The results indicate that isoflurane-induced cardioprotection in stunned myocardium is partially mediated by adenosine type 1 receptor activation and is accompanied by decreases in endogenous adenosine release.
The bioassay technique was utilized to quantitate endothelium-derived relaxing factor (EDRF) released from perfused donor segments of control and diabetic rat aorta. In the presence of indomethacin, perfusates of donor segments with endothelium were allowed to superfuse recipient detector rings of normal rat aorta without endothelium. Under basal conditions, relaxations of the bioassay rings to perfusates of control and diabetic donor segments were similar. Perfusion of donor segments with acetylcholine produced relaxation of bioassay rings, which was decreased from endothelial perfusion of diabetic donor segments. These relaxations were inhibited by addition of methylene blue to the detector ring or by perfusion of donor segments with nitro-L-arginine. Infusion of superoxide dismutase (SOD) at a site proximal to the donor segment normalized relaxations induced by acetylcholine addition to diabetic donors. In contrast, infusion of SOD distal to the donor had no effect on acetylcholine-stimulated relaxations of detector rings from control donors while attenuating, paradoxically, the relaxations of detector rings from diabetic donors. These results suggest that diabetic rat aortas release similar levels of EDRF in response to acetylcholine, but the action of EDRF arising from diabetic donors is attenuated by enhanced release of oxygen-derived free radicals, which limits EDRF-mediated relaxation of vascular smooth muscle.
The cardioprotective effect of myocardial preconditioning (PC) to reduce infarct size has been shown to last approximately 90 min (early PC), and then a second window of protection (SWOP or late PC) appears 24 h later. Although much work has been done to characterize early PC, little has been done to investigate potential mediators of SWOP. To that end, we have used monophosphoryl lipid A (MLA), a nontoxic endotoxin derivative, to produce SWOP and have examined the role of ATP-sensitive potassium (KATP) channels in mediating its cardioprotection. Adult mongrel dogs were given MLA (3, 10, or 35 micrograms/kg i.v.) 24 h before a 60-min left anterior descending coronary artery occlusion and 3 h of reperfusion. After reperfusion, the hearts were stained for myocardial infarction with triphenyltetrazolium. MLA produced a dose-dependent reduction in infarct size that was associated with an enhanced shortening of the monophasic action potential duration during early ischemia. To further examine the role of KATP channels, animals were treated with MLA (35 micrograms/kg) and 24 h later were administered either glibenclamide (0.3 mg/kg i.v.) or 5-hydroxydecanoate (7.5 mg/kg intracoronary over 20 min), two structurally distinct KATP-channel antagonists. Both glibenclamide and 5-hydroxydecanoate abolished the cardioprotection produced by MLA. These results demonstrate that the cardioprotective effect of late PC produced by MLA is dependent on functional KATP channels and is the first study to suggest that late PC may be the result of an increased KATP current during ischemia.
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