© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Effect of classic preconditioning and diazoxide on endothelial function and O2– and NO generation in the post-ischemic guinea-pig heart
sewicz*
M
czewskiDepartment of Clinical Physiology, Medical Centre of Postgraduate Education, Marymoncka 99, 01-813 Warsaw, Poland
*Corresponding author. Tel.: +48-22-8340367; fax: +48-22-8340470. Email address: aberesew{at}cmkp.edu.pl
Objectives: A hypothesis was tested that a reaction product between superoxide (O2–) and nitric oxide (NO) mediates post-ischemic coronary endothelial dysfunction that ischemic preconditioning (IPC) protects the endothelium by preventing post-ischemic cardiac O
– and/or NO formation, and that the opening of the mitochondrial ATP-dependent potassium channel (mKATP) plays a role in the mechanism of IPC. Methods: Langendorff-perfused guinea-pig hearts were subjected either to 30 min global ischemia/30 min reperfusion (IR) or were preconditioned prior to IR with three cycles of either 5 min ischemia/5 min reperfusion or 5 min infusion/5 min wash-out of mKATP opener, diazoxide (0.5 µM). Coronary flow responses to acetylcholine (ACh) and nitroprusside were used as measures of endothelium-dependent and -independent vascular function, respectively. Myocardial outflow of O2– and NO, and functional recoveries were followed during reperfusion. Results: IR impaired the ACh response by approximately 60% and augmented cardiac O2– and NO outflow. Superoxide dismutase (150 U/ml) and NO synthase inhibitor, L-NMMA (100 µM) inhibited the burst of O2– and NO, respectively, and afforded partial preservation of the ACh response in IR hearts. NO scavenger, oxyhemoglobin (25 µM), afforded similar endothelial protection. IPC and diazoxide preconditioning attenuated post-ischemic burst of O2–, but not of NO, and afforded a complete endothelial protection. Diazoxide given after 30-min ischemia increased the O2– burst and was not protective. The effects of IPC and diazoxide preconditioning were not affected by HMR-1098 (25 µM), a selective blocker of plasmalemmal KATP, and were abolished by glibenclamide (0.6 µM) and 5-hydroxydecanoate (100 µM), a nonselective and selective mKATP blocker, respectively. 5-Hydroxydecanoate produced similar effects, whether it was given as a continuous treatment or was washed out prior to IR. Conclusion: The results suggest that in guinea-pig heart: (i) a reaction product between O2– and NO mediates the post-ischemic endothelial dysfunction; (ii) the mKATP opening serves as a trigger of the IPC and diazoxide protection; and (iii) the mKATP opening protects the endothelium in the mechanism that involves the attenuation of the O2– burst at reperfusion.
KEYWORDS Endothelial dysfunction; Nitric oxide; Ischemic preconditioning; Oxygen free radicals; Ischemia; Reperfusion
Time for primary review 30 days
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