Myocardial Protection Afforded by Nicorandil and Ischaemic Preconditioning in a Rabbit Infarct Model In Vivo

Abstract

We previously showed that preoperative nicorandil, a hybrid potassium channel opener and nitrate compound, conferred cardioprotective effects in a hypoxia/reoxygenation model of isolated human atrial muscle by using functional recovery as an end point, and that ischaemic preconditioning surprisingly abolished the protection afforded by nicorandil. In view of this paradoxic result, this study was undertaken to assess whether ischaemic preconditioning influences any protective effect of nicorandil by using infarct size as an end point. In addition, we investigated the underlying mechanisms of the protective action of nicorandil. Rabbits underwent a midline sternotomy under anaesthesia. A left coronary branch was occluded for 30 min followed by 120 min of reperfusion. Nicorandil (100 microg/kg bolus + 10 microg/kg/min) was given intravenously 30 min before coronary occlusion and continued to the time of reperfusion (early treatment) or 5 min before reperfusion and continued throughout reperfusion (late treatment). Ischaemic preconditioning was achieved by a single episode of 5-min coronary occlusion followed by 10-min reperfusion before the 30-minute occlusion in the presence or absence of nicorandil. Risk volume and infarct volume were determined by fluorescent microspheres and tetrazolium staining, respectively. Early treatment with nicorandil conferred a significant decrease in percentage of infarct size within the risk zone (24.9 +/- 2.9%) when compared with control (39.2 +/- 4.3%; p < 0.01). Late treatment with nicorandil had no effect on infarct size (43.5 +/- 3.4%). Ischaemic preconditioning also resulted in significant reduction in infarct size (13.4 +/- 4.3%; p < 0.01 vs. control). The combination of ischaemic preconditioning with nicorandil (early treatment) showed an intermediate protective efficacy between early treatment with nicorandil alone and ischaemic preconditioning alone (18.1 +/- 4.2%; p < 0.01 vs. control). Nitroglycerin (10 microg/kg bolus + 1 microg/kg/kg/min, i.v.) given before and during ischaemia tended to reduce infarct size, but the effect was not statistically significant (28.9 +/- 2.9%; p > 0.05 vs. control). Although an adenosine triphosphate (ATP)-sensitive potassium channel blocker, 5-hydroxydecanoate (5 mg/kg, i.v.) by itself had no effect on infarct size (38.8 +/- 3.6%), the protective effect of nicorandil was abolished by 5-hydroxydecanoate (37.7 +/- 5.8%; p < 0.05 vs. early treatment of nicorandil). There were no differences in area at risk or haemodynamics between groups. Our results show that nicorandil has a protective effect against myocardial infarction in our rabbit model when infused before and during ischaemia, but not during reperfusion, and the protective effect is abolished by an ATP-sensitive potassium channel blocker. Furthermore, the addition of ischaemic preconditioning does not detrimentally influence the effect of nicorandil. This suggests that nicorandil can confer an infarct-limiting effect by opening of ATP-sensitive potassium channels with or without intermi...

Nicorandil, a Hybrid Between Nitrate and ATP-Sensitive Potassium Channel Opener, Preconditions Human Heart to Ischemia During Percutaneous Transluminal Coronary Angioplasty

“…Its cardioprotective action has been reported in various animal models 17,18 and in humans. [19][20][21][22][23][24][25] The present study investigated whether or not nicorandil affects ischemic preconditioning during PTCA.…”

Cardioprotective Effects of Sarcolemmal and Mitochondrial K-ATP Channel Openers in an Experimental Model of Autoimmune Myocarditis

“…Cardioprotection by the use of K-ATP channel openers: The cardioprotective effect of Nic is known to be associated with a pharmacological preconditioning effect in acute ischemia. 3,20,21) Although two possible mechanisms for this cardioprotective effect have been discussed, a reduction in the intracellular calcium overload by shortening the action potential duration through sarcolemmal K-ATP channel opening and the protection of mitochondrial function by opening the mitochondrial K-ATP channels, the latter has been more emphasized in recent reports because the effect of Nic on mitochondrial K-ATP channels is much stronger than that on sarcolemmal K-ATP channels. [21][22][23] Therefore, Nic is now mainly viewed as a mitochondrial K-ATP channel opener, at least at the clinical dose.…”

“…This result indicates that shortening the myocardial action potential duration in the acute phase of myocardial injury may result in later myocardial protection possibly through the reduction in the intracellular calcium overload. 4,20,21) In contrast, Nic affected neither the myocarditis nor MAPD in the acute phase, but the Nic treatment resulted in better ventricular function in the chronic phase. Because the redox state of the mitochondria improved in the EAM+Nic groups in comparison with the control EAM group, protection of the mitochondrial function during the acute phase seemed to be the mechanism of the cardioprotection by Nic, similar to the acute ischemia model.…”

Nicorandil Improves Post-Ischemic Myocardial Dysfunction in Association With Opening the Mitochondrial K_ATP Channels and Decreasing Hydroxyl Radicals in Isolated Rat Hearts

“…However, previous studies have shown that antioxidant drugs improve post-ischemic cardiac dysfunction in isolated hearts. 22,23 Therefore, because nicorandil has been reported to have many beneficial effects, such as opening the mitochondrial KATP channels, 4,5 inhibiting apoptosis, 24 inhibiting platelet aggregation, 25 direct preservation of mitochondrial function, 26 and coronary capillary architecture and volume, 27 besides free radical scavenging effects, it is still difficult to say whether the decrease in 2,3-DHBA concentration is the main cause of the attenuation of ischemia -reperfusion injury.…”