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Nicorandil attenuates myocardial dysfunction associated with transient ischemia by opening ATP-dependent potassium
J A Auchampach1, I Cavero, G J Gross
1Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226.
Abstract:
The objective of this study was to determine whether ATP-dependent potassium channel activation is involved in the mechanism by which nicorandil reduces postischemic contractile dysfunction produced by a brief period of ischemia (myocardial stunning). Barbital-anesthetized dogs were subjected to 15-min left anterior descending (LAD) coronary artery occlusion followed by 3-h reperfusion. Saline or nicorandil (100 micrograms/kg + 25 micrograms/kg/min) were infused 15 min before and throughout occlusion with or without addition of the KATP channel antagonist, glibenclamide 0.3 mg/kg as an intravenous (i.v.) bolus. Regional myocardial blood flow was measured by radioactive microspheres, and left ventricular (LV) segment function was measured by sonomicrometry. There were no significant differences between the groups in area-at-risk size or collateral blood flow. In contrast, nicorandil significantly reduced mean aortic blood pressure (BP) and the rate-pressure product (RPP) which persisted throughout the occlusion period. In addition, nicorandil markedly accelerated recovery of segment shortening in the ischemic/reperfused region as compared with control dogs. Pretreatment of dogs with glibenclamide blocked none of the hemodynamic effects of nicorandil, but it did prevent improvement in reperfusion segment function. The small dose of glibenclamide used had no effect on hemodynamics or the degree of stunning. Thus, these results suggest that nicorandil attenuates stunning in anesthetized dogs by a direct cardioprotective effect as a result of KATP channel activation in ischemic myocardium.
Insights
Nicorandil reduces myocardial stunning by activating ATP-dependent potassium channels (KATP). This cardioprotective effect, observed in dogs, enhances recovery of heart function after ischemia, independent of blood pressure changes.
Area of Science:
- Cardiology and Pharmacology
- Myocardial Ischemia and Reperfusion Injury
Background:
- Myocardial stunning, a transient contractile dysfunction post-ischemia, is a significant clinical concern.
- Nicorandil is known to have cardioprotective effects, but its precise mechanism, particularly regarding potassium channels, requires elucidation.
Purpose of the Study:
- To investigate the role of ATP-dependent potassium channel (KATP) activation in nicorandil's mechanism of reducing postischemic myocardial stunning.
- To determine if nicorandil's cardioprotective effects are mediated through KATP channels.
Main Methods:
- Anesthetized dogs underwent 15-minute coronary artery occlusion followed by 3-hour reperfusion.
- Nicorandil was administered with or without the KATP channel antagonist, glibenclamide.
- Regional myocardial blood flow and left ventricular segment function were assessed using radioactive microspheres and sonomicrometry, respectively.
Main Results:
- Nicorandil significantly improved segment shortening recovery in the ischemic/reperfused region compared to controls.
- Glibenclamide pretreatment blocked the functional improvement from nicorandil but did not affect its hemodynamic effects (blood pressure, rate-pressure product).
- No significant differences in area-at-risk size or collateral blood flow were observed between groups.
Conclusions:
- Nicorandil attenuates myocardial stunning in dogs through a direct cardioprotective effect.
- This cardioprotection is mediated by the activation of ATP-dependent potassium channels (KATP) in the ischemic myocardium.
- The findings highlight KATP channel activation as a key mechanism underlying nicorandil's therapeutic benefit in myocardial stunning.