Experiments were designed to assess whether (1)
nicorandil given before global low-flow
ischemia or (2) included in low-flow continuous
cardioplegia improved the recovery of cardiac function in the isolated rat heart. The first investigated the effect of
nicorandil (2, 10, or 100 mumol/L), given for 3 minutes before 30 minutes of normothermic global
ischemia, on recovery after 30 minutes of reperfusion. In aerobically perfused hearts, doses of 10 and 100 mumol/L significantly increased coronary flow; the dose of 100 mumol/L exerted a negative inotropic effect. These doses shortened the time to contractile arrest (282 +/- 18 and 276 +/- 22 seconds versus 354 +/- 16 seconds in the control hearts with unmodified
ischemia; p < 0.05 in both instances).
Nicorandil also improved the postischemic recovery of coronary flow (79.1% +/- 1.7% and 78.0% +/- 1.6%, respectively, versus 71% +/- 1.8%; p < 0.05). However, there was no significant improvement in recovery of contractile function,
creatine kinase leakage, or tissue
adenosine triphosphate and
creatine phosphate contents. Second, pretreatment with
nicorandil (10 mumol/L) was shown to increase susceptibility of the hearts to reperfusion-induced
ventricular fibrillation from 0% (n = 8) in control hearts to 50% in the
drug-treated group (p < 0.05). Third,
nicorandil (10 mumol/L) was added to cardioplegic and noncardioplegic solutions infused into the coronary tree throughout 100 minutes of low-flow (0.7 ml/min)
ischemia: in eight of nine control hearts electrical activity was maintained throughout, whereas in all
nicorandil-treated hearts electrical activity was suppressed for at least part of the time.
Nicorandil also reduced the prevalence of
ischemic contracture to 0% during continuous infusion of
cardioplegic solution (compared with 30% in
nicorandil-free control hearts) and improved the recovery of contractile function after 40 minutes of reperfusion. Thus, in the noncardioplegia groups, left ventricular developed pressure recovered to 77.8% +/- 4.0% versus 51.7% +/- 2.6% in control hearts (p < 0.05) and in the
cardioplegia groups to 96.2% +/- 4.2% versus 79.7% +/- 5.5% (p < 0.05). Ventricular compliance (the ventricular volume required to achieve a left ventricular end-diastolic pressure of 4 mm Hg) was better preserved in the
nicorandil-containing noncardioplegia group (133 +/- 6 microliters) than in the control group (88 +/- 10 microliters; p < 0.05). In conclusion,
nicorandil has been shown to (1) reduce
ischemic contracture, (2) lessen the effects of ischemic arrest, and (3) improve the postischemic recovery of contractile function. In this species and preparation it may, however, enhance vulnerability to reperfusion-induced arrhythmias.