Apoptosis, Coronary Arterial Remodeling, and Myocardial Infarction After Nitric Oxide Inhibition in SHR

Abstract

Abstract-This study was designed to investigate the relationship between apoptosis (programmed cell death) and coronary arterial remodeling in spontaneously hypertensive rats (SHR) following prolonged nitric oxide synthesis inhibition. In addition, we evaluated whether the development of coronary arterial smooth muscular cell apoptosis was related to hemodynamics or to vascular hypertrophy. Three groups of 20-week-old male SHR were investigated: controls, and two groups that received two doses of N G -nitro-L arginine (L-NAME, 50 mg/L and 80 mg/L) each for 3 weeks. Mean arterial pressure and total peripheral resistance index increased whereas cardiac index diminished with L-NAME. Pathohistological study demonstrated increased pericardiac fibrosis and coronary arterial injury score in the L-NAME group in a dose-dependent manner. The high dose of L-NAME (Group 3) produced myocardial infarction in 78% of the rats. The wall:lumen ratio of epicardial coronary arteries was greater in L-NAME treated SHR (0.23Ϯ0.02 versus 0.16Ϯ0.02; PϽ0.05) and was associated with markedly increased apoptosis (15.3Ϯ6 versus 1.9Ϯ1; PϽ0.05) without smooth muscle cell proliferation (PCNA positive cells). Apoptosis occurred predominantly in hypertrophic coronary arterial smooth muscular cells; myocardial infarction and ventricular fibrosis were exacerbated by impaired hemodynamics induced by L-NAME. These data suggest that coronary endothelial dysfunction and myocardial ischemic disease induced by L-NAME were responsible for apoptosis of coronary arterial smooth muscle cells, myocardial fibrosis, and infarction, all pathological findings that are consistent with what may be found in clinical hypertensive heart disease. (Hypertension. 1999;34:609-616.)

Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization

“…NO is an important modulator of blood pressure due to its vasodilatory capability (36,37) and plays a critical role in VEGF-induced angiogenesis and vascular hyperpermeability (38). In addition, several studies have demonstrated that NO is involved in modulation of cell proliferation, differentiation, and apoptosis in the vasculature (39). Furthermore, there is increasing evidence that NO-derived oxidants, such as peroxynitrite, might be important in situ mediators of oxidative injury in experimental models of retinal ischemia (40).…”

Year-Long Antihypertensive Therapy With Candesartan Completely Prevents Development of Cardiovascular Organ Injuries in Spontaneously Hypertensive Rats

“…Therefore, the efficacy of antihypertensive drugs on inhibition of hypertensive tissue injury and preservation of cardiovascular organ function is a matter of primary importance. Several studies have investigated the protective effects of antihypertensive drugs against cardiovascular organ injury using various animal models of hypertension, including mineralocorticoid-salt administration, 1,2) renovascular hypertension, [3][4][5] renal ablation 6,7) and nitric oxide synthase inhibition, 8,9) in which hypertensive organ injury progresses rapidly over a period of several weeks to months. However, this rapid temporal course of organ damage does not accurately reflect the organ damage that occurs over a span of decades in humans with essential hypertension.…”

Apoptosis in the left ventricle of chronic volume overload causes endocardial endothelial dysfunction in rats

“…However, a differential regulation of MMP release and activation in vivo versus in vitro may account for this discrepancy. The inhibition of NO production as well as the degradation of the ECM facilitate apoptosis (36,48,63). Oxidative stress instigates the decrease in endothelial NO availability (10,65) as well as increases the levels of cytokines, growth factors, and neurohormones (11,17,26).…”