cyclic-gmp and Hypertrophy--Left-Ventricular

Topics: Animals; Atrial Natriuretic Factor; Cardiovascular Diseases; Cyclic GMP; Disease Models, Animal; Gene Expression Regulation; Humans; Hypertrophy, Left Ventricular; Models, Genetic; Nitric Oxide; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Risk Assessment; Sensitivity and Specificity; Signal Transduction

Group II pulmonary hypertension (PH) commonly occurs in the setting of a pressure-overloaded left ventricle (LV) which is also conducive to the development of heart failure with preserved ejection fraction. Population trends and a high prevalence of underlying causative conditions, such as essential hypertension or aortic stenosis, have increased the awareness of the pressure-overloaded LV and associated group II pulmonary hypertension. Patients often exhibit poor exercise tolerance and signs of heart failure indistinguishable from systolic heart failure; but effective medical treatments in this area have been lacking. Recent preclinical work has shed light on how the down-regulated nitric oxide - cyclic GMP pathway (within the myocardium and pulmonary vasculature) contributes to the pathophysiology of these associated conditions. This article will discuss the impact of the nitric oxide - cyclic GMP pathway on the pathogenesis of the pressure-overloaded LV and group II pulmonary hypertension, and will also introduce the potential therapeutic value of modulating this pathway.

Topics: Antihypertensive Agents; Aortic Valve Stenosis; Cardiomyopathies; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Diastole; Heart Failure; Humans; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Nitric Oxide; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Signal Transduction; Stroke Volume; Systole; Ventricular Dysfunction, Left; Ventricular Remodeling

Left ventricular hypertrophy (LVH), an increased left ventricular (LV) mass, is common to many cardiovascular disorders, initially developing as an adaptive response to maintain myocardial function. In the longer term, this LV remodelling becomes maladaptive, with progressive decline in LV contractility and diastolic function. Indeed LVH is recognised as an important blood-pressure independent predictor of cardiovascular morbidity and mortality. The clinical efficacy of current treatments for LVH is reduced, however, by their tendency to slow disease progression rather than induce its reversal, and thus the development of new therapies for LVH is paramount. The signalling molecule cyclic guanosine-3',5'-monophosphate (cGMP), well-recognised for its role in regulating vascular tone, is now being increasingly identified as an important anti-hypertrophic mediator. This review is focused on the various means by which cGMP can be stimulated in the heart, such as via the natriuretic peptides, to exert anti-hypertrophic actions. In particular we address the limitations of traditional nitric oxide (NO*) donors in the face of the potential therapeutic advantages offered by novel alternatives; NO* siblings, ligands of the cGMP-generating enzymes, soluble (sGC) and particulate guanylyl cyclases (pGC), and phosphodiesterase inhibitors. Further impact of cGMP within the cardiovascular system is also discussed with a view to representing cGMP-based therapies as innovative pharmacotherapy, alone or concurrent with standard care, for the management of LVH.

Topics: Carbon Monoxide; Cardiovascular System; Cyclic GMP; Guanylate Cyclase; Humans; Hypertrophy, Left Ventricular; Natriuretic Peptides; Nitric Oxide Donors; Phosphodiesterase Inhibitors

Left ventricular hypertrophy and diastolic dysfunction (LVDD) remain highly frequent markers of cardiac damage and risk of progression to symptomatic heart failure, especially in resistant hypertension (RHTN). We have previously demonstrated that administration of sildenafil in hypertensive rats improves LVDD, restoring phosphodiesterase type 5 (PDE-5) inhibition in cardiac myocytes.. We hypothesized that the long-acting PDE-5 inhibitor tadalafil may be clinically useful in improving LVDD in RHTN independently of blood pressure (BP) reduction. A single blinded, placebo-controlled, crossover study enrolled 19 patients with both RHTN and LVDD. Firstly, subjects received tadalafil (20 mg) for 14 days and after a 2-week washout period, they received placebo orally for 14 days. Patients were evaluated by office BP and ambulatory BP monitoring (ABPM), endothelial function (FMD), echocardiography, plasma brain natriuretic peptide (BNP-32), cyclic guanosine monophosphate (cGMP) and nitrite levels.. No significant differences were detected in BP measurements. Remarkably, at least four echocardiographic parameters related with diastolic function improved accompanied by decrease in BNP-32 in tadalafil use. Although increasing cGMP, tadalafil did not change endothelial function or nitrites. There were no changes in those parameters after placebo.. The current findings suggest that tadalafil improves LV relaxation through direct effects PDE-5-mediated in the cardiomyocytes with potential benefit as an adjunct to treat symptomatic subjects with LVDD such as RHTN patients.

Topics: Aged; Blood Pressure; Carbolines; Cross-Over Studies; Cyclic GMP; Diastole; Drug Resistance; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain; Nitrites; Phosphodiesterase 5 Inhibitors; Single-Blind Method; Tadalafil; Ventricular Dysfunction, Left; Ventricular Function, Left

Cardiovascular diseases are among the main causes of mortality in the world. There is evidence of cardiovascular harm after exposure to low lead or mercury concentrations, but the effects of chronic exposure to the association of low doses of these toxic metals are still unknown. This work evaluated after 4 weeks, the association effects of low concentrations of lead and mercury on blood pressure and vascular resistance reactivity. Wistar rats were exposed for 28 days to lead acetate (1st dose of 4 μg/100 g and subsequent doses of 0.05 μg /100 g/day to cover daily losses) and mercury chloride (1st dose of 2.17 μg/kg and subsequent doses of 0.03 μg/kg/ day to cover daily losses) and the control group received saline, i.m. Results showed that treatment increased blood pressure and induced left ventricular hypertrophy. The mesenteric vascular reactivity to phenylephrine and the endothelium-dependent vasodilator response assessed by acetylcholine did not change. Additionally, reduced involvement of vasoconstrictor prostanoids derived from cyclooxygenase was observed in the PbHg group. By other regulatory routes, such as potassium channels, the vessel showed a greater participation of BK

Topics: Animals; Arterial Pressure; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Down-Regulation; Hypertension; Hypertrophy, Left Ventricular; Mercuric Chloride; Mesenteric Arteries; Muscle, Smooth, Vascular; Organometallic Compounds; Rats, Wistar; Second Messenger Systems; Time Factors; Vascular Resistance; Vasodilation

Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies. Here, we explore the effects of chronic PDE9 inhibition with CRD-733 in the mouse transverse aortic constriction pressure overload HF model.. CRD-733 treatment reversed existing LV hypertrophy compared with vehicle (. The PDE9 inhibitor, CRD-733, improves key hallmarks of HF including LV hypertrophy, LV dysfunction, left atrial dilation, and pulmonary edema after pressure overload in the mouse transverse aortic constriction HF model. Additionally, elevated plasma cGMP may be used as a biomarker of target engagement. These findings support future investigation into the therapeutic potential of CRD-733 in human HF.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Aorta; Carrier Proteins; Collagen; Constriction, Pathologic; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Fibrosis; Heart; Heart Atria; Heart Failure; Heart Ventricles; Hypertrophy, Left Ventricular; Lung; Male; Mice; Organ Size; Phosphodiesterase Inhibitors; Phosphorylation; Pulmonary Edema; Stroke Volume; Ventricular Remodeling

The heart is constantly challenged with acute bouts of stretching or overload. Systolic adaptations to these challenges are known but adaptations in diastolic stiffness remain unknown. We evaluated adaptations in myocardial stiffness due to acute stretching and characterized the underlying mechanisms.. Left ventricles (LVs) of intact rat hearts, rabbit papillary muscles and myocardial strips from cardiac surgery patients were stretched. After stretching, there was a sustained >40% decrease in end-diastolic pressure (EDP) or passive tension (PT) for 15 min in all species and experimental preparations. Stretching by volume loading in volunteers and cardiac surgery patients resulted in E/E' and EDP decreases, respectively, after sustained stretching. Stretched samples had increased myocardial cGMP levels, increased phosphorylated vasodilator-stimulated phosphoprotein phosphorylation, as well as, increased titin phosphorylation, which was reduced by prior protein kinase G (PKG) inhibition (PKGi). Skinned cardiomyocytes from stretched and non-stretched myocardia were studied. Skinned cardiomyocytes from stretched hearts showed decreased PT, which was abrogated by protein phosphatase incubation; whereas those from non-stretched hearts decreased PT after PKG incubation. Pharmacological studies assessed the role of nitric oxide (NO) and natriuretic peptides (NPs). PT decay after stretching was significantly reduced by combined NP antagonism, NO synthase inhibition and NO scavenging, or by PKGi. Response to stretching was remarkably reduced in a rat model of LV hypertrophy, which also failed to increase titin phosphorylation.. We describe and translate to human physiology a novel adaptive mechanism, partly mediated by titin phosphorylation through cGMP-PKG signalling, whereby myocardial compliance increases in response to acute stretching. This mechanism may not function in the hypertrophic heart.

Topics: Adaptation, Physiological; Animals; Case-Control Studies; Cell Adhesion Molecules; Compliance; Connectin; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Humans; Hypertrophy, Left Ventricular; Isolated Heart Preparation; Male; Mechanoreceptors; Mechanotransduction, Cellular; Microfilament Proteins; Myocardial Contraction; Myocytes, Cardiac; Papillary Muscles; Phosphoproteins; Phosphorylation; Rabbits; Rats, Wistar; Second Messenger Systems; Ventricular Function, Left; Ventricular Pressure

Cyclic guanosine monophosphate-protein kinase G-phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl-peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function.. We assessed LV hypertrophy and function at the organ and cellular level in aortic-banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end-systolic pressure-volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil-treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening-frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium-retention capacity and Complex II-dependent respiratory control, was present in both HF and tadalafil-treated animals.. Both saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

Topics: Adamantane; Animals; Atrial Natriuretic Factor; Cyclic GMP; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Echocardiography; Hypertrophy, Left Ventricular; Male; Natriuretic Peptide, Brain; Neuropeptide Y; Phosphodiesterase 5 Inhibitors; Signal Transduction; Swine; Swine, Miniature; Tadalafil; Ventricular Function, Left

Presence of pulmonary hypertension (PH) and right ventricular dysfunction worsens prognosis in patients with chronic heart failure (CHF). Preclinical and clinical studies suggest a role for the impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway in both PH and CHF. Hence, we examined the effects of the NO-sGC-cGMP pathway modulation by the PDE5 inhibitor sildenafil or sGC stimulator riociguat on pulmonary hemodynamics and heart function in a murine model of secondary PH induced by transverse aortic constriction.. C57Bl/6N mice were subjected to transverse aortic constriction (TAC) for 6weeks to induce left heart failure and secondary PH and were subsequently treated with either sildenafil (100mg/kg/day) or riociguat (10mg/kg/day) or placebo for 2weeks.. Six weeks after surgery, TAC induced significant left ventricular hypertrophy and dysfunction associated with development of PH. Treatment with riociguat and sildenafil neither reduced left ventricular hypertrophy nor improved its function. However, both sildenafil and riociguat ameliorated PH, reduced pulmonary vascular remodeling and improved right ventricular function.. Thus, modulation of the NO-sGC-cGMP pathway by the PDE5 inhibitor sildenafil or sGC stimulator riociguat exerts direct beneficial effects on pulmonary hemodynamics and right ventricular function in the experimental model of secondary PH due to left heart disease and these drugs may offer a new therapeutic option for therapy of this condition.

Topics: Animals; Cyclic GMP; Disease Models, Animal; Heart Function Tests; Humans; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Pyrazoles; Pyrimidines; Signal Transduction; Sildenafil Citrate; Soluble Guanylyl Cyclase; Treatment Outcome

Pathologic myocardial hypertrophy develops when the heart is chronically pressure-overloaded. Elevated intracellular cGMP-levels have been reported to prevent the development of pathologic myocardial hypertrophy, therefore we investigated the effects of chronic activation of the cGMP producing enzyme, soluble guanylate cyclase by Cinaciguat in a rat model of pressure overload-induced cardiac hypertrophy. Abdominal aortic banding (AAB) was used to evoke pressure overload-induced cardiac hypertrophy in male Wistar rats. Sham operated animals served as controls. Experimental and control groups were treated with 10 mg/kg/day Cinaciguat (Cin) or placebo (Co) p.o. for six weeks, respectively. Pathologic myocardial hypertrophy was present in the AABCo group following 6 weeks of pressure overload of the heart, evidenced by increased relative heart weight, average cardiomyocyte diameter, collagen content and apoptosis. Cinaciguat did not significantly alter blood pressure, but effectively attenuated all features of pathologic myocardial hypertrophy, and normalized functional changes, such as the increase in contractility following AAB. Our results demonstrate that chronic enhancement of cGMP signalling by pharmacological activation of sGC might be a novel therapeutic approach in the prevention of pathologic myocardial hypertrophy.

Topics: Animals; Apoptosis; Benzoates; Blood Pressure; Cyclic GMP; Hypertrophy, Left Ventricular; Male; Myocardium; Rats; Rats, Wistar; Second Messenger Systems

To determine the effect of gestational hypertension on the developmental origins of blood pressure (BP), altered kidney gene expression, salt-sensitivity and cardiac hypertrophy (CH) in adult offspring.. Female mice lacking atrial natriuretic peptide (ANP-/-) were used as a model of gestational hypertension. Heterozygous ANP+/- offspring was bred from crossing either ANP+/+ females with ANP-/- males yielding ANP+/-(WT) offspring, or from ANP-/- females with ANP+/+ males yielding ANP+/-(KO) offspring. Maternal BP during pregnancy was measured using radiotelemetry. At 14weeks of age, offspring BP, gene and protein expression were measured in the kidney with real-time quantitative PCR, receptor binding assay and ELISA.. ANP+/-(KO) offspring exhibited normal BP at 14weeks of age, but displayed significant CH (P<0.001) as compared to ANP+/-(WT) offspring. ANP+/-(KO) offspring exhibited significantly increased gene expression of natriuretic peptide receptor A (NPR-A) (P<0.001) and radioligand binding studies demonstrated significantly reduced NPR-C binding (P=0.01) in the kidney. Treatment with high salt diet increased BP (P<0.01) and caused LV hypertrophy (P<0.001) and interstitial myocardial fibrosis only in ANP+/-(WT) and not ANP+/-(KO) offspring, suggesting gestational hypertension programs the offspring to show resistance to salt-induced hypertension and LV remodeling. Our data demonstrate that altered maternal environments can determine the salt-sensitive phenotype of offspring.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Female; Fetal Development; Gene Expression; Gene Expression Regulation; Hypertension, Pregnancy-Induced; Hypertrophy, Left Ventricular; Kidney; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; p300-CBP Transcription Factors; Pregnancy; Prenatal Exposure Delayed Effects; Proto-Oncogene Protein c-ets-1; Receptors, Atrial Natriuretic Factor; Salt Tolerance; Sodium, Dietary; Ventricular Remodeling

Pulmonary hypertension as a frequent complication of left heart disease (PH-LHD) is characterized by lung endothelial dysfunction and vascular remodeling. Although PH-LHD contributes to morbidity and mortality in heart failure, established therapies for PH-LHD are lacking. We tested the effect of chronic sildenafil treatment in an experimental model of PH-LHD.. In Sprague-Dawley rats, PH-LHD was induced by supracoronary aortic banding. Oral sildenafil treatment (60 mg/kg daily) was initiated after 7 days, and lung endothelial function (n=5), vascular remodeling, and right ventricular function (n=11 each) were analyzed 9 weeks after banding. As compared with sham-operated controls, aortic banding induced pulmonary hypertension and lung endothelial dysfunction evident as lack of endothelial nitric oxide production and endothelium-dependent vasodilation. These changes were associated with an increased pulmonary vascular resistance, medial thickening, and biventricular cardiac hypertrophy. Sildenafil treatment largely attenuated these pathological changes and was not associated with detectable adverse effects pertinent to lung vascular barrier function, edema formation, or systemic hemodynamics.. Our data identify sildenafil as a promising therapy for PH-LHD. In light of its documented protective effects at the myocardial level in heart failure, sildenafil presents a particularly attractive strategy in that it simultaneously targets cardiac remodeling and secondary PH-LHD.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Endothelium, Vascular; Heart Failure, Diastolic; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Lung; Male; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Time Factors; Vascular Resistance; Vasodilation; Ventricular Function, Left; Ventricular Function, Right

Statins have pleiotropic effects that can reverse endothelial dysfunction and prevent the development of left ventricular hypertrophy (LVH). The goal of this study was to assess the effect of treatment with atorvastatin on the endothelial dysfunction of epicardial coronary arteries and the development of LVH in a porcine model. LVH was induced through 2 months of aortic banding (AB) of the ascending aorta. Experimental groups were (1) sham untreated: without AB, (2) LVH untreated: with AB, and (3,4) LVH treated: with AB treated with 40 and 80 mg of atorvastatin, respectively, for 60 days, and (5) sham treated: without AB treated with 80 mg of atorvastatin for 60 days. Vascular reactivity studies were performed in organ chambers experiments. NO bioavailability was assessed using cyclic guanosine monophosphate quantification. Oxidative stress levels were measured by quantifying angiotensin II) and nitrite/nitrate levels. LVH and LV diastolic function were evaluated using echocardiography. Atorvastatin decreased endothelium-dependent relaxations and cyclic guanosine monophosphate levels in all treated animals. Angiotensin II levels were increased, whereas nitrite levels were similar among groups (P > 0.05). LV diastolic dysfunction and LVH were significantly greater in all treated animals (P < 0.01). High-density lipoprotein levels and low-density lipoprotein levels were significantly decreased in animals receiving atorvastatin (P < 0.05). In this swine model of LVH, atorvastatin did not prevent LVH development or coronary endothelial dysfunction and resulted in worsening of the LV diastolic dysfunction.

Topics: Angiotensin II; Animals; Aorta; Atorvastatin; Coronary Vessels; Cyclic GMP; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Echocardiography; Endothelium, Vascular; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy, Left Ventricular; Male; Nitrates; Nitrites; Pyrroles; Random Allocation; Swine; Vasodilation; Ventricular Dysfunction, Left

Genistein has been shown to increase nitric oxide (NO) production derived from endothelial nitric oxide synthase (eNOS). This study was to investigate whether genistein could prevent myocardial hypertrophy in the 2-kidney 1-clip (2K1C) renohypertensive rat through the NO pathway and to clarify the underlying mechanisms. After the 2K1C operation, plasma angiotensin II increased, and the rats developed significant left ventricular hypertrophy (LVH) and increased collagen I expression. Phosphorylated eNOS, NOS activity, NO production and cGMP contents were markedly decreased in ventricular tissues of 2K1C rats. Chronic administration of genistein to 2K1C rats restored NO, NOS activity, phosphorylated eNOS expression, cGMP in ventricular tissues, and the restoration was parallel with the improvement of LVH and attenuated the excessive ventricular collagen I expression. Genistein also elevated angiotensin II type 2 receptor (AT2) expression, and the effects of genistein on LVH could be completely abolished by an AT2 antagonist, PD123319. The antagonist also reversed the increase in eNOS activity, NO and cGMP restored by genistein in hypertensive rats. We further explored the mechanisms by which genistein restored NO in hypertension and found that genistein significantly enhanced phosphorylated eNOS but left relatively unchanged total eNOS and the eNOS dimer/monomer ratio. In addition, genistein decreased the binding of eNOS with caveolin 3 and simultaneously promoted its binding with calmodulin and heat shock protein 90. We conclude that the preventive effects of genistein on cardiac remodeling induced by 2K1C hypertension are mediated by AT2-dependent NO production.

Topics: Angiotensin II; Animals; Collagen Type I; Cyclic GMP; Gene Expression Regulation; Genistein; Hypertension, Renovascular; Hypertrophy, Left Ventricular; Male; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; Ventricular Remodeling

Using a working perfused heart model, we investigated the hypothesis that alterations in the NO-cGMP pathway may exacerbate postischaemic mechanical dysfunction in the hypertrophied heart. Ischaemia for 25 min followed by reperfusion for 30 min produced marked cardiac mechanical dysfunction in both stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar Kyoto rats (WKY). Exogenous treatment with S-nitroso-N-acetyl-dl-penicillamine (SNAP), a NO donor, had beneficial effects on the cardiac dysfunction induced by ischaemia-reperfusion (I/R) in the WKY heart, but the cardioprotective effect of SNAP was eliminated by guanylyl cyclase inhibitor. Cardiac cGMP levels were increased by SNAP or ischaemia in WKY. In contrast, in SHRSP hearts, SNAP could not alleviate the cardiac dysfunction caused by I/R. Pre-ischaemia, the cardiac cGMP level was significantly higher in SHRSP than in WKY; however, no significant difference was found after SNAP and ischaemia. The myocardial Ca(2+)-dependent NO synthase (NOS) activity increased at the end of ischaemia in WKY. Conversely, the Ca(2+)-independent NOS activity and protein levels were upregulated by I/R in the SHRSP myocardium. In the SHRSP hearts, non-selective NOS and selective Ca(2+)-independent NOS inhibitors or antioxidant treatment alleviated cardiac dysfunction caused by I/R. Moreover, mRNA expression and Western blotting analysis of cGMP-dependent protein kinase type I showed more deterioration of SHRSP hearts compared with WKY. These results suggest that: (1) the NO-dependent cardioprotective effect is depressed; and (2) overproduction of NO derived from Ca(2+)-independent NOS contributes to postischaemic heart injury in the hypertrophied heart of hypertensive status.

Topics: Animals; Antioxidants; Calcium; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation; Guanylate Cyclase; Hypertension; Hypertrophy, Left Ventricular; Ischemic Preconditioning, Myocardial; Male; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Time Factors; Ventricular Function, Left; Ventricular Pressure

Reduced endogenous NO production has been described in cardiovascular disorders as cardiac hypertrophy and heart failure. The therapy with conventional nitrates is limited by their adverse hemodynamic effects and drug tolerance. The novel NO donor LA419 has demonstrated important antithrombotic and anti-ischemic properties without those adverse effects. The aim of this study was to evaluate the effect of LA419 chronic treatment on cardiac hypertrophy development in a progressive model of left ventricular hypertrophy. Rats were randomly divided into 6 groups: sham and clip (euthanized 7 weeks after aortic stenosis), sham+vehicle, sham+LA419, clip+vehicle, and clip+LA419 (euthanized 14 weeks after the surgery and treated with vehicle or 30 mg/kg of LA419 once left ventricular hypertrophy was established). LA419 treatment for 7 weeks induced a marked reduction in the heart:body weight ratio (4.10+/-0.28 and 3.38+/-0.06 mg/g in clip+vehicle versus clip+LA419; P<0.001) and left ventricular diameter (11.96+/-0.25 and 9.90+/-0.20 mm in clip+vehicle versus clip+LA419; P<0.001) without modifying the high blood pressure observed in stenosed rats. Histological analysis revealed that LA419 attenuated myocardial and perivascular fibrosis observed in rats with pressure overload for 14 weeks. In addition, LA419 treatment restored endothelial NO synthase and caveolin-3 expression levels, enhanced the interaction between endothelial NO synthase and its positive regulator the heat shock protein 90, and re-established the normal cardiac content of cGMP in stenosed rats. Thus, LA419 prevented the progression to maladaptative cardiac hypertrophy in response to prolonged pressure overload through a mechanism that involved the re-establishment of the endothelial NO synthase signaling pathway.

Topics: Animals; Blood Pressure; Caveolin 3; Cyclic GMP; Fibrosis; HSP90 Heat-Shock Proteins; Hypertrophy, Left Ventricular; Isosorbide Dinitrate; Male; Myocardium; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Ventricular Remodeling

The antiproliferative action of nitric oxide (NO) has been well established and increased production was reported in the infarcted rat heart. Concomitantly, increased DNA synthesis and hyperplasia of cardiac myocytes were documented in the hypertrophied myocardium. Despite these observations, the effect of NO on DNA synthesis in hypertrophied cardiac myocytes remains unexamined. Hypertrophy of the non-infarcted left ventricle (NILV) in 1-week post-MI rats was characterized by the increased prepro-ANP and reduction of alpha-myosin heavy chain protein expression. Inducible NO synthase was expressed in the NILV and associated with a concomitant attenuation of MnSuperoxide dismutase protein content. The latter data suggest that an antiproliferative action of NO in the hypertrophied NILV may proceed via either a cyclic GMP-dependent pathway and/or facilitated by a peroxynitrite-dependent mechanism. In neonatal rat ventricular myocytes (NNVM), the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) promoted a dose-dependent attenuation of DNA synthesis via a cyclic GMP-independent pathway. The permeable superoxide dismutase mimetic and peroxynitrite scavenger MnTBAP abrogated SNAP-dependent attenuation of DNA synthesis in NNVM. MnTBAP failed to inhibit SNAP-mediated recruitment of extracellular signal regulated kinase 1/2 (ERK1/2) but partially attenuated p38 phosphorylation. In hypertrophied NNVM induced by norepinephrine, SNAP-mediated peroxynitrite-dependent inhibition of DNA synthesis, ERK1/2 and p38 phosphorylation were significantly attenuated. Collectively, these data suggest that despite a favourable environment for NO and subsequent peroxynitrite generation in the NILV, hypertrophied cardiac myocytes may be partially refractory to their biological actions.

Topics: Animals; Animals, Newborn; Cyclic GMP; DNA; Heart Ventricles; Hypertrophy; Hypertrophy, Left Ventricular; Mitogen-Activated Protein Kinases; Muscle Cells; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; p38 Mitogen-Activated Protein Kinases; Penicillamine; Peroxynitrous Acid; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Ventricular Myosins

Natriuretic peptides (NP) mediate their effects by activating membrane-bound guanylyl cyclase-coupled receptors A (NPR-A) or B (NPR-B). Whereas the pathophysiological role of NPR-A has been widely studied, only limited knowledge on the cardiovascular function of NPR-B is available. In vitro studies suggest antiproliferative and antihypertrophic actions of the NPR-B ligand C-type NP (CNP). Because of the lack of a specific pharmacological inhibitor, these effects could not clearly be attributed to impaired NPR-B signaling. Recently, gene deletion revealed a predominant role of NPR-B in endochondral ossification and development of female reproductive organs. However, morphological abnormalities and premature death of NPR-B-deficient mice preclude detailed cardiovascular phenotyping. In the present study, a dominant-negative mutant (NPR-BDeltaKC) was used to characterize CNP-dependent NPR-B signaling in vitro and in transgenic rats. Here we demonstrate that reduced CNP- but not atrial NP-dependent cGMP response attenuates antihypertrophic potency of CNP in vitro. In transgenic rats, NPR-BDeltaKC expression selectively reduced NPR-B but not NPR-A signaling. NPR-BDeltaKC transgenic rats display progressive, blood pressure-independent cardiac hypertrophy and elevated heart rate. The hypertrophic phenotype is further enhanced in chronic volume overload-induced congestive heart failure. Thus, this study provides evidence linking NPR-B signaling to the control of cardiac growth.

Topics: Animals; Animals, Genetically Modified; Blood Pressure; Bone Development; Cyclic GMP; Genes, Dominant; Guanylate Cyclase; Heart Rate; Heart Ventricles; Hypertrophy, Left Ventricular; Kidney; Mutation; Natriuretic Peptide, C-Type; Rats; Receptors, Atrial Natriuretic Factor; Sequence Deletion

We tested the hypothesis that the negative functional effects of cyclic GMP would be attenuated by cyclic AMP and this interaction would be reduced in pacing-induced failure of hypertrophic hearts.. 8-Bromo-cGMP (2 microg/kg/min) was infused into a coronary artery in eight control, eight ventricular hypertrophy (HYP), and eight hypertrophic failure (HYP-FAIL) dogs. Then isoproterenol (0.1 microg/kg/min) was infused, followed by 8 Br-cGMP. Regional myocardial work (force*shortening/min), and O(2) consumption (VO(2)) (coronary blood flow*O(2) extraction) were measured. Cyclic GMP levels were determined by radioimmunoassay.. 8-Br-cGMP significantly decreased regional work from 3812 +/- 839 g*mm/min by 17% and VO(2) by 29% in control, but not in HYP (1073 +/- 182 by -10%, VO(2) by -16%) or HYP-FAIL (495 +/- 145 by -9%, VO(2) by 0%). Isoproterenol increased work by 43% and VO(2) by 48% in controls and in HYP (work by 54%, VO(2) by 39%), but not in HYP-FAIL (work by -28%, VO(2) by -5%). Subsequently, 8-Br-cGMP had no effect on work or VO(2) in control (-2%, -13%), HYP (-12%, -30%), or HYP-FAIL (+13%, +14%). Cyclic AMP levels were elevated by isoproterenol in control (381 +/- 115 versus 553 +/- 119 pmol/g) and HYP (313 +/- 55 versus 486 +/- 227), but not in HYP-FAIL (300 +/- 60 versus 284 +/- 126). After isoproterenol, 8-Br-cGMP further elevated cyclic AMP in control (687 +/- 122), but not in HYP or HYP-FAIL.. In controls, cyclic AMP attenuated cyclic GMPs negative functional and metabolic effects. The effects and the interaction were blunted in the HYP and HYP-FAIL groups.

Topics: Animals; Cardiac Output, Low; Cardiotonic Agents; Coronary Circulation; Coronary Vessels; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Dogs; Hypertrophy, Left Ventricular; Isoproterenol; Myocardial Contraction; Myocardium; Oxygen Consumption

The lipid-lowering agent probucol may be efficacious, through its antioxidant properties, to limit and reverse the vascular endothelial dysfunction associated with left ventricular hypertrophy (LVH). LVH was induced by performing an aortic banding (AB) on swine, except for controls (group 1). The untreated AB group received a placebo (group 2) whereas the treated groups received probucol (1000 mg/d orally); the third group began its treatment on the day of the banding (for 60 d), the fourth began on day 30 and the fifth on day 60 after AB (both for 30 d). Hypertrophy was assessed by echocardiography and histology. Coronary vascular reactivity was evaluated in organ chambers and endothelial function by quantification of NO2/NO3 and cyclic guanosine-3',5'-monophosphate. To assess oxidative stress, hydroperoxides and angiotensin II levels as well as superoxide dismutase activity were evaluated. After treatment with probucol, a significant decrease in left ventricle/body weight ratio was observed compared with the untreated group. Dose-response curves of the probucol groups showed an improvement in endothelium-dependent relaxations, associated with increased nitric oxide bioavailability and decreased angiotensin II and hydroperoxide levels. In conclusion, the antioxidant probucol limited the development and induced the regression of LVH and the associated coronary endothelial dysfunction.

Topics: Angiotensin II; Animals; Antioxidants; Bradykinin; Coronary Vessels; Cyclic GMP; Endothelium, Vascular; Fibrosis; Hypertrophy, Left Ventricular; In Vitro Techniques; Lipid Peroxides; Male; Myocytes, Cardiac; Nitrates; Nitrites; Probucol; Serotonin; Superoxide Dismutase; Swine; Vasodilation

Baseline function and signal transduction are depressed in hearts with hypertrophic failure. We tested the hypothesis that the effects of cGMP and its interaction with cAMP would be reduced in cardiac myocytes from hypertrophic failing hearts. Ventricular myocytes were isolated from control dogs, dogs with aortic valve stenosis hypertrophy, and dogs with pacing hypertrophic failure. Myocyte function was measured using a video edge detector. Cell contraction data were obtained at baseline, with 8-bromo-cGMP (10(-7), 10(-6), and 10(-5) M), with erythro-9-(2-hydroxy-3-nonyl)adenine [EHNA; a cAMP phosphodiesterase (PDE(2)) inhibitor] plus 8-bromo-cGMP, or milrinone (a PDE(3) inhibitor) plus 8-bromo-cGMP. Baseline percent shortening and maximal rates of shortening (R(max)) and relaxation were slightly reduced in hypertrophic myocytes and were significantly lower in failing myocytes (R(max): control dogs, 95.3 +/- 17.3; hypertrophy dogs, 88.2 +/- 5.5; failure dogs, 53.2 +/- 6.4 mum/s). 8-Bromo-cGMP dose dependently reduced myocyte function in all groups. However, EHNA (10(-6) M) and milrinone (10(-6) M) significantly reduced the negative effects of cGMP on cell contractility in control and hypertrophy but not in failing myocytes (R(max) for control dogs: cGMP, -46%; +EHNA, -21%; +milrinone, -19%; for hypertrophy dogs: cGMP, -40%; +EHNA, -13%; +milrinone, -20%; for failure dogs: cGMP, -40%; +EHNA, -29%; +milrinone, -32%). Both combinations of EHNA-cGMP and milrinone-cGMP significantly increased intracellular cAMP in control, hypertrophic, and failing myocytes. These data indicated that the cGMP signaling pathway was preserved in hypertrophic failing cardiac myocytes. However, the interaction of cGMP with the cAMP signaling pathway was impaired in these failing myocytes.

Topics: Adenine; Animals; Body Weight; Cardiotonic Agents; Cyclic AMP; Cyclic GMP; Dogs; Drug Interactions; Enzyme Inhibitors; Heart Failure; Hypertrophy, Left Ventricular; Milrinone; Myocardial Contraction; Myocytes, Cardiac; Organ Size; Signal Transduction

Portal hypertension induces neuroendocrine activation and a hyperkinetic circulation state. This study investigated the consequences of portal hypertension on heart structure and function. Intrahepatic portal hypertension was induced in male Sprague-Dawley rats by chronic bile duct ligation (CBDL). Six weeks later, CBDL rats showed higher plasma angiotensin-II and endothelin-1 (P <.01), 56% reduction in peripheral resistance and 73% reduction in pulmonary resistance (P <.01), 87% increase in cardiac index and 30% increase in heart weight (P <.01), and increased myocardial nitric oxide (NO) synthesis. In CBDL rats, macroscopic analysis demonstrated a 30% (P <.01) increase in cross-sectional area of the left ventricular (LV) wall without changes in the LV cavity or in the right ventricle (RV). Histomorphometric analysis revealed increased cell width (12%, P <.01) of cardiomyocytes from the LV of CBDL rats, but no differences in myocardial collagen content. Myocytes isolated from the LV were wider (12%) and longer (8%) than right ventricular myocytes (P <.01) in CBDL rats but not in controls. CBDL rats showed an increased expression of ANF and CK-B genes (P <.01). Isolated perfused CBDL hearts showed pressure/end-diastolic pressure curves and response to isoproterenol identical to sham hearts, although generated wall tension was reduced because of the increased wall thickness. Coronary resistance was markedly reduced. This reduction was abolished by inhibition of NO synthesis with N-nitro-L-arginine. Expression of eNOS was increased in CBDL hearts. In conclusion, portal hypertension associated to biliary cirrhosis induces marked LV hypertrophy and increased myocardial NO synthesis without detectable fibrosis or functional impairment. This observation could be relevant to patients with cirrhosis.

Topics: Animals; Bile Ducts; Cyclic GMP; Enzyme Inhibitors; Heart; Hypertension, Portal; Hypertrophy, Left Ventricular; In Vitro Techniques; Isoenzymes; Ligation; Liver Cirrhosis, Biliary; Male; Myocardium; Nitric Oxide Synthase; Nitroarginine; Organ Size; Rats; Rats, Sprague-Dawley

To determine the effects of chronic nitric oxide (NO) blockade on the pulmonary vasculature, 58-day-old spontaneously hypertensive rats of the stroke-prone substrain (SHRSP) and Wistar-Kyoto rats (WKY) received N(omega)-nitro-L-arginine (L-NNA; 15 mg. kg(-1). day(-1) orally for 8 days). Relaxation to acetylcholine (ACh) in hilar pulmonary arteries (PAs), the ratio of right ventricular (RV) to body weight (RV/BW) to assess RV hypertrophy (RVH), and the percent medial wall thickness (WT) of resistance PAs were examined. L-NNA did not alter the PA relaxation, RV/BW, or WT in WKY. Although the PA relaxation and RV/BW in control SHRSP were comparable to those in WKY, the WT was increased (31 +/- 2 vs. 19 +/- 1%). L-NNA-treated SHRSP showed two patterns: in one group, the relaxation, RV/BW, and WT were comparable to those in the control SHRSP; in the other, impaired relaxation (36 +/- 7 vs. 88 +/- 4% for WKY) was associated with an increase in WT (37 +/- 1%) and RV/BW (0. 76 +/- 0.05). Thus the abnormal pulmonary vasculature in SHRSP at <10 wk of age is not accompanied by impaired relaxation in PAs or RVH; however, impaired relaxation is associated with increased WT and RVH.

Topics: Animals; Blood Pressure; Blood Vessels; Cyclic AMP; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Genetic Predisposition to Disease; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Lung; Nitric Oxide Synthase; Nitroarginine; Pulmonary Circulation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Vasodilation

We recently demonstrated that rapid ventricular pacing caused cardiac failure (Failure) in dogs with aortic stenosis-induced left ventricular hypertrophy (Hypertrophy) and isoproterenol caused no significant increases in function, O2 consumption and intracellular cyclic AMP level in the failing hypertrophied hearts. We tested the hypothesis that alterations in the beta1-adrenoceptor-signal transduction pathway would correlate with the reduced functional and metabolic responses to beta-adrenergic stimulation during the transition from the compensated hypertrophy to failure. Pressure overload-induced left ventricular hypertrophy was created using aortic valve plication in 10 dogs over a 6-month period. Five months after aortic valve plication, congestive heart failure was induced in 5 dogs by rapid ventricular pacing at 240 bpm for 4 weeks. The density of myocardial beta1-adrenoceptors (fmoles/mg membrane protein; fmoles/g wet tissue) was significantly reduced in the Failure dogs (176+/-19; 755+/-136) when compared to those of the Control (344+/-51; 1,551+/-203) and the Hypertrophy (298+/-33; 1,721+/-162) dogs. The receptor affinities were not significantly different among all groups. There was a small but significant decrease in the percentage of beta1-adrenoceptors of the failing hypertrophied hearts (62+/-3%) when compared to that of the hypertrophied hearts (77+/-5%). The basal myocardial adenylyl cyclase activity (pmoles/mg protein/min) was significantly lower in the Failure dogs (45+/-4) than in the Control (116+/-14) and Hypertrophy (86+/-6) dogs. The forskolin (0.1 mM)-stimulated adenylyl cyclase activity was also significantly lower in the Failure dogs (158+/-17) than in the Control dogs (296+/-35) and slightly lower than in the Hypertrophy dogs (215+/-10). There were no significant differences in low Km cyclic AMP-phosphodiesterase activities among all groups. We conclude that down regulation of beta1-adrenoceptors and reduced adenylyl cyclase activities contribute to the decreases in myocardial functions and beta-adrenergic responses in the failing hypertrophied hearts induced by rapid ventricular pacing.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adenylyl Cyclases; Adrenergic beta-Agonists; Analysis of Variance; Animals; Aortic Valve Stenosis; Cardiac Pacing, Artificial; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Dogs; Down-Regulation; Heart Failure; Hypertrophy, Left Ventricular; Isoproterenol; Myocardium; Oxygen Consumption; Protein Binding; Receptors, Adrenergic, beta-1; Signal Transduction

1. We hypothesized that acetylcholine would attenuate the metabolic effect of increasing cAMP and decreasing cGMP on cardiac myocyte O2 consumption (VO2) in dog, and this effect would be altered in left ventricular hypertrophy (LVH) produced by aortic valve placation. 2. Steady-state VO2 of a suspension of ventricular myocytes from control (n = 7) and LVH (n = 6) dogs was measured by Clark O2 electrodes during electrical stimulation (5 ms, 1 Hz, in 2 mm Ca2+). Cyclic AMP and cyclic GMP were determined by radioimmunoassay. Cellular cAMP was increased by forskolin (adenylate cyclase stimulator) and cGMP was decreased by LY83583 (guanylate cyclase inhibitor) both at 10(-7,-6,-5,-4) M with and without 10(-6) M acetylcholine. 3. Baseline cGMP level in LVH (62 +/- 10 fmol 10(-5) myocytes) was significantly greater than that in control (20 +/- 3), although the myocyte VO2 (356 +/- 39 nL O2 min(-1) 10(-5) myocytes) and cAMP levels (3.9 +/- 0.6 nmol 10(5-1) myocytes) were similar to control (312 +/- 23 and 6.9 +/- 3.1). 4. Forskolin increased myocyte cAMP in both control and LVH myocytes and increased VO2 by 51 +/- 13 in control and 91 +/- 65 in LVH myocytes. LY83583 decreased myocyte cGMP levels in control and LVH myocytes and increased VO2 by 128 +/- 57 in control and 43 +/- 26 in LVH myocytes. 5. Acetylcholine altered the cAMP, cGMP, and VO2 levels in control to 2.4 +/- 0.4, 30 +/- 3 and 213 +/- 27 and LVH to 2.5 +/- 0.3, 85 +/- 9 and 261 +/- 32. Acetylcholine attenuated the maximal effects of forskolin on VO2 to 32 +/- 27 in control and 66 +/- 56 in LVH myocytes. Acetylcholine also decreased the maximal effects of LY83583 to 82 +/- 50 in control and 19 +/- 19 in LVH myocytes. 6. The positive metabolic effects of both increases in myocyte cAMP and decreases in cGMP were blunted by acetylcholine. There was a significant increase in myocyte cGMP with forskolin in LVH myocytes. Acetylcholine decreased the increased myocyte VO2 caused by elevated cAMP or decreased cGMP in both control and LVH myocytes, although the absolute decrease in cAMP was reduced and the absolute values of cGMP were higher in LVH myocytes.

Topics: Acetylcholine; Aminoquinolines; Animals; Cell Separation; Colforsin; Cyclic AMP; Cyclic GMP; Dogs; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Hypertrophy, Left Ventricular; In Vitro Techniques; Oxygen Consumption; Radioimmunoassay; Vasodilator Agents

We tested the hypothesis that pacing-induced cardiac failure of hypertrophic hearts would reduce the functional and metabolic responses of these hearts to guanylate cyclase inhibition and this was associated with alterations in cyclic GMP.. Methylene blue (MB, 2 mg/kg/min, guanylate cyclase inhibitor) was infused into the left anterior descending coronary artery in 5 control, 5 left ventricular hypertrophy (LVH), and 5 LVH pacing-induced failure dogs. Regional myocardial work was calculated as the integrated product of force and segment shortening and regional myocardial O(2) consumption (VO(2)) from coronary blood flow and O(2) extraction measurements. Cyclic GMP was determined by radioimmunoassay.. MB increased regional work (635 +/- 169 vs 1649 +/- 500, 781 +/- 184 vs 1569 +/- 203 g * mm/min) and VO(2) (8.3 +/- 1.4 vs 10.9 +/- 1.4, 7.3 +/- 0.7 vs 9.1 +/- 0.7 ml O(2)/min/100 g) in both control and LVH dogs but not in failure dogs (536 +/- 234 vs 623 +/- 193, 3.6 +/- 1.1 vs 4.7 +/- 1.9). MB also decreased cyclic GMP in control dogs (1170 +/- 142 vs 812 +/- 105 pmol/g). LVH dogs had elevated baseline cyclic GMP (5875 +/- 949) compared to control dogs but also demonstrated decreased cyclic GMP in response to MB (2820 +/- 372). In failure dogs, basal cyclic GMP was also elevated (4650 +/- 613) compared to control dogs but there was a lack of response to MB (3670 +/- 640).. We conclude that the myocardial function, VO(2) and cyclic GMP responses to methylene blue are diminished in the transition from hypertrophy to cardiac failure.

Topics: Animals; Cardiac Output, Low; Cardiac Pacing, Artificial; Cyclic GMP; Dogs; Hypertrophy, Left Ventricular; Methylene Blue; Myocardial Contraction; Myocardium; Reference Values

Although heme oxygenase (HO) has been suggested to be involved in the regulation of cardiovascular function through production of carbon monoxide (CO), the pathophysiological significance of HO in hypertensive organ damage remains unknown. We examined the effects of inducing HO-1 mRNA by stannous chloride (SnCl2) on cardiac hypertrophy in stroke-prone spontaneously hypertensive rats (SHR-SP/Izm). Chronic administration of SnCl2 resulted in a significant decrease in left ventricular (LV) weight/body weight ratio and LV brain natriuretic peptide (BNP) mRNA levels as a marker of cardiac hypertrophy and a significant increase in LV HO-1 mRNA levels and LV cGMP contents in SHR-SP/Izm, while there was no significant change in systemic blood pressure. These results provide the first evidence that induction of HO in the heart attenuates cardiac hypertrophy in load-independent mechanism in genetically hypertensive rats.

Topics: Animals; Blood Pressure; Body Weight; Cyclic GMP; Enzyme Induction; Heart Rate; Heart Ventricles; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hypertension; Hypertrophy, Left Ventricular; Male; Natriuretic Peptide, Brain; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Tin Compounds

This study was designed to test whether increased inotropy caused by raising intracellular cAMP would add to the positive inotropy caused by reducing cGMP and whether this relationship was affected by experimental hypertrophy. We used open chest anesthetized dogs with left ventricular hypertrophy (LVH) induced by valvular aortic stenosis and age matched controls (CON). Hearts were instrumented to measure local segment shortening, force, and regional work. Milrinone (MIL), a selective cyclic AMP-phosphodiesterase inhibitor, and methylene blue (MB), a guanylate cyclase inhibitor, were used to alter cAMP and cGMP levels. Ten CON and 11 LVH animals were randomly assigned to receive first either MIL (1 microg/kg/min) or MB (2 mg/kg/min) intracoronary (i.c.) infusion. After 10 min, simultaneous i.c. infusion of the other agent was begun. MIL increased regional minute work (g x mm/min) in both CON (1311 +/- 207 to 2072 +/- 285) and LVH (1052 +/- 136 to 1371 +/- 351) hearts. MB did not increase work significantly, but did increase contractile force. MIL + MB increased work from baseline; however, the combination did not increase work more than either agent alone (1961 +/- 510 CON; 1390 +/- 285 LVH). Myocardial cAMP levels (pmol/g) were significantly increased by MIL in both CON (329 +/- 53 to 437 +/- 13) and LVH hearts (351 +/- 67 to 538 +/- 32), and the addition of MB further raised cAMP (879 +/- 115 CON; 741 +/- 96 LVH). MB resulted in decreased myocardial cGMP (pmol/g) (3.20 +/- 0.61 to 2.16 +/- 0.92 CON; 5.21 +/- 1.15 to 2.46 +/- 0.56 LVH), while MIL increased cGMP (3.20 +/- 0.61 to 6.24 +/- 1.79 CON; 5.21 +/- 1.15 to 6.53 +/- 0.41 LVH). Both MIL and MB caused increases in O2 consumption, with MIL + MB together increasing O2 consumption further. The current findings demonstrate a potentiation of cAMP production in the presence of MIL + MB above either agent alone, but this did not lead to potentiation of positive functional effects. High levels of cGMP caused by milrinone may have limited the positive functional effects of cAMP.

Topics: Animals; Cyclic AMP; Cyclic GMP; Dogs; Drug Combinations; Drug Synergism; Enzyme Inhibitors; Guanylate Cyclase; Heart; Hemodynamics; Hypertrophy, Left Ventricular; Methylene Blue; Milrinone; Myocardium; Oxygen Consumption; Phosphodiesterase Inhibitors; Pyridones; Reference Values

We tested the hypothesis that nitric oxide (NO) cyclic guanosine 5'-monophosphate (GMP) signaling is deficient in pressure overload hypertrophy due to ascending aortic stenosis, and that long-term L-arginine treatment will increase cardiac cyclic GMP production and modify left ventricular (LV) pressure overload hypertrophy and beta-adrenergic contractile response.. Nitric oxide cyclic GMP signaling is postulated to depress vascular growth, but its effects on cardiac hypertrophic growth are controversial.. Forty control rats and 40 rats with aortic stenosis left ventricular hypertrophy ([LVH] group) were randomized to receive either L-arginine (0.40 g/kg/day) or no drug for 6 weeks.. The dose of L-arginine did not alter systemic blood pressure. Animals with LVH had similar LV constitutive nitric oxide synthase (cNOS) mRNA and protein levels, and LV cyclic GMP levels as compared with age-matched controls. In rats with LVH L-arginine treatment led to a 35% increase in cNOS protein levels (p = 0.09 vs untreated animals with LVH) and a 1.7-fold increase in LV cyclic GMP levels (p < 0.05 vs untreated animals with LVH). However, L-arginine treatment did not suppress LVH in the animals with aortic stenosis. In contrast, in vivo LV systolic pressure was depressed in L-arginine treated versus untreated rats with LVH (163 +/- 16 vs 198 +/- 10 mm Hg, p < 0.05). In addition, the contractile response to isoproterenol was blunted in both isolated intact hearts and isolated myocytes from L-arginine treated rats with LVH compared with untreated rats with LVH. This effect was mediated by a blunted increase in peak systolic intracellular calcium in response to beta-adrenergic stimulation.. Left ventricular hypertrophy due to chronic mechanical systolic pressure overload is not characterized by a deficiency of LV cNOS and cyclic GMP levels. In rats with aortic stenosis, L-arginine treatment increased cardiac levels of cyclic GMP, but it did not modify cardiac mass in rats with aortic stenosis. However, long-term stimulation of NO-cyclic GMP signaling depressed in vivo LV systolic function in LVH rats and markedly blunted the contractile response to beta-adrenergic stimulation.

Topics: Adrenergic beta-Agonists; Animals; Aortic Valve Stenosis; Arginine; Blood Pressure; Calcium; Case-Control Studies; Cyclic GMP; Hypertension; Hypertrophy, Left Ventricular; Isoproterenol; Longitudinal Studies; Male; Myocardial Contraction; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Random Allocation; Rats; Rats, Wistar; Signal Transduction; Systole; Ventricular Function, Left; Ventricular Pressure

Atrial natriuretic peptide (ANP) depresses contractility in left ventricular myocytes. Its expression is upregulated in pressure-overloaded hypertrophied hearts; however, the effects of ANP on contractility in hypertrophied myocytes are not known. Our aims were (1) to examine the cellular mechanisms of this depression in contractility in normal myocytes and (2) to test the hypothesis that the effects of ANP on contractility differ in hypertrophied myocytes from rats with ascending aortic stenosis.. We measured the myocyte shortening as an index of contractility, [Ca2+]i with fluo 3, and pHi with seminaphthorhodafluor-1 (SNARF-1). In normal control myocytes (n=26), ANP caused a concentration-dependent depression of contractility and reduction in pHi. In the presence of 10(-6) mol/L ANP, fractional cell shortening was 78+/-5% of baseline (P<0.05) and pHi was reduced by 0.16+/-0.04 U from baseline (P<0.01) without changes in [Ca2+]i. The magnitude of the depression of contraction caused by ANP was similar to that caused by intracellular acidification induced by an NH4Cl pulse. The effects of ANP on contractility and pHi were prevented in the presence of 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), which inhibits the Na+/H+ exchanger. In hypertrophied myocytes (n=23), ANP did not depress either myocyte contractility or pHi at concentrations of either 10(-8), 10(-7), or 10(-6) mol/L. ANP caused no change in pHi or the [Ca2+]i transient in hypertrophied myocytes. The cGMP level was increased and Na+/H+ exchanger mRNA levels were normal in left ventricles from aortic stenosis rats compared with controls.. ANP directly depresses contractility in normal myocytes via intracellular acidification, which decreases myofilament [Ca2+]i sensitivity. In contrast, ANP causes no effects on contractility and pHi in hypertrophied myocytes, suggesting a suppression in the coupling of the ANP-cGMP intracellular signaling pathway to the Na+/H+ exchanger.

Topics: Animals; Aortic Valve Stenosis; Atrial Natriuretic Factor; Cell Size; Cells, Cultured; Cyclic GMP; Dose-Response Relationship, Drug; Heart Ventricles; Hydrogen-Ion Concentration; Hypertrophy, Left Ventricular; Intracellular Fluid; Male; Myocardial Contraction; Rats; Rats, Wistar; Ventricular Function, Left

The aim of the current study was to determine if lowering myocardial cyclic GMP by guanylate cyclase inhibition would add independently to the positive inotropic effects caused by raising cyclic AMP and if these effects are modified in left ventricular hypertrophy (LVH) produced by aortic valve plication. Isoproterenol (ISO) (0.1 mg x kg(-1) x min(-1)) was infused into a branch of the left anterior descending coronary artery of seven control and eight hypertrophy open-chest anesthetized dogs. After 10 min, simultaneous infusion of methylene blue (MB) (2 mg x kg(-1) x min(-1)) was initiated at the same site. Hypertrophy increased heart weight and heart weight/body weight ratio. While both drugs increased left ventricular dP/dt(max), no additional global effects were observed in either group. Changes in regional variables followed the same pattern in both groups, i.e., ISO produced an increase that was enhanced by the addition of MB. ISO increased segment shortening, with a significant change in the control group. ISO increased regional force in both groups. The addition of MB increased force above ISO levels, with a significant change in the LVH group. ISO increased regional minute work (g x mm x min(-1)) (control, 1779 +/- 428 to 2541 +/- 500; LVH, 1157 +/- 253 to 1839 +/- 404) and O2 consumption. MB further increased regional work (control, 2993 +/- 952; LVH, 2416 +/- 853) and O2 consumption. ISO raised cyclic AMP (pmoles x g(-1)) (control, 468 +/- 41 to 580 +/- 84; LVH, 445 +/- 43 to 562 +/- 71) and had no effect on cyclic GMP (pmoles x g(-1)) (control, baseline 3.27 +/- 0.22, ISO 2.87 +/- 0.23; LVH, baseline 6.84 +/- 1.12, ISO 5.66 +/- 0.54). The addition of MB lowered cyclic GMP (control, 2.41 +/- 0.26; LVH, 3.68 +/- 0.35), but also increased cyclic AMP (control, 1021 +/- 121; LVH, 1107 +/- 134). Similar results were observed in control hearts using a specific soluble guanylate cyclase inhibitor (ODQ) in terms of changes in local work, O2 consumption, and cyclic nucleotides. Thus, at least part of the positive inotropic response to lowering cyclic GMP was mediated by changes in cyclic AMP in the current model. This was true in both control and LVH animals, although baseline cyclic GMP levels were higher, and a larger reduction in cyclic GMP was observed with MB in the LVH group.

Topics: Animals; Cardiotonic Agents; Cyclic AMP; Cyclic GMP; Dogs; Enzyme Inhibitors; Guanylate Cyclase; Heart; Hypertrophy, Left Ventricular; In Vitro Techniques; Isoproterenol; Methylene Blue; Myocardium; Oxygen Consumption

To examine the contribution of the cyclic guanosine monophosphate (cGMP) pathway in changes in pulmonary vasoconstriction during the initial days of altitude exposure, we tested the effects of LY83583 (an inhibitor of guanylate cyclase activation) and those of N(G)-monomethyl-L-arginine (an inhibitor of nitric oxide synthesis) on airway hypoxia- (3% O2) and angiotensin II- (AII, 0.2 microg) induced vasoconstrictions in lungs from the rats exposed to either moderate altitude (MA, 570 torr) or high altitude (HA, 430 torr) At 2 days' exposure, hypoxic response was significantly blunted compared with the response in low-altitude (LA, 710 torr) lungs in an altitude-dependent manner. At 7 days' exposure, the response was recovered fully in MA lungs but partially in HA lungs. AII response was not significantly blunted at 2 days' exposure, but was significantly augmented in an altitude-dependent manner at 7 days' exposure. LY83583 (10 micromol L(-1)) potentiated both responses in LA lungs but did not significantly potentiate either response in any altitude-exposed lungs. N(G)-monomethyl-L-arginine (10 micromol L(-1)) potentiated both responses in LA lungs but did not significantly potentiate either response in HA lungs at 2 days' and 7 days' exposure. Thus the cGMP pathway is not responsible for either the change in hypoxic vasoconstriction or the change in AII vasoconstriction in rat lungs during the initial 7 days of altitude exposure.

Topics: Altitude; Animals; Cyclic GMP; Enzyme Inhibitors; Guanylate Cyclase; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Male; Nitric Oxide; Nitric Oxide Synthase; Perfusion; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Vasoconstriction; Vasoconstrictor Agents

In this study, the dynamic interrelationships between myocardial functional state and changes in the second messenger content in pressure-overloaded hypertrophied hearts were investigated. Forty-three rat hearts were used after partial clamping of the abdominal aorta. The isolated hearts were perfused with Krebs-Henseleit buffer and allocated to perfusion for 20 s or 40 min as controls (n = 12); or with noradrenaline (10(-6) mol l-1, n = 11); carbachol (3 x 10(-7) mol l-1, n = 9); or noradrenaline plus carbachol (10(-6) mol l-1 + 3 x 10(-7) mol l-1, respectively, n = 11). maxdP/dt increased more than 2-fold already after 20 s on noradrenaline stimulation, followed by a significant increase in cAMP. After 40 min, maxdP/dt was lower than the maximal value, although higher than controls. cAMP was also decreased, but still significantly higher than controls. Perfusion with noradrenaline plus carbachol produced the same changes in maxdP/dt as those seen after noradrenaline stimulation alone, but failed to increase cAMP content after both 20 s and 40 min. The inositol trisphosphate (IP3) content was increased 40 min of control perfusion (p < 0.05). Noradrenaline and carbachol, separately, produced an increase in IP3 content already after 20 s (p < 0.05). The combination of noradrenaline plus carbachol also produced an increase of IP3 (p < 0.05; compared to controls), but to a lesser extent when compared either to noradrenaline or carbachol (p < 0.05). After 40 min of perfusion, IP3 was in the same range regardless of added agonist(s) and still slightly above control level (p < 0.05). The early increase in maxdP/dt induced by noradrenaline or the combination of noradrenaline plus carbachol was not paralleled by a decrease in ATP content. This was also the case upon addition of carbachol alone. However, after 40 min of agonistic perfusion, ATP levels were substantially decreased. In conclusion, myocardial IP3 content in pressure-overloaded hypertrophied hearts was not different from that of sham-operated hearts. After agonistic stimulation, an early increase in IP3 formation was seen. Attenuation of the IP3 response by combined stimulation with noradrenaline and carbachol was initially present in pressure-overloaded hypertrophied hearts. After 40 min no attenuation was found for either IP3 or for cAMP content, suggestive of induction of a desensitization.

Topics: Adrenergic Agonists; Animals; Aorta, Thoracic; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Hypertrophy, Left Ventricular; Inositol 1,4,5-Trisphosphate; Ligation; Male; Muscarinic Agonists; Myocardium; Rats; Rats, Sprague-Dawley; Second Messenger Systems; Ventricular Pressure

The aim of the current study was to determine if the effects of muscarinic stimulation on left ventricular function and metabolism are greater during beta-adrenergic activation, whether a cyclic GMP-mediated mechanism is responsible, and if this is altered by left ventricular hypertrophy (LVH) induced by aortic valve stenosis. Acetylcholine (Ach) (5 micrograms/kg/min) and/or isoproterenol (Iso) (0.1 micrograms/kg/min) was infused into a branch of the left anterior descending (LAD) artery in 8 control and 8 LVH open-chest anesthetized dogs. LVH increased heart weight, heart-to-body weight ratio and systolic left ventricular pressure. LVH reduced muscarinic receptor density (fmol/mg protein) (control: 149.2+/-18.6; LVH: 77.8+/-8.6), but not affinity. Alone, Ach had no effect on regional force, work or metabolism. Iso increased peak force (g) (control: baseline-7.4+/-0.4; Iso-12.4+/-2.2; LVH: baseline-6.7+/-0.8; Iso-16.3+/-2.7, regional work (g mm/min)) (control: baseline-1250+/-186; Iso-1813+/-409; LVH: baseline-927+/-235; Iso-1244+/-222), and O2 consumption (ml O2/min/100 g) (control: baseline-3.3+/-0.2; Iso-8.1+/-2.0; LVH: baseline-4.8+/-1.0; Iso-8.3+/-1.1). During Iso, Ach reduced segment shortening (control: Iso-14.5+/-1.2; Iso+Ach-10.5+/-1.8; LVH: Iso-10.4+/-1.5; Iso+Ach-7.6+/-1.3) and peak force (control: Iso+Ach-7.7+/-1.0; LVH: Iso+Ach-10.5+/-1.4). Ach also reduced work (control: Iso+Ach-875+/-217; LVH: Iso+Ach-776+/-180) and O2 consumption (control: Iso+Ach-3.4+/-0.7; LVH: Iso+Ach-3.6+/-0.6) in the presence of Iso. Cyclic GMP was higher in the LVH animals during all treatments and was elevated from baseline by Ach in both groups. Neither Iso nor Iso+Ach had a significant effect on cyclic GMP. Thus, the negative functional and metabolic effects of muscarinic stimulation are enhanced during beta-adrenergic activation. This does not, however, appear to be dependent on a cyclic GMP-mediated mechanism. Despite reduced number of muscarinic receptors, this response was not altered by pressure-induced cardiac hypertrophy.

Topics: Animals; Cardiomegaly; Cyclic GMP; Dogs; Hypertrophy, Left Ventricular; Receptors, Adrenergic, beta; Receptors, Muscarinic

Left ventricular hypertrophy (LVH) produced by aortic valve plication leads to increased myocardial cyclic GMP. We tested whether this was a result of increased soluble guanylate cyclase activity or nitric oxide (NO) synthase and its functional consequences. We used the nitric oxide donor 3-morpholino-sydnonimine (SIN-1) or the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME) in 12 control and 12 LVH anesthetized open-chest mongrel dogs. L-NAME (6 mg/kg) or SIN-1 (1 microgram/kg per min) was infused into the left anterior descending coronary artery and regional segment work and cyclic GMP levels were determined. In vitro myocardial guanylate cyclase sensitivity (0.43 +/- 0.04 to 0.28 +/- 0.04 mM [EC50]) and maximal activity (10.1 +/- 2.9 to 25.5 +/- 6.5 pmol/mg protein per min) were significantly increased in LVH as compared with control animals in response to nitroprusside stimulation, but cyclic GMP-phosphodiesterase activity was similar. In LVH dogs, basal cyclic GMP was significantly elevated in vivo when compared with controls. Treatment of dogs with SIN-1 resulted in a significant increase in cyclic GMP in control (1.09 +/- 0.12 to 1.48 +/- 0.19 pmol/gram) and a greater increase in the LVH group (1.78 +/- 0.16 to 3.58 +/- 0.71 pmol/g). L-NAME had no effect on myocardial cyclic GMP levels in control or LVH dogs. Segment work decreased in the control group after SIN-1 (1,573 +/- 290 to 855 +/- 211 grams x mm/min). LVH dogs showed no decrement in work as a result of treatment with SIN-1. L-NAME did not cause significant changes in myocardial cyclic GMP, O2 consumption, or work in either control or LVH dogs, but vascular effects were evident. SIN-1 increased cyclic GMP, and with greater effect on LVH; however, this resulted in a decrement in function only in the control group. The greater increased cyclic GMP in LVH dogs is not related to increased NO production, but is related to significantly higher sensitivity and maximal activity of soluble myocardial guanylate cyclase.

Topics: Animals; Arginine; Cyclic GMP; Dogs; Female; Guanylate Cyclase; Hypertrophy, Left Ventricular; Male; Molsidomine; NG-Nitroarginine Methyl Ester; Oxygen Consumption

We tested the hypotheses that decreased myocardial cyclic GMP levels produced by intracoronary injection of methylene blue would increase local myocardial work and O2 consumption while decreasing intracellular cyclic GMP and that the relation between work, O2 consumption, and cyclic GMP may be altered in left ventricular hypertrophy (LVH) produced by aortic valve plication. In 8 control and 8 LVH open-chest anesthetized dogs, 1 mg/kg/min methylene blue was infused into the left anterior descending coronary artery (LAD); the circumflex region (CFX) served as control area. Regional work was calculated as the integrated product of force (miniature transducer) and segment shortening (sonomicrometry). Regional myocardial O2 consumption was calculated from flow measurements (radioactive microspheres), and regional O2 saturations (microspectrophotometry). A radioimmunoassay was used to determine intracellular level of cyclic GMP in the myocardium. Global hemodynamics and blood gases were unchanged by methylene blue in both control and LVH animals. Intracoronary methylene blue increased regional work from 762 +/- 129 to 1,451 +/- 307 g center dot mm/min in controls and from 912 +/- 173 to 1581 +/- 253 g center dot mm/min in the LVH groups. No significant changes in CFX regional work were observed. Regional blood flow, O2 extraction, and O2 consumption remained unchanged after injection of methylene blue in both control and LVH animals. The basal levels of cyclic GMP in the LVH group were fivefold higher than that in controls. In both groups, cyclic GMP levels were significantly decreased by methylene blue and to a greater extent in the LVH animals (from 6.16 +/- 1.2 to 3.34 +/- 0.44 pmol/g) than in the control animals (from 1.32 +/- 0.20 to 1.09 +/- 0.19 pmol/g). Therefore, intracoronary methylene blue increased regional myocardial work equally in control and LVH hearts without affecting regional metabolism (i.e., increased efficiency). For the same increased mechanical function, the hypertrophic myocardium exhibited a greater reduction in cyclic GMP pool size.

Topics: Animals; Cyclic GMP; Dogs; Hypertrophy, Left Ventricular; Methylene Blue; Myocardial Contraction; Myocardium; Oxygen Consumption

The effect of 4 weeks' inhibition of NO synthase by nitro-L-arginine methyl ester (L-NAME) on haemodynamic parameters and cGMP and cAMP content was studied in rat tissues. L-NAME in both 20 mg/kg/day and 40 mg/kg/day doses significantly increased systolic blood pressure by 28% and 30% and decreased the heart rate by 14% and 23%, respectively, after the first week. These changes persisted during the following three weeks. Left ventricular weight/body weight (LVW/BW) ratio was significantly elevated in both L-NAME-treated groups by 19% and 29%, respectively. Radioimmunoassay was used to determine the cGMP and cAMP content. Cyclic GMP content in animals treated by L-NAME (20 mg/kg/day and 40 mg/kg/day) decreased significantly by 13% and 22% in the left ventricle, by 28% and 62% in the aorta, by 20% and 34% in the brain, and by 10% and 15% in the kidney, respectively. On the other hand, the cAMP content increased in both L-NAME treated groups by 8% and 9% in the left ventricle, by 28% and 46% in the aorta, and by 23% and 32% in the brain, respectively. There were no significant changes in kidney cAMP content as compared to control animals. The results suggest a simultaneous decrease of cGMP and increase of cAMP content in the majority of studied tissues during NO-deficient hypertension.

Topics: Animals; Aorta; Blood Pressure; Brain; Cyclic AMP; Cyclic GMP; Enzyme Inhibitors; Hypertrophy, Left Ventricular; Kidney; Male; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Wistar; Time Factors

We investigated the effect of chronic angiotensin-covering enzyme (ACE) inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRsp). Animals were treated prenatally and, subsequently, up to the age of 20 weeks with the ACE inhibitor perindopril (0.01 and 1 mg/kg per day). The contribution of endogenous bradykinin potentiation to the actions of the ACE inhibitor was assessed by co-treatment with the bradykinin B2-receptor antagonist, icatibant (500 micrograms/kg/day s.c.), from 6 to 20 weeks of age and by measurement of myocardial prostacyclin and cyclic guanosine monophosphate (GMP) concentrations. Chronic high-dose treatment with perindopril attenuated the development of hypertension and left ventricular hypertrophy while low-dose perindopril treatment had no effect on these parameters. However, low-dose perindopril improved cardiac function of isolated perfused hearts as demonstrated by an increasing left ventricular pressure and dp/dtmax without change in heart rate. Low-dose perindopril further reduced lactate concentrations and the enzymatic activities of lactate dehydrogenase and creatine kinase in the coronary venous effluent and increased tissue concentrations of glycogen, adenosine triphosphate, and creatine kinase in the myocardium. Concomitant chronic bradykinin receptor blockade abolished all ACE inhibitor-induced effects on cardiac function and metabolism. Cardiac prostacylin concentrations were 3-fold elevated in perindopril-treated animals when compared to vehicle-treated controls, while cardiac cyclic GMP concentrations remained unchanged. Our data demonstrate that chronic ACE inhibitor treatment can improve cardiac function and metabolism independently of the antihypertensive and antihypertrophic drug actions by potentiation of endogenous bradykinin.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Cerebrovascular Disorders; Cyclic GMP; Epoprostenol; Heart; Hypertension; Hypertrophy, Left Ventricular; Indoles; Myocardium; Perindopril; Rats; Rats, Inbred SHR; Ventricular Pressure

NG-nitro-L-arginine methyl ester (L-NAME) and 11-desoxycorticosterone plus salt intake (DOCA-salt) hypertensive rat models were compared to study the possible involvement of model-specific factors in the development of renal angiopathy and left ventricular hypertrophy (LVH). Blood pressure was measured in L-NAME, DOCA-salt hypertensive, and control Wistar rats, and the lesions of nephroangiosclerosis and left ventricular hypertrophy were evaluated after 7 weeks. Arterial wall cyclic guanosine monophosphate, plasma renin activity (PRA), and renal renin storage were assessed in parallel. For the same level of hypertension in the two models, the renal arterial fibrinoid necrotic lesions were significantly more frequent in L-NAME than in DOCA-salt hypertensive rats. In DOCA-salt hypertensive rats, PRA was decreased and arterial cGMP increased compared to controls. In the L-NAME model, arterial cGMP decreased and PRA showed a bimodal distribution in this intermediate stage of hypertensive disease. LVH was observed in DOCA-salt rats and only in the L-NAME rats with a high level of PRA. There was a close correlation between the lesions of nephroangiosclerosis, left ventricular index, and plasma renin activity in L-NAME rats. We therefore suggest that the activation of the renin-angiotensin system participates specifically in the development of the second stage of hypertension during chronic blockade of NO synthase involving nephroangiosclerosis and LVH.

Topics: Animals; Aorta; Arginine; Blood Pressure; Blood Urea Nitrogen; Body Weight; Creatinine; Cyclic GMP; Desoxycorticosterone; Disease Models, Animal; Hypertension, Renal; Hypertrophy, Left Ventricular; Male; Mortality; NG-Nitroarginine Methyl Ester; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System

Experimental myocardial infarction is a model of cardiac overload in which part of the cardiac muscle is removed. The resulting left ventricle insufficiency depends on the size of the infarct and time. The infarcted area remodels, due to proteolytic activity of inflammatory cells and collagenogenesis from fibroblast activity. The phenotype of the residual healthy cardiac muscle undergoes modification, and there are peripheral vascular changes which are partly dependent on the activation of pressor systems and/or inactivation of dilator systems. The changes are proportional to the infarct size at any given time after induction of the model. The degree of right ventricular hypertrophy and the drop in arterial pressure are upstream and downstream markers of the loss of left ventricular function and therefore indicate the extent of the remodelling. The increase of type V3isomyosin, the amount of subendocardial collagen, and the biosynthesis, storage and secretion of atrial natriuretic factor (ANF) are all proportional to the infarct size and the degree of cardiac overload. The level of urinary cGMP is also correlated with infarct size. These indices show ventricular remodelling, increased stress and energy restriction of the residual healthy cardiac muscle. The activation of peripheral pressor systems also depends on infarct size. They reflect the influence of defective cardiac pumping on the kidney, liver, brain and endothelium. Massive infarcts are accompanied by an increase in circulating renin and in renal renin content, by a decrease in angiotensinogen due to its consumption by renin, and to its insufficient hepatic synthesis, and by an increase in vasopressin secretion and biosynthesis in the hypothalamus. Converting enzyme inhibition has beneficial effect in this model by lowering cardiac load. It reduces arterial pressure, reverses bi-atrial and right ventricular hypertrophy, reduces the changes in the myosin isoenzyme patterns, and normalizes subendocardial fibrosis and the level of ANF. Although the effects of converting enzyme inhibition are beneficial in this model, they are restricted by their inability to normalize the load and stress when the initial loss of cardiac contractile material exceeds 40%.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Atrial Natriuretic Factor; Collagen; Cyclic GMP; Hypertrophy, Left Ventricular; Indoles; Isoenzymes; Kidney; Myocardial Infarction; Myocardium; Myosins; Perindopril; Rats; Rats, Wistar; Renin; Vasopressins; Ventricular Dysfunction, Left

Angiotensin-converting enzyme (ACE) inhibitors can improve cardiac function independent of their blood pressure (BP)-lowering actions. We investigated the effect of chronic subantihypertensive ACE inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRSP). Animals were treated in utero and subsequently to age 20 weeks with the ACE inhibitor perindopril (0.01 mg/kg/day). The contribution of endogenous bradykinin (BK) potentiation to the actions of the ACE inhibitor was assessed by cotreatment with the BK beta 2-receptor antagonist Hoe 140 (500 micrograms/kg/day subcutaneously, s.c.) from age 6 to 20 weeks and by measurement of myocardial prostacyclin and cyclic GMP concentrations. Chronic low-dose perindopril treatment had no effect on development of hypertension and left ventricular hypertrophy (LVH), but perindopril improved cardiac function, as demonstrated by increased LV pressure (LVP) (19.4%) and LVdp/dtmax (27.8%) but no change in heart rate (HR). The activities of lactate dehydrogenase (LDH) and creatine kinase (CK) as well as lactate concentrations in the coronary venous effluent were reduced by 39.3, 50, and 60.6%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and CK were increased by 16.3, 33.1, and 28.2%, respectively. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by concomitant chronic BK receptor blockade. Cardiac prostacyclin concentrations were threefold elevated in perindopril-treated animals whereas cardiac cyclic GMP concentration remained unchanged as compared with that of controls. Our data demonstrate that chronic low-dose ACE inhibitor treatment can improve cardiac function and metabolism by potentiating endogenous BK.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Cerebrovascular Disorders; Coronary Circulation; Creatine Kinase; Cyclic GMP; Disease Models, Animal; Glycogen; Heart; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Indoles; L-Lactate Dehydrogenase; Myocardium; Perindopril; Rats; Rats, Inbred SHR

Nitroprusside can produce negative inotropy by activating cGMP. We hypothesized that in left ventricular hypertrophy produced by aortic valve plication (LVH), control of myocardial work and metabolism by cGMP production would be altered in response to nitroprusside. In anesthetized open chest preparations using 9 LVH and 12 control dogs, nitroprusside (4 micrograms/kg/min) was infused into the left anterior descending coronary artery. The circumflex (CFX) region served as an internal control. Segment force (miniature gauge) and length (sonomicrometer) were measured in both regions. Segment work was calculated as the integrated products of local force and segment shortening. Regional myocardial O2 consumption was calculated from blood flow measurements (radioactive microspheres) and regional O2 saturations (microspectrophotometry). Radioimmunoassay was used to determine regional cGMP levels. In control dogs, nitroprusside significantly reduced force in the treated region (from 10.3 +/- 0.8 to 7.9 +/- 0.9 g) and segment work (from 1889 +/- 296 to 1254 +/- 252 g.mm/min). In the LVH group, regional work, force, and shortening did not change. In the CFX regions of both groups, regional myocardial mechanics, as well as regional myocardial O2 consumption, were not altered during nitroprusside infusion. Cyclic GMP levels were elevated to a much greater extent in the LVH animals (from 3.26 +/- 0.60 to 15.23 +/- 4.65 pmole/g) than in the control animals (from 2.16 +/- 0.60 to 2.89 +/- 0.56 pmole/g). Thus, in contrast to control myocardium, significant increases in cGMP production during nitroprusside infusion failed to produce negative inotropy in LVH. These findings suggest an uncoupling between the second messenger and systems controlling muscle contraction.

Topics: Animals; Blood Flow Velocity; Coronary Vessels; Cyclic GMP; Disease Models, Animal; Dogs; Heart; Hypertrophy, Left Ventricular; Infusions, Intra-Arterial; Nitroprusside; Oxygen Consumption; Radioimmunoassay; Regional Blood Flow