanisms for BPH/LUTS-associated sexual dysfunction include the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway, rho-kinase and endothelin-1 activity, autonomic nervous system overactivity and the metabolic syndrome, and pelvic organ atherosclerosis. Both BPH/LUTS and sexual dysfunction can have a substantial negative impact on a man's quality of life. However, urologists and primary care physicians appear to under-recognise sexual dysfunction in men with BPH/LUTS. Current guidelines recommend alpha-blockers and 5-alpha reductase inhibitors, either alone or in combination, among appropriate medical treatment options for BPH/LUTS. Randomised, controlled trials demonstrate that these therapies can be associated with sexual adverse effects (AEs) such as loss of libido, erectile dysfunction and ejaculatory disorders. Sexual dysfunction should be fully evaluated in men requiring treatment for BPH/LUTS using validated questionnaires. Management of sexual dysfunction in men treated for BPH/LUTS should involve assessment of co-morbidities and concomitant medications, consideration of lifestyle interventions such as weight loss and increased physical activity to improve risk factors and, if necessary, introduction of pharmacotherapies. In addition, physicians should provide patients with proper counselling on the possible sexual AEs of medical therapies for BPH/LUTS and their impact on sexual satisfaction, while being aware of the possibility that counselling in itself is likely to influence reported rates of sexual dysfunction.

Topics: 5-alpha Reductase Inhibitors; Adrenergic alpha-Antagonists; Adult; Aged; Atherosclerosis; Autonomic Nervous System Diseases; Cyclic GMP; Drug Combinations; Endothelin-1; Humans; Male; Metabolic Syndrome; Middle Aged; Nitric Oxide; Prostatic Hyperplasia; Prostatism; rho-Associated Kinases; Sexual Dysfunction, Physiological

About one third of people in the world suffer from metabolic syndrome (MetS), with symptoms such as hypertension and elevated blood cholesterol, and with increased risk of developing additional diseases such as diabetes mellitus and heart disease. The progression of this multifactorial pathology, which targets various tissues and organs, might necessitate a renewal in therapeutic approaches. Since cyclic nucleotide phosphodiesterases (PDEs), enzymes which hydrolyze cyclic AMP and cyclic GMP, play a crucial role in regulating endocrine and cardiovascular functions, inflammation, oxidative stress, and cell proliferation, all of which contribute to MetS, we wonder whether PDE inhibitors might represent new therapeutic approaches for preventing and treating MetS.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic AMP; Cyclic GMP; Endothelium, Vascular; Heart; Humans; Isoenzymes; Metabolic Syndrome; Molecular Targeted Therapy; Muscle, Smooth, Vascular; Myocardium; Phosphodiesterase Inhibitors

Studied for nearly 30 years for its ability to control many parameters, such as vascular smooth muscle cell relaxation, heart fibrosis, and kidney function, the natriuretic peptide (NP) system is now considered to be a key element in several other major metabolic pathways. After stimulation by NPs, natriuretic peptide receptors (NPR) convert GTP to the second messenger cGMP. In addition to its vasodilatory effects and natriuretic and diuretic functions, cGMP has been positively associated with fat cell function, apoptosis, and NPR expression/activity modulation. The NP system is also closely linked to metabolic syndrome (MetS) progression and obesity control. A new era is now on its way targeting the NP system to not only treat high blood pressure, but to also assist in the fight against the obesity pandemic. Here, we summarize recent data on the role of NPs in hypertension and MetS.

Topics: Cyclic GMP; Guanylate Cyclase; Humans; Hypertension; Metabolic Syndrome; Natriuretic Peptides; Obesity; Signal Transduction

The aim of this study was to evaluate the effects of a new L-arginine-enriched biscuit on endothelial function, insulin sensitivity/secretion and body composition.. The project was composed of two studies. The first study was an acute pilot postprandial study in 7 healthy subjects that evaluated bio-availability and vascular effects of L-arginine-enriched biscuits that contained 6.6 gL-arginine, 21.9 g carbohydrates, 3.6 g protein, 7.5 g fat and 4.3 g dietary fiber compared with placebo biscuits and 6.6 g powdered L-arginine. Subjects underwent the tests in random order, in at least 14-day intervals. The second study was a double-blind crossover study in 15 obese subjects with IGT and MS. These subjects consumed 6.6 g of L-arginine-enriched biscuits or placebo biscuits in a 1600 kcal diet. Each study period lasted 2 weeks with a 2-week washout in between. Endothelial function, glucose tolerance, insulin sensitivity and insulin secretion were evaluated at the end of each intervention period.. In the first study, the groups that received the L-arginine-enriched biscuits and the powdered L-arginine had similarly increased L-arginine, NOx and cGMP levels and post-ischemic blood flow (PI-BF). In both cases, these levels were significantly higher than those in the placebo biscuit recipient group. In the second study, the L-arginine-enriched biscuit recipient group displayed increased L-arginine, NOx, cGMP, PI-BF, and Matsuda index levels, whereas their circulating glucose, proinsulin/insulin ratio and fat mass were decreased compared with the placebo biscuit recipient group.. L-Arginine-enriched biscuits with low sugar and protein content enhance endothelial function and improve glucose metabolism, insulin sensitivity and insulin secretion in subjects with IGT and MS.

Topics: Arginine; Body Composition; Body Weight; Cholesterol; Cross-Over Studies; Cyclic GMP; Double-Blind Method; Endothelium, Vascular; Female; Glucose Intolerance; Humans; Insulin; Insulin Secretion; Male; Metabolic Syndrome; Middle Aged; Nitric Oxide Synthase Type II; Obesity; Pilot Projects; Snacks; Triglycerides

Metabolic syndrome (MetS) denotes a clustering of risk factors that may affect nitric oxide (NO) bioavailability and predispose to cardiovascular diseases, which are delayed by exercise training. However, no previous study has examined how MetS affects markers of NO formation, and whether exercise training increases NO formation in MetS patients. Here, we tested these two hypotheses. We studied 48 sedentary individuals: 20 healthy controls and 28 MetS patients. Eighteen MetS patients were subjected to a 3-month exercise training (E+group), while the remaining 10 MetS patients remained sedentary (E-group). The plasma concentrations of nitrite, cGMP, and ADMA (asymmetrical dimethylarginine; an endogenous nitric oxide synthase inhibitor), and the whole blood nitrite concentrations were determined at baseline and after exercise training using an ozone-based chemiluminescence assay, and commercial enzyme immunoassays. Thiobarbituric acid reactive species (TBA-RS) were measured in the plasma to assess oxidative stress using a fluorometric method. We found that, compared with healthy subjects, patients with MetS have lower concentrations of markers of NO formation, including whole blood nitrite, plasma nitrite, and plasma cGMP, and increased oxidative stress (all P<0.05). Exercise training increased the concentrations of whole blood nitrite and cGMP, and decreased both oxidative stress and the circulating concentrations of ADMA (both P<0.05). These findings show clinical evidence for lower endogenous NO formation in patients with MetS, and for improvements in NO formation associated with exercise training in MetS patients.

Topics: Adult; Arginine; Biomarkers; Cyclic GMP; Exercise Therapy; Humans; Lipid Peroxides; Metabolic Syndrome; Middle Aged; Nitric Oxide; Nitrites; Oxidative Stress; Thiobarbituric Acid Reactive Substances

Hydrogen sulfide (H

Topics: Adipose Tissue; Animals; Cyclic GMP; Fatty Acids, Nonesterified; Hydrogen Sulfide; Lipolysis; Male; Metabolic Syndrome; Obesity; Rats; Rats, Wistar; Receptors, Adrenergic, beta; Sulfides

Metabolic syndrome is linked to an increased risk of cardiovascular complications by a mechanism involving mainly decreased nitric oxide (NO) bioavailability and impaired NO-soluble guanylate cyclase (sGC)- cyclic guanosine monophosphate (cGMP) signalling (NO-sGC-cGMP). To further develop this scientific point, this study aimed to investigate the effects of long-term treatment with BAY 41-2272 (a sGC stimulator) on cardiovascular reactivity of spontaneously hypertensive rats (SHR) as a model of metabolic syndrome. SHR were randomly divided into 3 groups: control group, cafeteria diet (CD)-fed group and CD-fed group treated daily with BAY 41-2272 (5 mg/kg) by gastric gavage for 12 weeks. In vivo measurements of body weight, abdominal circumference, blood pressure and glucose tolerance test were performed. At the end of the feeding period, ex vivo cumulative concentration-response curves were performed on isolated perfused heart (isoproterenol (0.1 nM - 1 μM)) and thoracic aorta (phenylephrine (1 nM-10 μM), acetylcholine (1 nM-10 μM), and sodium nitroprusside (SNP) (0.1 nM-0.1 μM)). We showed that chronic CD feeding induced abdominal obesity, hypertriglyceridemia, glucose intolerance and exacerbated arterial hypertension in SHR. Compared to control group, CD-fed group showed a decrease in β-adrenoceptor-induced cardiac inotropy, in coronary perfusion pressure and in aortic contraction to phenylephrine. While relaxing effects of acetylcholine and SNP were unchanged. BAY 41-2272 long-term treatment markedly prevented arterial hypertension development and glucose intolerance, enhanced the α

Topics: Animals; Aorta, Thoracic; Cardiovascular Diseases; Coronary Circulation; Cyclic GMP; Disease Models, Animal; Enzyme Activation; Enzyme Activators; Glucose Intolerance; Hypertension; Hypertriglyceridemia; Isolated Heart Preparation; Male; Metabolic Syndrome; Nitric Oxide Synthase Type II; Obesity, Abdominal; Pyrazoles; Pyridines; Rats, Inbred SHR; Soluble Guanylyl Cyclase; Vasoconstriction; Vasodilation; Ventricular Function, Left; Ventricular Pressure

Topics: Animals; Aspartate Aminotransferases; Biomarkers; Blood Pressure; Body Weight; Cyclic GMP; Diastole; Diet, High-Fat; Electrocardiography; Fructose; Glucose; Hemodynamics; Insulin; Lipid Metabolism; Male; Metabolic Syndrome; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Protein Multimerization; Rats, Sprague-Dawley; Saponins; Signal Transduction; Systole; Triglycerides; Triterpenes; Ventricular Function, Left

Much evidence indicates that metabolic syndrome is strongly correlated with a decrease in nitric oxide and an increase in oxidative stress leading to cardiovascular alterations. In recent years, gut microbiota has emerged as a new contributor to the metabolic syndrome establishment and associated cardiovascular diseases, but the underlying mechanisms remain unclear. We hypothesized that a positive modulation of cyclic guanosine monophosphate (cGMP) pathway, through phosphodiesterase type 5 (PDE5) inhibition could prevent cardiovascular alterations and gut dysbiosis that may be associated to metabolic syndrome. Spontaneously hypertensive rats (SHR) were randomly divided into 4 groups: control, cafeteria diet (CD) and sildenafil citrate treated groups (5mg/kg per os) were given either a CD or a standard chow diet for 10 weeks. Body weight, arterial blood pressure and glucose tolerance test were monitored. At the 10th week, cardiac inotropy and coronary perfusion pressure were evaluated on isolated heart according to Langendorff method. Cumulative concentration response curves to phenylephrine and acetylcholine were determined on thoracic aorta rings for vascular reactivity evaluation. Faecal samples were collected for the gut microbiota analysis. Compared to the control group, CD-fed rats showed a significant increase in body weight gain, arterial blood pressure and were glucose intolerant. This group showed also a decrease in β-adrenoceptor-induced cardiac inotropy and coronary vasodilation. Gut microbiota analysis revealed a significant reduction in the abundance of Lactobocillus spp in cafeteria diet-fed rats when compared to the control ones. Sildenafil citrate long-term treatment decreased weight gain and arterial blood pressure, improved coronary vasodilation and reduced α1-adrenoceptor-induced vasoconstriction in CD group. However, it did not reverse gut dysbiosis induced by chronic CD feeding. These results suggest that cGMP pathway targeting may be a potential therapeutic strategy for the management of the metabolic syndrome and associated cardiovascular disorders.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Blood Pressure; Cardiovascular Diseases; Cyclic GMP; Diet; Disease Models, Animal; Gastrointestinal Microbiome; Glucose Tolerance Test; Male; Metabolic Syndrome; Phenylephrine; Phosphodiesterase 5 Inhibitors; Rats; Rats, Inbred SHR; Sildenafil Citrate; Vasodilation; Vasodilator Agents

To determine the effects of PVAT on vasodilators in SHRSP.ZF and control Wistar-Kyoto (WKY) rats, we used organ bath bioassay techniques to assay acetylcholine and nitroprusside-induced relaxations of isolated mesenteric arterial ring preparations with PVAT intact or removed.. A PVAT-mediated enhancement of relaxations induced by acetylcholine and nitroprusside occurred in SHRSP.ZF at 20 weeks of age, but not at 10 and 30 weeks, and did not occur in WKY. Furthermore, the enhancing effects of PVAT from SHRSP.ZF at 20 weeks could not be substituted by replacement with PVAT from either WKY or 30-week-old SHRSP.ZF, was inhibited by NO synthase inhibitor, and abolished by removal of the arteries' endothelium. Cyclic guanosine monophosphate (cGMP) accumulation elicited by nitroprusside was higher in SHRSP.ZF arteries with PVAT than arteries without PVAT at 20 weeks, but the enhancement of cGMP accumulation did not occur at 30 weeks.. PVAT may regulate arterial tone by releasing diffusible vasorelaxing factor(s), which, through endothelium-derived NO production, compensates for impaired vasodilations at early stages of MetS.

Topics: Acetylcholine; Adipose Tissue; Animals; Crosses, Genetic; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; In Vitro Techniques; Male; Mesenteric Arteries; Metabolic Syndrome; Nitric Oxide; Nitroprusside; Paracrine Communication; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Zucker; Time Factors; Vasodilation; Vasodilator Agents

Metabolic syndrome (MetS) is a risk factor for erectile dysfunction (ED), but the underlying mechanisms are unclear. The aims of this study were to determine the underlying mechanisms of metabolic syndrome-related ED (MED). Sprague Dawley (SD) rats were fed a high-fat diet for 6 months, and metabolic parameters were then assessed. An apomorphine test was conducted to confirm MED. Only rats with MED were administered an intracavernosal injection of either epidermal growth factor (EGF) or vehicle for 4 weeks. Erectile responses were evaluated by determining the mean arterial blood pressure (MAP) and intracavernosal pressure (ICP). Levels of protein expression were examined by western blotting and immunohistochemistry. Body weight, fasting blood glucose, plasma insulin and plasma total cholesterol were increased in the MetS rats compared with those in control rats (each p < 0.05). The  maximum ICP/MAP, total ICP/MAP and concentration of cyclic guanosine mono-phosphate (cGMP) were significantly decreased in MED rats (each p < 0.05). The expression levels of p110α, p-Akt1 (Tyr308)/Akt1 and p-eNOS (Ser1177)/eNOS were reduced in MED rats (each p < 0.05). Activation of the PI3K/Akt/eNOS signaling cascade (intracavernosal injection of EGF) reversed these changes (each p < 0.05). The present study demonstrates that downregulation of the PI3K/Akt/eNOS signaling pathway is involved in MED.

Topics: Animals; Biomarkers; Cyclic GMP; Diet, High-Fat; Disease Models, Animal; Enzyme Activation; Epidermal Growth Factor; Erectile Dysfunction; Fluorescent Antibody Technique; Immunohistochemistry; Male; Metabolic Syndrome; Nitric Oxide Synthase Type III; Penile Erection; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction

Topics: Aging; Animals; Aorta; Cyclic GMP; Disease Models, Animal; Down-Regulation; Endothelium, Vascular; Gene Expression; Male; Metabolic Syndrome; Nitric Oxide; Nitroprusside; Oligopeptides; Oxidative Stress; Rats; Rats, Inbred Strains; Receptor, PAR-2; RNA, Messenger; Thiobarbituric Acid Reactive Substances; Thionucleotides; Trypsin; Vasodilation; Vasodilator Agents

Panax notoginseng saponins (PNS) are major components of Panax notoginseng, a herb with established clinical efficacy against vascular diseases. SHRSP.Z-Lepr(fa) /IzmDmcr (SHRSP.ZF) rats, a new animal model for metabolic syndrome, display an impaired vasorelaxation response in aortas and mesenteric arteries that is mediated by nitric oxide (NO). This study investigated whether PNS and its components can ameliorate this vascular dysfunction in SHRSP.ZF rats. In an in vitro study, in the presence or absence of PNS and its components, vasodilation in response to nitroprusside was determined from myographs under isometric tension conditions in aortas and mesenteric arteries from male SHRSP.ZF rats at 18-20 weeks of age. In an in vivo study, PNS (30 mg/kg per day) was orally administered to SHRSP.ZF rats from 8 to 20 weeks of age. In vitro treatment with PNS and Ginsenoside Rb1 increased nitroprusside-induced relaxation of aortas and mesenteric arteries in SHRSP.ZF rats. The PNS-induced increase was not affected by a nitric oxide (NO) synthase inhibitor or endothelium denudation. Relaxation in response to a cell-permeable cGMP analogue was increased by PNS, but cGMP accumulation by nitroprusside was not altered. In vivo treatment with PNS in SHRSP.ZF rats lowered blood pressure and increased relaxation and the expression of soluble guanylyl cyclase protein in arteries, without affecting metabolic abnormalities. These results indicate that PNS causes an increase in vasodilation in response to NO and a decrease in blood pressure, resulting in protection against vascular dysfunction in SHRSP.ZF rats. PNS might be beneficial in alleviating impaired vasodilation in metabolic syndrome.

Topics: Animals; Aorta; Biomarkers; Blood Pressure; Cyclic GMP; Disease Models, Animal; Male; Mesenteric Arteries; Metabolic Syndrome; Nitric Oxide; Oxidative Stress; Panax notoginseng; Rats; Saponins; Signal Transduction; Vasodilation

The seriousness of metabolic syndrome is not due to the disease itself but its promotion of other diseases, such as erectile dysfunction and cardiovascular and cerebrovascular diseases. We investigated the effects of Korean red ginseng (KRG, Panax ginseng) extract on erectile function in a rat model of metabolic syndrome. We divided the rats into three groups: control, metabolic syndrome+normal saline (N/S) and metabolic syndrome+KRG. To determine the occurrence of metabolic syndrome in all groups, body weight and various biochemical parameters (e.g., blood glucose, insulin, cholesterol) were measured, and the intra-abdominal glucose tolerance test was performed. To investigate penile erection, the peak intracavernosal pressure (ICP), mean arterial pressure (MAP) and Masson's trichrome stain were evaluated. Erectile function was also investigated by measuring the cyclic guanosine monophosphate (cGMP) levels of the corpus cavernosum. We found that the various biochemical parameters and body weight were similar in the metabolic syndrome+KRG group and the control group, although the values were slightly higher. The peak ICP/MAP ratio of the metabolic syndrome+N/S group was markedly decreased compared to the other groups. The cGMP level of the corpus cavernosum in the metabolic syndrome+N/S group was significantly lower than that of the other groups. As demonstrated in this model of metabolic syndrome with erectile dysfunction, KRG may improve erectile function.

Topics: Animals; Arterial Pressure; Cyclic GMP; Disease Models, Animal; Erectile Dysfunction; Male; Metabolic Syndrome; Panax; Penile Erection; Penis; Phytotherapy; Plant Extracts; Rats; Rats, Inbred WKY; Transforming Growth Factor beta

High-fat diet and consequent metabolic syndrome (MS) can lead to elevated risk for cardiac arrhythmias. This preclinical study was to investigate if cicletanine (CIC) could produce cardioprotective effects in conscious rabbits exhibiting the main symptoms of MS.. NZW rabbits that had undergone an 8-week-long cholesterol-enriched diet (1.5%) were instrumented with a pacemaker electrode and randomly assigned into 3 groups according to the oral treatment of either CIC (50 mg·kg) or sotalol (25 mg·kg) and their placebo b.i.d. over 5 days. Study groups were subjected to either "arrhythmia challenge" by programmed electrical stimulation in the "Arrhythmogenesis" study (N = 54) or global myocardial ischemia by rapid pacing in the "Ventricular Overdrive Pacing-induced Myocardial Ischemia" study (N = 18). The antiarrhythmic effect was evaluated by the establishment of the incidence of programmed electrical stimulation-induced arrhythmias. Proarrhythmia indicators (eg, QTc, Tpeak-Tend) were also measured to assess the cardiac safety profile of CIC. To evaluate the background of antiarrhythmic effect, cardiac cyclic nucleotide (cyclic 3',5'-guanosine monophosphate [cGMP], cyclic 3',5'-adenosine monophosphate [cAMP]) and nitric oxide content were determined. The antiischemic effect was characterized by change of intracavital ST segment.. Cicletanine treatment significantly decreased the incidence of ventricular arrhythmias, increased cardiac cGMP and nitric oxide content and reduced cardiac cAMP level. Cicletanine did not modify significantly QTc and Tpeak-Tend interval. The ST-segment change in response to rapid pacing was reduced significantly by CIC. (P < 0.05).. Cicletanine exerts beneficial cardiac effects in rabbits with symptoms of MS, which may be of influence with regard to the clinical application of the drug.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Cardiac Pacing, Artificial; Cholesterol, Dietary; Consciousness; Cyclic AMP; Cyclic GMP; Diet, High-Fat; Disease Models, Animal; Electrocardiography; Heart Rate; Lipids; Male; Metabolic Syndrome; Myocardium; Nitric Oxide; Pyridines; Rabbits; Sotalol; Time Factors

The prevalence of metabolic syndrome has increased in modern society and the condition is proving to be a common precursor of cardiovascular disease. The aim of the present study was to investigate whether astragaloside IV, a major active constituent of Astragalus membranaceus (Fisch) Bge., is able to prevent the development of hypertension and endothelial dysfunction in fructose-fed rats. Rats were fed with 10% fructose in their drinking water for 8 weeks. From the beginning of week 5, two groups of fructose-fed rats were treated with 0.5 or 2 mg/kg, i.p., astragaloside IV. Another group of fructose-fed rats, injected with the same volume of vehicle (dimethylsulfoxide, DMSO) from week 5, served as the control group. At the end of the treatment period, blood pressure, blood glucose, glucose tolerance, blood insulin and lipids were determined. In addition, in vitro experiments were conducted at the end of the eight week treatment period to evaluate endothelium-dependent aortic vasorelaxation, as well as myocardial and aortic tissue levels of nitrate and nitrite (NOx) and cGMP. Fructose-fed rats developed clustering signs of metabolic syndrome, such as increased bodyweight, mild hypertension, hyperinsulinaemia, hypertriglyceridaemia, impaired glucose tolerance and impaired endothelium-dependent vasorelaxation. Administration of astragaloside IV reduced blood pressure and triglyceride levels in fructose-fed rats and high dose of astragaloside IV also improved glucose tolerance and endothelium-dependent vasorelaxation. The astragaloside IV-induced improvement in vasorelaxation was associated with increased levels of aortic NOx and cGMP and was abrogated by blockade of nitric oxide synthase with NG-nitro-l-arginine methyl ester (l-NAME). On the basis of its favourable effects on lipid metabolism, endothelium-dependent vasorelaxation and the nitric oxide-cGMP-related pathway, astragaloside IV may be useful in ameliorating food-induced metabolic syndrome.

Topics: Animals; Blood Pressure; Body Weight; Cyclic GMP; Endothelium, Vascular; Fructose; Glucose Tolerance Test; Male; Malondialdehyde; Metabolic Syndrome; Rats; Rats, Sprague-Dawley; Saponins; Triterpenes; Vasodilation

1. Metabolic syndrome is an independent risk factor for cardiovascular disease. SHRSP.Z-Lepr(fa) /IzmDmcr (SHRSP fatty) rat, established as a new rat model of metabolic syndrome, spontaneously develops obesity, severe hypertension and shows hypertriglyceridaemia, hypercholesterolaemia and abnormal glucose tolerance. Using SHRSP fatty rats, we examined whether or not oxidative stress was correlated with vascular dysfunction in small and large calibre coronary arteries in ex vivo beating hearts, isolated mesenteric arteries and aortas in comparison with normal rats, Wistar-Kyoto rats (WKY). Vasodilation of coronary arteries was determined by microangiography of the Langendorff heart. 2. Compared with WKY, acetylcholine (ACh) and sodium nitroprusside (SNP)-induced relaxations were impaired in the coronary arteries of SHRSP fatty rats. The mesenteric arteries and aorta of SHRSP fatty rats showed impaired relaxation responses to ACh and SNP, decreased 3',5'-monophosphate (cGMP) production, and reduced soluble guanylyl cyclase protein expression. Superoxide release, angiotensin II and 3-nitrotyrosine contents were increased. 3. SHRSP fatty rats were orally administered olmesartan, an angiotensin II receptor type 1 (AT(1) ) antagonist, and amlodipine, a calcium channel blocker, at doses of 5 and 8mg/kg per day, respectively, for 8weeks. Both olmesartan and amlodipine reduced blood pressure, but only olmesartan prevented the development of abnormal vascular and biochemical parameters in the SHRSP fatty rats. 4. The results showed that in the SHRSP fatty rats, the impaired nitric oxide- and cGMP-mediated relaxation of vascular smooth muscle cells were linked to AT(1) receptor-induced oxidative-nitrative stress, which occurred concurrently with severe hypertension and metabolic abnormalities in vivo.

Topics: Acetylcholine; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Coronary Vessels; Cyclic GMP; Disease Models, Animal; Endothelium, Vascular; Insulin; Lipids; Metabolic Syndrome; Nitric Oxide; Nitroprusside; Oxidative Stress; Rats; Rats, Inbred Strains; Vasodilation

Nitric oxide (NO) is a short-lived gaseous messenger with multiple physiological functions including regulation of blood flow, platelet adhesion and aggregation inhibition. NO synthases (NOS) catalyze the conversion of cationic amino acid L-arginine in L-citrulline and NO. Despite an increasing prevalence of obesity and metabolic syndrome (MetS) in the last decades, the exact mechanisms involved in the pathogenesis and cardiovascular complications are not fully understood. We have examined the effects of obesity and MetS on the L-arginine-NO-cGMP pathway in platelets from a population of adolescents.. A total of twenty six adolescent patients (13 with obesity and 13 with MetS) and healthy volunteers (n=14) participated in this study. Transport of L-arginine, NO synthase (NOS) activity and cGMP content in platelets were analyzed. Moreover, platelet function, plasma levels of L-arginine, metabolic and clinical markers were investigated in these patients and controls.. L-arginine transport (pmol/10(9) cells/min) in platelets via system y(+)L was diminished in obese subjects (20.8±4.7, n=10) and MetS patients (18.4±3.8, n=10) compared to controls (52.3±14.8, n=10). The y(+)L transport system correlated negatively to insulin levels and Homeostasis Model Assessment of Insulin Resistance (HOMA IR) index. No differences in NOS activity and cGMP content were found among the groups. Moreover, plasma levels of L-arginine were not affected by obesity or MetS.. Our study provides the first evidence that obesity and MetS lead to a dysfunction of L-arginine influx, which negatively correlates to insulin resistance. These findings could be a premature marker of future cardiovascular complications during adulthood.

Topics: Adolescent; Arginine; Biological Transport; Blood Platelets; Cardiovascular Diseases; Case-Control Studies; Cyclic GMP; Humans; Insulin Resistance; Metabolic Syndrome; Nitric Oxide; Obesity

We examined mechanisms leading to the impairment of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)-dependent vasorelaxation in response to acutely administered leptin in rats with the metabolic syndrome.. Effects of leptin on blood pressure and NO and cGMP in the aortic wall were studied in four groups of rats: (1) lean control, (2) obese, fed "cafeteria diet" for 3months (hyperleptinemia and hyperinsulinemia), (3) hyperleptinemia induced by administration of exogenous leptin for 8days, and (4) fructose-fed, receiving 20% fructose in the drinking water for 8weeks (hyperinsulinemia with slightly elevated leptin).. Stimulatory effect of leptin on NO and cGMP production in the aortic wall was impaired in obese and hyperleptinemic groups but not in the fructose group. In contrast, EDHF-mimetic effect of leptin was impaired in obese and fructose-fed but not in the hyperleptinemic group. Leptin increased tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in the aortic wall, and this effect was impaired in obese and fructose-fed animals. The EDHF-mimetic effect of leptin was abolished by phosphoinositide 3-kinase inhibitor, wortmannin, whereas its effect on NO was not. In addition, IRS-1 phosphorylation at Ser(307) and Ser(612) was enhanced in obese and fructose-fed but not in hyperleptinemic rats.. These results indicate that: (1) long-term hyperleptinemia induces resistance to acute vascular NO-mimetic effect of leptin in obesity/metabolic syndrome, (2) leptin stimulates EDHF in IRS-1 and PI3K-dependent manner, and this effect is impaired in obesity due to excessive serine phosphorylation of IRS-1.

Topics: Animals; Aorta; Biological Factors; Blood Pressure; Cyclic GMP; Disease Models, Animal; Endothelium, Vascular; Insulin; Leptin; Male; Metabolic Syndrome; Nitric Oxide; Obesity; Phosphorylation; Rats; Rats, Wistar; Recombinant Proteins; Vasodilation

To examine the relationship between metabolic syndrome and endothelial dysfunction, we investigated cross-sectionally the correlation between metabolic risk factors and urinary excretion of cyclic guanosine 3',5'-monophosphate (cGMP), a second messenger of nitric oxide (NO), in 1541 Japanese men and women aged 40-79 years. The 24-h urinary excretion of cGMP was measured using a (125)I-labeled cGMP radioimmunoassay and was adjusted for urinary creatinine excretion (nmol/mmol creatinine). The components of metabolic syndrome were defined based on the following criteria: body mass index (BMI)> or =25.0 kg/m(2), fasting plasma glucose> or =6.11 mmol/l or non-fasting plasma glucose level> or =11.1 mmol/l, systolic blood pressure> or =130 mm Hg or diastolic blood pressure> or =85 mm Hg, high-density lipoprotein (HDL)-cholesterol<1.03 mmol/l for men and <1.29 mmol/l for women, and triglyceride> or =1.69 mmol/l. The number of components of metabolic syndrome correlated inversely with urinary cGMP excretion; means of cGMP excretion for the whole group adjusted for age, sex, and cardiovascular risk factors were 53.6, 48.6, 47.9, 44.4 and 42.3 nmol/mmol for 0, 1, 2, 3, and 4-5 components of metabolic syndrome, respectively (p=0.002). Our data suggest that a reduction of NO bioactivity concur with clustered features of the metabolic syndrome.

Topics: Adult; Aged; Biomarkers; Cardiovascular Diseases; Cyclic GMP; Endothelium, Vascular; Female; Health Surveys; Humans; Japan; Male; Metabolic Syndrome; Middle Aged; Risk Factors

Although much is known about the anti-inflammatory effects of an acute corticosteroid therapy, little is known about the effects on chronic hypercortisolism on endothelial dysfunction and proinflammatory alterations in patients with Cushing's disease (CD).. We studied 9 patients with CD, 10 patients with metabolic syndrome and 27 normal controls. The tests consisted of an intravenous bolus of 0.1 U/kg insulin combined with a euglycaemic clamp technique with an arterialized forearm and assessment of the training parameters deep-venous balance of forearm glucose uptake (as an index of insulin sensitivity); NO(x) (nitric oxide end-products), c-GMP (second messenger of nitric oxide) and endothelin-1 release, as indices of endothelial function and proinflammatory systemic markers.. Forearm glucose uptake incremental area was significantly lower in Cushing's disease and in the metabolic syndrome than in controls, suggesting a state of severe insulin resistance. Compared to controls and to the metabolic syndrome, basal and insulin-stimulated NO(x) release incremental areas were significantly reduced in Cushing's disease, while forearm c-GMP release was similarly decreased in CD and metabolic syndrome. By contrast, endothelin-1 incremental areas after insulin bolus were significantly higher in CD than in controls and the metabolic syndrome, in the presence of increased TNF-alpha, IL-6 and CRP levels. Forearm glucose uptake incremental area significantly correlated with NO(x) incremental area, forearm c-GMP release incremental area, TNF-alpha levels and ET-1 incremental area.. In patients with CD, supraphysiological insulin levels are not able to overcome the insulin resistance due to chronic hypercortisolism. Furthermore, an increased proatherogenic risk profile is characterized by decreased nitric oxide synthesis and activity, enhanced endothelin-1 levels and increased proinflammatory markers.

Topics: Adult; Analysis of Variance; C-Reactive Protein; Case-Control Studies; Cyclic GMP; Diagnosis, Differential; Endothelin-1; Female; Humans; Insulin; Interleukin-6; Linear Models; Male; Metabolic Syndrome; Nitric Oxide; Pituitary ACTH Hypersecretion; Tumor Necrosis Factor-alpha

Feeding high fructose (Frc) to rats induces a moderate increase in blood pressure, which is associated with insulin resistance. The present study was designed to evaluate the effect of the methanol extract of Sorbus commixta cortex (MSC) on vascular inflammation in a rat model of the metabolic syndrome induced by a high Frc-diet. Male Sprague-Dawley rats were divided into 4 groups and treated for 7 weeks as follows: 1) control, 2) high Frc-diet group, 3) Frc/MSC1 group; high Frc-diet group treated with MSC (100 mg/kg/day), and 4) Frc/MSC2 group; high Frc-diet group treated with MSC (200 mg/kg/day). High Frc-induced decreases of the expression level of aortic endothelial nitric oxide synthase (ecNOS) while the production of cyclic GMP (cGMP) was restored by treatment with MSC. On the contrary, increases of the expression level of endothelin-1 (ET-1) in the aorta, the transcription factor, the cytokine related with vascular inflammation, and the adhesion molecules were suppressed by MSC treatment. Moreover, MSC treatment was shown to lessen the thickening noted in the aortic intima and media of the high Frc-diet group. Our findings suggest that MSC may have an anti-vascular inflammatory effect on rats with a high Frc-induced metabolic syndrome.

Topics: Animals; Aorta, Thoracic; Cell Adhesion Molecules; Cyclic GMP; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Fructose; Guanosine Monophosphate; Inflammation; Male; Metabolic Syndrome; Methanol; NF-kappa B; Nitrites; Plant Extracts; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sorbus; Sweetening Agents; Triglycerides; Tunica Intima; Tunica Media

Metabolic syndrome is a cluster of metabolic abnormalities, including hypertension, hyperlipidemia, hyperinsulinemia, glucose intolerance and obesity. In such lifestyle-related diseases, impairment of nitric oxide (NO) production or bioactivity has been reported to lead to the development of atherogenic vascular diseases. Therefore, in the present study we investigated changes in the NO/cyclic guanosine monophosphate (cGMP) system in aortas of SHR/NDmcr-cp (cp/cp) rats (SHR-cp), a model of the metabolic syndrome. In aortas of SHR-cp, endothelium-dependent relaxations induced by acetylcholine and endothelium-independent relaxations induced by sodium nitroprusside were significantly impaired in comparison with Wistar-Kyoto rats. Furthermore, protein levels of soluble guanylyl cyclase and cGMP levels induced by sodium nitroprusside were significantly decreased. In contrast, protein levels of endothelium NO synthase and cGMP levels induced by acetylcholine were significantly increased, and plasma NO2 plus NO3 levels were also increased. The levels of lipid peroxide in plasma and the contents of 3-nitrotyrosine, a biomarker of peroxynitrite, in aortas were markedly increased. These findings indicate that in the aortas of SHR-cp, NO production from the endothelium is augmented, although the NO-induced relaxation response is impaired. Enhanced NO production may be a compensatory response to a variety of factors, including increases in oxidative stress.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Blood Glucose; Blood Pressure; Cyclic GMP; Disease Models, Animal; Endothelium, Vascular; Lipids; Male; Metabolic Syndrome; Nitric Oxide; Nitroprusside; Rats; Rats, Inbred Strains; Thiobarbituric Acid Reactive Substances; Vasodilation; Vasodilator Agents

1. Abnormal vasorelaxation responses are seen in the context of various disease states, including obesity, hypertension, hyperlipidemia and diabetes. Metabolic syndrome, which is characterized by the concomitant presence of all of these disease states, develops spontaneously in the SHR/NDmcr-cp (cp/cp) rat (SHR-cp). The goal of the present study was to determine whether abnormal vasorelaxation responses were present with metabolic syndrome. 2. Acetylcholine-induced endothelial-dependent relaxation was significantly enhanced in aortas isolated from SHR-cp at the age of 18 weeks when compared to that from control rats [lean littermates SHR/NDmcr-cp (+/+) (SHR)]. In contrast, endothelium-independent relaxation in response to sodium nitroprusside was equally attenuated in the two rat groups compared with normotensive Wistar-Kyoto rats. 3. These results suggest that endothelial nitric oxide (NO) production increased in the aorta of SHR-cp as compared to SHR. This may compensate for the concomitant impairment in the NO-mediated relaxation response in smooth muscle cells, that probably results from hypertension. Enhanced NO production may result from a variety of factors, including increases in oxidative stress in the context of the metabolic syndrome.

Topics: Acetylcholine; Animals; Antihypertensive Agents; Aorta, Thoracic; Cyclic GMP; Disease Models, Animal; Hypertension; In Vitro Techniques; Male; Metabolic Syndrome; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasodilation; Vasodilator Agents