Nicorandil induces late preconditioning against myocardial infarction in conscious rabbits

Abstract

Nicorandil has been shown to induce an infarct-limiting effect similar to that induced by the early phase of ischemic preconditioning (PC). The goals of this study were to determine whether nicorandil induces a delayed cardioprotection that is analogous to the late phase of ischemic PC and, if so, whether nicorandil-induced late PC is associated with upregulation of cardioprotective proteins. Chronically instrumented, conscious rabbits received vehicle (intravenous normal saline; control group, n = 10), nicorandil (100 μg/kg bolus + 30 μg·kg–1·min–1 iv for 60 min; nicorandil group, n = 10), or ischemic PC (6 cycles of 4-min coronary occlusion/4-min reperfusion; PC group, n = 8). Twenty-four hours later, rabbits underwent a 30-min coronary occlusion, followed by 3 days of reperfusion. Myocardial infarct size was significantly reduced in rabbits pretreated with nicorandil (27.5 ± 5.3% of the risk region) or with ischemia (30.3 ± 4.2%) versus controls (59.1 ± 4.7%, P < 0.05 vs. both). Furthermore, the expression of cyclooxygenase-2 (COX-2) and Bcl-2 was significantly elevated (+38% and +126%, respectively; P < 0.05) in myocardium of rabbits given nicorandil 24 h earlier versus controls. We conclude that nicorandil induces delayed cardioprotection against myocardial infarction similar to that afforded by the late phase of ischemic PC, possibly by upregulating COX-2 and Bcl-2.

GATA-4 Transcription Factor Regulates Cardiac COX-2 Expression Induced by Nicorandil in Left Ventricle of Rats

“…We clearly demonstrated that oral administration of nicorandil significantly increased both COX-2 mRNA and protein, resulting in the increased synthesis of prostaglandin I 2 at 6 h after treatment. These results are comparable with an earlier report that intravenous infusion of nicorandil reduced cardiac infarction in rabbits after ischemia/reperfusion injury and was accompanied by an increase in COX-2 expression 24 h after infusion [9]. Moreover, induction of GATA-4 by nicorandil preceded COX-2 induction.…”

“…Previous reports have indicated that Bcl-2 was upregulated in the myocardium of rabbits subjected to ischemia/reperfusion injury 24 h after dosing with nicorandil [9] and was upregulated by GATA-4 in doxorubicin-treated heart 24 h after doxorubicin treatment [17]. Furthermore, a recent report has indicated that nicorandil inhibited the doxorubicin-induced decrease in Bcl-2 expression [35], while our present data indicated no such effect of nicorandil at 1-6 h after treatment.…”

“…Nicorandil, a K ATP channel opener with nitrate-like activity, has been shown to have cardioprotective effects both in animals [8] and in clinical studies [9] as well as vascular endothelial protective effects [10,11]. Intravenous administration of nicorandil improved regional ventricular function after percutaneous coronary intervention in patients with ischemic heart disease [12], and it also improved the prognosis of patients with stable angina pectoris in the IONA study [13] and the JCAD study [2].…”

“…From these results, it is considered that nicorandil has a preconditioning-like cardioprotective effect against ischemic injury that acts via mitochondrial K ATP channel opening. In addition, Tang et al [9] reported that nicorandil induced cardioprotection against myocardial infarction by upregulating cardioprotective factors COX-2 and Bcl-2 in rabbits. Until now, however, the precise pharmacological profiles of cardioprotective substances induced by nicorandil have not been investigated.…”

Pharmacological Intervention for Prevention of Left Ventricular Remodeling and Improving Prognosis in Myocardial Infarction

“…26,54,55 Although the opening of the K-ATP channels is related to classic or first-window preconditioning, it has also been reported that nicorandil treatment upregulates the expression of cyclooxygenase-2 and Bcl-2 in MI, resulting in delayed cardioprotection similar to that afforded by the late phase of ischemic preconditioning. 56 Reports indicate that intravenous nicorandil treatment ameliorates early functional and clinical problems in patients with AMI. Ito et al 45 investigated whether intravenous nicorandil (6 mg for 24 hours after a 4-mg bolus injection) followed by oral administration of nicorandil would exert beneficial effects on microvascular function and clinical outcomes in a prospective, single-center study including 81 patients with a first anterior AMI who received successful PCI within 12 hours after symptom onset.…”