s-nitro-n-acetylpenicillamine and Hypertrophy

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

Blood flow participates in vascular remodeling during development and growth by regulating cell apoptosis and proliferation. However, its significance in the development of vascular hypertrophy and vascular remodeling in hypertensive patients is not known. We investigated how changing blood flow through the common carotid artery (CA) of young adult rats rendered hypertensive via aortic coarctation affects CA hypertrophy and/or remodeling responses to hypertension. Blood flow was reduced by approximately 50% as a result of ligation of the external CA immediately after hypertension was induced, and the effects of that procedure were compared with those in similarly treated normotensive rats. Reducing blood flow in the hypertensive animals markedly augmented the development of CA hypertrophy over the ensuing 14 days by increasing the vessel wall cross-sectional area. In those animals, CA lumen size was unaltered by reducing blood flow, as was CA structure in normotensive animals. The greater hypertrophy in the hypertensive animals with reduced blood flow was associated with enhanced smooth muscle cell (SMC) proliferation 3 days after the hemodynamic changes were induced. There also appeared to be more extensive remodeling of the endothelium in the hypertensive animals with normal flow; this was indicated by the greater frequency of apoptotic endothelial cells at that time. This reduction in blood flow also attenuated endothelial cell nitric oxide synthase expression in hypertensive animals but not in normotensive animals. Severe reductions in blood flow ( approximately 90%) were required to reduce endothelial cell nitric oxide synthase in the normotensive animals. Increasing CA nitric oxide levels by perivascular application of S-nitroso-N-acetylpenicillamine (SNAP) to the CAs of hypertensive animals with reduced endothelial cell nitric oxide synthase attenuated the greater SMC proliferation. Thus, reduced blood flow in hypertensive animals promotes hypertrophy by enhancing SMC proliferation via mechanisms that reduce the inhibitory effects of nitric oxide on SMC proliferation.

Topics: Animals; Apoptosis; Body Weight; Carotid Arteries; Cell Division; Fibroblast Growth Factor 2; Hemodynamics; Hypertension; Hypertrophy; Male; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Penicillamine; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Regional Blood Flow