Calcium antagonists show two modes of protection in ischemic heart failure

Retrogradely perfused, isovolumically beating, paced rat hearts were subjected to 30 min of global ischemia in the absence and presence of nifedipine, verapamil, bepridil and quaternary bepridil at a concentration ranging from 3 to 10,000 nmol/l. Under constant pressure conditions, the arrest of coronary flow and the reduction of ventricular contraction during global ischemia were readily reversible and quickly returned at reperfusion. During ischemia, however, a diastolic contracture developed, which was slowly reversible upon reperfusion. The calcium antagonists studied appeared to delay and diminish in a concentration-dependent way the diastolic contracture during ischemia. Furthermore, they accelerated the reduction of this contracture at reperfusion. Nifedipine, bepridil and quaternary bepridil showed a 100 to 1000 times higher potency in accelerating the recovery of the diastolic contracture during the reperfusion phase than in reducing the development of diastolic tension during the ischemic period itself, whereas verapamil hardly discriminated these two phases. When the hearts were reperfused with nifedipine under constant flow conditions, reduction of the diastolic contracture during ischemia could still be observed, but the accelerated reduction of end-diastolic pressure during reperfusion was no longer present. The results are discussed in relation to the energy saving, negative inotropic activity of the drugs before the ischemic period and the strong coronary vasodilation, which seems to be involved in the protective activity of the drugs, especially during reperfusion.