Hypercholesterolemia impairs a detoxification mechanism against peroxynitrite and renders the vascular tissue more susceptible to oxidative injury

Previous studies have shown that glutathione (GSH) plays a central role in the protection against peroxynitrite (ONOO-) toxicity. The present study evaluated the changes of the GSH cytoprotective system against ONOO- in hypercholesterolemia and determined the effects of carvedilol, a beta-blocker with free radical-scavenging activity, on these hypercholesterol-induced changes. New Zealand White rabbits were fed either a normal diet, a high-cholesterol diet, or a high-cholesterol diet supplemented with either carvedilol or propranolol. Eight weeks later, the rabbits were killed, and the thoracic aortas were isolated. Total GSH content of aortic tissue, vasorelaxation response of aortic rings to exogenous ONOO-, (NO)-N-. regeneration from ONOO- by aortic homogenate, and ONOO--induced aortic tissue injury were examined. Hypercholesterolemia decreased tissue GSH content (0.52+/-0.08 versus 0.86+/-0.03 mu mol/g in control, P<.01), attenuated the vasorelaxation response to ONOO- (40+/-4.1% versus 76+/-3.2%, P<.01), reduced (NO)-N-. regeneration from ONOO- (387+/-40 versus 662+/-51 pmol, P<.01), and potentiated ONOO--induced vascular tissue injury (37+/-1.3% versus 14+/-2.6% of increase in lactate dehydrogenase release after 3-morpholinosydnonimine exposure, P<.01). Treatment of the hypercholesterolemic rabbits with carvedilol, but not propranolol, significantly preserved tissue GSH content (0.79+/-0.05 mu mol/g, P<.01 versus nontreated hypercholesterolemic rabbits), restored the vasorelaxation to ONOO- (61+/-2%, P<.01), increased (NO)-N-. regeneration from ONOO- (583+/-39 pmol, P<.01), and attenuated ONOO--induced tissue injury (19+/-1.8%, P<.01). These results suggest that hypercholesterolemia impairs the GSH-mediated detoxification mechanism against ONOO- and renders the vascular tissue more susceptible to oxidative injury. Carvedilol, a novel vasodilating beta-blocker with antioxidant activity, significantly preserved this self-defense system and protected tissue from oxidant injury.