Experimental diabetes and left ventricular hypertrophy (original) (raw)
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Bulletin of Egyptian Society for Physiological Sciences
The present work aimed to study the effects of carvedilol, a third generation -blocker with antioxidant and -blocking activities, on glycemic control and cardioprotection in type 2 diabetes mellitus (DM) induced in rats by high fat diet (HFD). Seventy-two male albino rats (5 weeks of age) weighing 80-90g were exposed to dark/light cycle of 12/12 hours and randomly divided into six groups, each of 12 rats. Rats of Control Group were fed standard rat chow. Rats of HFD Group were fed HFD for induction of type 2 DM. Rats of the last 4 groups were the Carvedilol-S Group, the Carvedilol-L Group, the Propranolol Group and the Aminoguanidine Group. They were fed HFD and treated with carvedilol (2mg/kg/day), carvedilol (20 mg/kg/day), propranolol (30 mg/kg/day) and aminguanidine (20 mg/kg/day) respectively All drugs were given orally by gavage in the morning. The animals were under feeding and subsequent treatments daily for 12 weeks. At the end of the experiment, rats were sacrificed, blood samples collected, centrifuged and sera were separated and stored at-80°C till the time of analysis. The epididymal fat pads and one of the gastrocnemius muscles were excised, blotted dry and weighed and the weight ratio was recorded as the body composition index (BCI). Hearts were rapidly exposed and excised, washed in cold phosphate buffered saline (PBS), pH 7.4, blotted dry and weighed. The ratio between heart weight and body weight was calculated as heart weight index (HWI). Immediately, the hearts were flash-frozen in liquid nitrogen and kept frozen at-80°C until the time of analysis. The parameters assayed were: serum lipid profile, lipid peroxides, insulin, glucose, myocardial lipid peroxides, superoxide dismutase (SOD) and catalase (CAT) enzymes, nitric oxide (NO) and oral glucose tolerence test (OGTT) where rats were fasted for 15 hours and glucose was given by gavage at a dose of 2 g/kg then 6 blood samples were taken from retroorbital vien at half hour intervals. Results: HFD in male albino rats for 12 weeks induced type 2 DM. Dyslipidemic changes in these animals were observed as increased serum levels of total cholesterol (TC), low density lipoporotein-cholesterol (LDL-C), triglycerides (TGs) and decreased levels of high density lipoporotein-cholesterol (HDL-C). In addition, HFD induced oxidative and nitrative stress as evidenced by the increase in serum and myocardial levels of lipid peroxides and concomitant decrease in myocardial SOD and CAT and increased NO metabolites. HFD also induced cardiovascular complications as indicated by increased HWI in the HFD group. Administration of carvedilol in both dose levels had positive impact on glucose
Carvedilol and Pycnogenol® improve the function of diabetic hearts in rats
Acta Facultatis Pharmaceuticae Universitatis Comenianae, 2013
We observed the changes in electrical activity, biometric and haemodynamic parameters of hearts in animals with experimental diabetes mellitus (DM). As well the effect of carvedilol, PycnogenolR and its combination with carvedilol on DM heart function was tested. DM was induced by streptozotocin over three sequential days at a dose of 25 mg/kg body weight i.p. We started therapy by suspension of carvedilol, PycnogenolR and their combination for six weeks. Blood pressure was measured using tail cuff plethysmography. ECG, haemodynamic and biometric parameters were measured in isolated hearts perfused according to the Langendorff. DM rats had increased systolic arterial blood pressure, thicker free wall of left ventricle but weakened myocardial contractility compared with controls. In contrast to controls, electrophysiological parameters showed prolonged QT interval and increased incidence of dysrhythmias in DM rats. The PycnogenolR administration induced regression of left ventricular...
Journal of Molecular and Cellular Cardiology, 2001
Left ventricular hypertrophy (LVH) is accompanied by progressive accumulations of extracellular matrix proteins. They are produced predominantly by cardiac fibroblasts that surround the cardiac myocytes. The aim of this study was to emphasize the role of a combined approach using both in vivo and in vitro studies to elucidate the effects of carvedilol on cardiac remodeling. We therefore used an established model of supravalvular aortic banding and cardiac fibroblasts. LVH was induced by banding of the ascending aorta. Male Wistar rats were allocated to four groups: sham-operated, sham+carvedilol, aortic stenosis (AS), and AS+carvedilol. Treatment time was four weeks. Fibroblasts were isolated from the entire left ventricle of sham and AS rats. Carvedilol/metoprolol/prazosin were added (0.1, 1.0 and 10 ; 24 h). In addition, interferon-was applied for 24 h (10, 100 and 1000 IU). AS rats revealed increased LV weights (+27%) and cardiomyocyte widths as compared to sham-operated rats (1.6-fold, P<0.01). Carvedilol reduced LVH by 20%. This finding was accompanied by a decrease of laminin, fibronectin, collagen I and III in vivo. Collagen I/III and fibronectin were increased in fibroblasts of AS v sham rats (P<0.0001, each). Carvedilol reduced collagen I, III and fibronectin by 40/60/35% (0.1 ; P<0.001) irrespective of LVH. Carvedilol had no effects on collagen IV and laminin. Carvedilol dose-dependently reduced the proliferation rate by 20% at 0.1 (P<0.0001). Metoprolol and prazosin had no effect on the expression of extracellular matrix proteins and on the proliferation of the cells of either origin. Interferonblunted the proliferation rate of cultured fibroblasts and lead to a significant decrease in extracellular matrix deposits. These results indicate that the effects of carvedilol may be due to the antiproliferative or antioxidative properties of this unselective beta-adrenergic receptor antagonist. These changes of the extracellular matrix represent a new mechanism of carvedilol that may contribute to the observed beneficial effects in congestive heart failure.
Brazilian Journal of Medical and Biological Research, 2008
The present investigation was undertaken to study the effect of β-blockers and exercise training on cardiac structure and function, respectively, as well as overall functional capacity in a genetic model of sympathetic hyperactivity-induced heart failure in mice (α 2A /α 2C ArKO). α 2A /α 2C ArKO and their wild-type controls were studied for 2 months, from 3 to 5 months of age. Mice were randomly assigned to control (N = 45), carvedilol-treated (N = 29) or exercise-trained (N = 33) groups. Eight weeks of carvedilol treatment (38 mg/kg per day by gavage) or exercise training (swimming sessions of 60 min, 5 days/week) were performed. Exercise capacity was estimated using a graded treadmill protocol and HR was measured by tail cuff. Fractional shortening was evaluated by echocardiography. Cardiac structure and gastrocnemius capillary density were evaluated by light microscopy. At 3 months of age, no significant difference in fractional shortening or exercise capacity was observed between wild-type and α 2A / α 2C ArKO mice. At 5 months of age, all α 2A /α 2C ArKO mice displayed exercise intolerance and baseline tachycardia associated with reduced fractional shortening and gastrocnemius capillary rarefaction. In addition, α 2A /α 2C ArKO mice presented cardiac myocyte hypertrophy and ventricular fibrosis. Exercise training and carvedilol similarly improved fractional shortening in α 2A / α 2C ArKO mice. The effect of exercise training was mainly associated with improved exercise tolerance and increased gastrocnemius capillary density while β-blocker therapy reduced cardiac myocyte dimension and ventricular collagen to wildtype control levels. Taken together, these data provide direct evidence for the respective beneficial effects of exercise training and carvedilol in α 2A /α 2C ArKO mice preventing cardiac dysfunction. The different mechanisms associated with beneficial effects of exercise training and carvedilol suggest future studies associating both therapies.
β-Adrenergic signal transduction following carvedilol treatment in hypertensive cardiac hypertrophy
Cardiovascular Research, 1998
Objective: Treatment with the b-blocker carvedilol leads to an improvement of outcome and ejection fraction in heart failure. These effects occur without affecting the number of b-adrenergic receptors, as determined in right ventricular biopsies from patients with heart failure. This study was aimed at investigating the effects of carvedilol on b-adrenergic signal transduction alterations in a model of left ventricular pressure overload, which is characterized by sympathetic activation and a desensitized b-adrenergic signal transduction. Methods: Transgenic rats with overexpression of renin [TG(mREN2)27] were treated with carvedilol (30 mg / kg) or held under control 125 conditions and were compared with Sprague-Dawley rats. Myocardial b-adrenoceptors (I-labeled iodocyanopindolol binding), Gia (pertussis toxin labeling), Gsa-activity (reconstitution into cyc2S49 membranes) and adenylyl cyclase activity were measured. Blood pressure and heart rate, increase in heart rate during sacrifice and pressure rate products were determined. Results: b-Adrenoceptors were downregulated and Gia-protein levels were significantly increased, producing a desensitization of basal, isoprenaline-and guanine nucleotide-stimulated adenylyl cyclase activity compared to controls. Carvedilol reduced heart rate, blood pressure and pressure rate product in TG(mREN2)27. Carvedilol did not restore biochemical alterations, but even further reduced b-adrenoceptor numbers and adenylyl cyclase. It exhibited a two affinity state, guanine nucleotide-sensitive binding to cardiac b-adrenergic receptors similar to isoprenaline but different from metoprolol. Conclusions: Carvedilol did not restore b-adrenergic signal transduction at concentrations producing antiadrenergic effects in vivo. This effect might be due to an atypical guanine nucleotide-dependent interaction with b-adrenergic receptors. Thus, ancillary properties could explain the recently reported beneficial effects in patients with heart failure independent from an upregulation of b-adrenergic receptors.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2002
Metaiodobenzylguanidine (MIBG) is a reliable marker for the detection of cardiac adrenergic neuronal damage in heart failure. The cardioprotective properties of carvedilol, a vasodilating beta-adrenoceptor-blocking agent, were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Twenty-eight days after immunization, surviving rats (41/55, or 75%) were divided into 2 groups treated with carvedilol, 2 mg/kg/d (group C, n = 19), or vehicle alone (0.5% methylcellulose, group V, n = 22). After oral administration for 2 mo, heart weight, heart rate, left ventricular end-diastolic pressure (LVEDP), and myocardial fibrosis were measured and compared with those in untreated rats (group N, n = 19). Myocardial uptake of (125)I-MIBG (differential absorption ratio) in the left ventricle was measured by autoradiography at 10, 30, or 240 min after tracer injection. Four (18%) of 22 rats in group V died between days 28 and 84 after immunization. None of the rats in group C...
PLoS ONE, 2013
The use of b-blockers is mandatory for counteracting heart failure (HF)-induced chronic sympathetic hyperactivity, cardiac dysfunction and remodeling. Importantly, aerobic exercise training, an efficient nonpharmacological therapy to HF, also counteracts sympathetic hyperactivity in HF and improves exercise tolerance and cardiac contractility; the latter associated with changes in cardiac Ca 2+ handling. This study was undertaken to test whether combined b-blocker and aerobic exercise training would integrate the beneficial effects of isolated therapies on cardiac structure, contractility and cardiomyocyte Ca 2+ handling in a genetic model of sympathetic hyperactivity-induced HF (a 2A /a 2C -adrenergic receptor knockout mice, KO). We used a cohort of 5-7 mo male wild-type (WT) and congenic mice (KO) with C57Bl6/J genetic background randomly assigned into 5 groups: control (WT), saline-treated KO (KOS), exercise trained KO (KOT), carvedilol-treated KO (KOC) and, combined carvedilol-treated and exercise-trained KO (KOCT). Isolated and combined therapies reduced mortality compared with KOS mice. Both KOT and KOCT groups had increased exercise tolerance, while groups receiving carvedilol had increased left ventricular fractional shortening and reduced cardiac collagen volume fraction compared with KOS group. Cellular data confirmed that cardiomyocytes from KOS mice displayed abnormal Ca 2+ handling. KOT group had increased intracellular peak of Ca 2+ transient and reduced diastolic Ca 2+ decay compared with KOS group, while KOC had increased Ca 2+ decay compared with KOS group. Notably, combined therapies re-established cardiomyocyte Ca 2+ transient paralleled by increased SERCA2 expression and SERCA2:PLN ratio toward WT levels. Aerobic exercise trained increased the phosphorylation of PLN at Ser 16 and Thr 17 residues in both KOT and KOCT groups, but carvedilol treatment reduced lipid peroxidation in KOC and KOCT groups compared with KOS group. The present findings provide evidence that the combination of carvedilol and aerobic exercise training therapies lead to a better integrative outcome than carvedilol or exercise training used in isolation.
Mechanisms of Carvedilol Action in Human Congestive Heart Failure
Hypertension, 2001
The precise mechanism by which -adrenoceptor blockers exert their beneficial actions in patients with heart failure remains unclear. Several possibilities have been proposed, including heart rate reduction, 2-adrenoceptormediated modulation of catecholamine release, antagonism of the receptor-mediated toxic actions of norepinephrine on the myocardium, and favorable effects on myocardial energetics. In the present study we evaluated the effect of 3 months of carvedilol therapy on hemodynamics, total systemic and cardiac norepinephrine spillover (isotope dilution method), and myocardial metabolism (myocardial oxygen consumption and carbon dioxide release) in 10 patients with severe congestive heart failure. Although carvedilol treatment was associated with a significant improvement in left ventricular ejection fraction (17Ϯ1% to 28Ϯ3%; PϽ0.01) and left ventricular stroke work (87Ϯ13 to 119Ϯ21 g ⅐ m per beat; PϽ0.05), this effect was unrelated to changes in total systemic or cardiac norepinephrine spillover. The rise in left ventricular stroke work was accompanied by a modest rise in myocardial oxygen consumption per beat (0.33Ϯ0.04 to 0.42Ϯ0.04; Pϭ0.05), although contractile efficiency was unchanged. The favorable effects of carvedilol on ventricular function in the failing heart are not explained by alterations in norepinephrine release or by changes in myocardial contractile efficiency.
Naunyn-Schmiedeberg's Archives of Pharmacology
The current study aimed to investigate the cardiotoxic effect of dexamethasone-high-dose in rats, the therapeutic effect of carvedilol and the role of α1-adrenergic receptor (α1AR). The experiment involved 6 groups: control, dexamethasone (10 mg/kg), carvedilol (10 mg/kg), phenylephrine (1 mg/kg), phenylephrine plus carvedilol and propranolol (30 mg/kg). Drugs and vehicles were given for 7 days. Dexamethasone was given with the drugs in the last 4 groups. On the 8th-day and after overnight fasting, serum and cardiac samples were collected. Serum levels of cardiac troponin I and creatine kinase–myoglobin as well as cardiac levels of diacylglycerol, malondialdehyde, kinase activity of Akt, transforming growth factor-β, Smad3 and alpha smooth muscle actin were measured. Cardiac samples were also used for histopathological examination using hematoxylin–eosin and Sirius red stains, in addition to immunohistochemical examination using β-arrestin2 antibody. Dexamethasone induced cardiac in...
2008
β-blockers, as class, improve cardiac function and survival in heart failure (HF). However, the molecular mechanisms underlying these beneficial effects remain elusive. In the present study, metoprolol and carvedilol were used in doses that display comparable heart rate reduction to assess their beneficial effects in a genetic model of sympathetic hyperactivity-induced HF (α 2A /α 2C -ARKO mice). Five month-old HF mice were randomly assigned to receive either saline, metoprolol or carvedilol for 8 weeks and age-matched wild-type mice (WT) were used as controls. HF mice displayed baseline tachycardia, systolic dysfunction evaluated by echocardiography, 50% mortality rate, increased cardiac myocyte width (50%) and ventricular fibrosis (3-fold) compared with WT. All these responses were significantly improved by both treatments. Cardiomyocytes from HF mice showed reduced peak [Ca 2+ ] i transient (13%) using confocal microscopy imaging. Interestingly, while metoprolol improved [Ca 2+ ] i transient, carvedilol had no effect on peak [Ca 2+ ] i transient but also increased [Ca 2+ ] transient decay dynamics. We then examined the influence of carvedilol in cardiac oxidative stress as an alternative target to explain its beneficial effects. Indeed, HF mice showed 10-fold decrease in cardiac reduced/oxidized glutathione ratio compared with WT, which was significantly improved only by carvedilol treatment. Taken together, we provide direct evidence that the beneficial effects of metoprolol were mainly associated with improved cardiac Ca 2+ transients and the net balance of cardiac Ca 2+ handling proteins while carvedilol preferentially improved cardiac redox state.