Evidence for enhanced eNOS function in coronary microvessels during the second window of protection

Abstract

Nitric oxide (NO) derived from endothelial NO synthase (NOS) (eNOS) has been identified as a trigger for the second window of protection (SWOP), but its role as a mediator during the SWOP is a matter of debate. Eighteen mongrel dogs were chronically instrumented to measure left ventricular function, coronary blood flow, and wall thickening. Myocardial preconditioning was induced by 10 min coronary artery occlusion. After 24 h of reperfusion (during the SWOP), the hearts were excised. Coronary microvessels were isolated and incubated in presence of 1) the endothelium-dependent agonists carbachol and bradykinin, 2) the calcium ionophore A23187, and 3) the angiotensin-converting enzyme (ACE) inhibitors enalaprilat and ramiprilat. Nitrite, a metabolite of NO, was measured. Under baseline conditions, nitrite production in microvessels from SWOP was 30% higher than that from normal (96 +/- 4 vs. 74 +/- 3 pmol/mg, P < 0.01, respectively). Nitrite production in response to carbachol, bradykinin, and A23187 was also enhanced in microvessels from SWOP (P < 0.05). These enhanced responses were abolished by N(G)-nitro-l-arginine methyl ester (l-NAME) or the endothelial receptor-specific antagonists atropine and HOE-140. The level of eNOS protein in the SWOP myocardium was twofold higher than that in the non-SWOP myocardium. Nitrite production in response to the ACE inhibitors was greater in microvessels from SWOP. These effects were blocked by l-NAME, HOE-140, or dichloroisocoumarin (which inhibits kinin formation). We found that a brief ischemic episode induced delayed, enhanced NO production in coronary microvessels and an upregulation of eNOS protein. These findings suggest that eNOS is a mediator during the SWOP. The ability of ACE inhibitors to enhance NO release during the SWOP points to an additional clinical application for these drugs.

Persistance et voie de l’inhibition de la production de superoxyde par les neutrophiles induite par isoflurane

“…The baseline and post-isoflurane values for systemic hemodynamic and myocardial variables are consistent with previous findings in conscious instrumented dogs in a relaxed state. [24][25][26] The hemodynamic findings during isoflurane administration in the present study conform to previous work in canine models, which have indicated that 1 MAC isoflurane causes hypotension and has negative inotropic and coronary vasodilating effects. 25,27,28 Coronary vasodilation was suggested by an uncoupling of coronary blood flow from the prevailing myocardial oxygen demands, with the result that coronary venous PO 2 increased markedly.…”

Preconditioning with periodic acceleration (pGz) provides second window of cardioprotection

“…Two distinct windows of preconditioning cardioprotection have been previously described: an early phase of cardioprotection and a late phase or second window of protection (SWOP) (Bell and Yellon, 2001;Bolli, 2007;Kim et al, 2007). In Fig.…”

“…pGz applied to rats has been shown to produce vasodilatation, increase eNOS expression and increases its phosphorylation Wu et al, 2009). eNOS has been shown to be cardioprotective (Kim et al, 2007;Rastaldo et al, 2007;Szelid et al, 2010;Talukder et al, 2010). Thus, pGz has the potential to provide preconditioning cardioprotection in an in-vivo animal model of regional ischemia reperfusion (I/R) injury, such as acute myocardial infarction.…”

The Coronary Circulation as a Target of Cardioprotection

“…140 Vice versa, delayed ischemic preconditioning 24 hours before the sustained myocardial ischemia/reperfusion increases the activity of endothelial nitric oxide synthase, which mediates preservation of coronary vasodilator response to acetylcholine, carbachol, and bradykinin. 141,142 Reactive oxygen species formation, although detrimental acutely for endothelium-dependent coronary vasodilation in response to acetylcholine, is mandatory for the delayed protection by ischemic preconditioning. 143 Ischemic preconditioning not only preserves endothelium-dependent 88 Copyright ©1995, the American Physiological Society.…”