Decreased Nitric Oxide Availability in Normotensive and Hypertensive Rats With Failing Hearts After Myocardial Infarction

Abstract

Abstract-Endothelial NO synthase, being deficient in arginine and/or tetrahydrobiopterin, produces in addition to NO a significant concentration of superoxide (O 2 Ϫ ). We investigated whether such an imbalance between O 2 Ϫ and NO production is present in dysfunctional aortas of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) with failing hearts after myocardial infarction. Heart failure was induced by permanent occlusion of the left coronary artery, resulting in a large infarction of the free left ventricular wall. Eight weeks after myocardial infarction, when WKY and SHR had compensated heart failure and congestive heart failure, respectively, calcium ionophore-induced NO release (assessed by a NO-sensitive microsensor) from aortic endothelial cells was significantly reduced from 478Ϯ48 to 216Ϯ16 nmol/L and 693Ϯ131 to 257Ϯ53 nmol/L in WKY and SHR, respectively. Concomitantly, significant increases in calcium ionophore-stimulated O 2 Ϫ production (assessed by an electrochemical sensor) could be observed in aortic endothelial cells from infarcted WKY rats (22Ϯ3.2 versus sham, 10.1Ϯ1.2 nmol/L) and SHR (102Ϯ8 versus sham, 67Ϯ5 nmol/L). A dramatic increase in endothelial peroxynitrite concentration (chemiluminescence method) from 35Ϯ4 to 90Ϯ3 nmol/L for WKY and from 60Ϯ5 to 170Ϯ10 nmol/L for SHR also was detected. Thus, the markedly decreased NO availability probably caused by impaired endothelial NO synthase activity with enhanced O 2 Ϫ and peroxynitrite production appears to be attributable to endothelial dysfunction in normotensive rats with chronic heart failure and especially in hypertensive rats with severe congestive heart failure. Key Words: heart failure Ⅲ endothelium Ⅲ nitric oxide Ⅲ rats, spontaneously hypertensive Ⅲ rats, WKY N umerous studies showed that impaired endotheliumdependent vasodilation and cardiac dysfunction in heart failure (HF) appear to be attributable to decreased endothelial NO synthesis and/or possibly to increased NO degradation by enhanced generation of superoxide (O 2 Ϫ ). Large deficiencies of endothelial NO synthase (eNOS) mRNA and protein as well as basal and stimulated NO production were observed in aortic endothelial cells 1 and cardiac microvessels 2 from conscious dogs with pacing-induced overt congestive heart failure (CHF). In the same animal model at the onset of cardiac decompensation, reduced basal cardiac NO production was associated with a fall of cardiac contractility and an elevated left ventricular end-diastolic pressure. 3 Similarly, impaired basal and stimulated NO productions, which were indirectly assessed by vascular cyclic GMP, were demonstrated in aortas 4 and pulmonary arteries 4,5 from Wistar-Kyoto rats (WKY) with chronic HF after myocardial infarction (MI). In comparison, a normal acetylcholine-induced relaxation with reduction of basal NO release was found in small mesenteric arteries from this rat HF model. 6,7 Conflicting data exist with regard to eNOS expression and activity in human beings with chronic HF. Increased cardiac express...

Increased superoxide production causes coronary endothelial dysfunction and depressed oxygen consumption in the failing heart

“…In addition, increased free radical production by the failing heart might be expected to oxidize tetrahydrobiopterin to result in uncoupling of NOS to produce O 2 Ϫ ⅐ rather than NO (35). The present data demonstrating O 2 Ϫ ⅐ effects on resistance vessel function in the setting of CHF are similar to previous studies using isolated aortic ring preparations that demonstrated impaired conduit vessel endothelial function in CHF animals that was associated with increased O 2 Ϫ ⅐ and ONOO Ϫ production (35,42). In those studies, treatment with SOD improved endothelium-dependent vasodilation and normalized cGMP responses to the NO donor sodium nitroprusside, indicating that endothelial dysfunction resulted from inactivation of NO by O 2 Ϫ ⅐ (3).…”

“…Several investigators have reported that superoxide (O 2 Ϫ ⅐) production is increased both in myocardial mitochondria (19) and in coronary arteries (3,4,42) …”

Natriuretic Peptide Receptor-C Attenuates Hypertension in Spontaneously Hypertensive Rats

“…47 In the present study, we demonstrate that the VSMC and aorta from SHRs exhibit decreased levels of NO which may be because of the decreased expression of eNOS as well as to the enhanced levels of O 2 − . In this regard, the decreased expression of eNOS and NO has been reported in cardiac myocyte and vascular smooth muscle of hypertensive animals 35,48,49 and suggests that the increased BP in SHRs may also be attributed to the decreased levels of NO. Furthermore, eNOS knockout mice were shown to exhibit increased BP.…”

Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase

“…Coronary and peripheral endothelial bioavailability of NO is severely reduced after experimental MI [11][12][13] and in patients with heart failure. 14 -17 In addition to the impairment of endothelium-dependent vasodilation, several mechanisms have now been identified whereby reduced eNO bioavailability may contribute to the pathophysiology of heart failure.…”

“…10 Interestingly, there is evidence that reduced eNO availability may play an important role in the pathophysiology of heart failure both after experimental MI [11][12][13] and in patients with heart failure. 14 -17 Inhibition of eNO production results in impaired endothelium-dependent vasodilation, reduced myocardial neovascularization, 18 and impaired vascular endothelial growth factor-induced mobilization of endothelial progenitor cells (EPCs).…”