Ischemia-reperfusion selectively impairs nitric oxide-mediated dilation in coronary arterioles: counteracting role of arginase.
A reduction in L-arginine availability has been implicated in the impairment of endothelium-dependent nitric oxide (NO)-mediated vasodilation by ischemia-reperfusion (I/R). However, the mechanisms contributing to dysregulation of the L-arginine pool remain unknown. Because endothelial cells can metabolize L-arginine via two major enzymes, that is, NO synthase (NOS) and arginase, we hypothesized that up-regulation of arginase during I/R reduces L-arginine availability to NOS and thus impairs NO-mediated vasodilation. To test this hypothesis, a local I/R was produced in the porcine heart by occlusion of a small branch of left anterior descending artery for 30 min, followed by reperfusion for 90 min. Arterioles (60-110 microm) isolated from non-ischemic and ischemic regions of subepicardium were cannulated and pressurized without flow for in vitro study. Vessels from both regions developed similar levels of basal tone. Although the dilation of I/R vessels to endothelium-independent agonist sodium nitroprusside was not altered, the endothelium-dependent NO-mediated dilations to adenosine and serotonin were attenuated. I/R not only inhibited arteriolar production of NO but also increased arteriolar arginase activity. Arginase inhibitor alpha-difluoromethylornithine enhanced NO production/dilation in normal vessels and also restored the NO-mediated function in I/R vessels. Treating I/R vessels with L-arginine also restored vasodilations. Immunohistochemical data revealed that I/R up-regulated arginase but down-regulated NOS expression in the arteriolar endothelium. Pretreating the animals with protein synthesis inhibitor cycloheximide prevented I/R-induced arginase up-regulation and also preserved NO-mediated vascular function. These results suggest that one mechanism by which I/R inhibits NO-mediated arteriolar dilation is through increased arginase activity, which limits the availability of L-arginine to NOS for NO production. In addition, the inability of arginase blockade or L-arginine supplementation to completely restore vasodilatory function may be attributable to the down-regulation of endothelial NOS expression.
Hein
Travis W
TW
Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, Texas A&M University System Health Science Center, College Station, TX 77843-1114, USA.
Zhang
Cuihua
C
Wang
Wei
W
Chang
Chiung-I
CI
Thengchaisri
Naris
N
Kuo
Lih
L
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000502:physiology*; D001120:Arginine / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D003331:Coronary Vessels / Q000201:enzymology / Q000503:physiopathology*; D046508:Culture Techniques; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008954:Models, Biological; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D012701:Serotonin / Q000494:pharmacology; D013552:Swine; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D012701:Serotonin; D001120:Arginine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D001119:Arginase; D000241:Adenosine; D000518:Eflornithine