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 intermittent ischaemia, as may happen in patients with
unstable angina.