cyclic-gmp and Cardiomyopathy--Hypertrophic

Cyclic nucleotide phosphodiesterases (PDE) 3 and 5 regulate cAMP and cGMP signalling in cardiac and smooth muscle myocytes. Important advances in the understanding of the roles of these enzymes have recently been made. PDE3 inhibitors have inotropic and vasodilatory properties, and although they acutely improve haemodynamics in patients with heart failure, they do not improve long-term morbidity and mortality. Although combination therapy with beta-adrenergic receptor antagonists or selective inhibition of specific PDE3 isoforms might result in a more favourable long-term outcome, more clinical data are needed to test this proposition. The role of PDE5 inhibitors in the treatment of cardiac disease is evolving. PDE5 inhibitors cause pulmonary and systemic vasodilation. How these drugs will compare with other vasodilators in terms of long-term outcomes in patients with heart failure is unknown. Recent studies also suggest that PDE5 inhibitors may have antihypertropic effects, exerted through increased myocardial cGMP signalling, that could be of additional benefit in patients with heart failure.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Adrenergic beta-Antagonists; Animals; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Coronary Circulation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Evaluation, Preclinical; Drug Therapy, Combination; Drugs, Investigational; Enzyme Activation; Forecasting; Half-Life; Heart Failure; Humans; Hypertension, Pulmonary; Isoenzymes; Multicenter Studies as Topic; Muscle, Smooth, Vascular; Myocytes, Cardiac; Phosphodiesterase Inhibitors; Phosphorylation; Prospective Studies; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Pulmonary Circulation; Randomized Controlled Trials as Topic; Rats; Treatment Outcome; Vasodilator Agents

This study investigated the role of nitric oxide(NO) in the prevention of myocardial hypertrophic response and its mechanisms. Left ventricular NO content decreases in the pathophysiogenesis of myocardial hypertrophy induced by pressure overload. Endogenous NO may attenuate cardiac hypertrophy induced by pressure overload, independent of cGMP mechanism. Angiotensin II (AII), endothelin-1 (ET-1) and norepinephrine(NE) can inhibit NOS activity and NO production, and induce hypertrophic response in cultured neonatal rat cardiomyocytes; these effects of AII, ET-1 and NE are mediated respectively by AII receptor, ETA receptor and alpha 1-adrenergic receptor; these effects of AII and ET-1 are mediated by PTX-sensitive G protein, while the effects of NE are mediated by PTX-insensitive G protein. eNOS gene is expressed in cultured neonatal rat cardiac myocytes and nonmyocytes. AII, ET-1 and NE can inhibit eNOS gene expression in cardiomyocytes. Exogenous NO can prevent hypertrophic response induced by AII, ET-1 and NE in cardiomyocytes. Both endogenous and exogenous NO can inhibit the expression of proto-oncogene c-fos induced by AII and ET-1, which may be involved in protein kinase C.

Topics: Academic Dissertations as Topic; Angiotensin II; Animals; Cardiomyopathy, Hypertrophic; Cyclic GMP; Endothelin-1; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Norepinephrine; Proto-Oncogene Proteins c-fos; Rats; Ventricular Pressure