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We have studied the effects of 60 min global ischaemia and 30 min of subsequent reperfusion on the binding of [H]-(+)-PN 200−110 and [H]-(−)-devapamil (desmethoxyverapamil or D888) in rat heart membranes. The hearts were perfused in the Langendorff-mode and pretreated with 1 μmol/l verapamil, 30 nmol/l and 1 μmol/l nifedipine. After 60 min of global ischaemia in the absence of drugs, we found a reduction of [H]-(+)-PN 200-110 binding sites, without changes in the equilibrium dissociation binding constant ( K). After the subsequent reperfusion maximum specific binding ( B) was further reduced, whereas the K remained constant. [H]-devapamil binding sites were influenced to a lower extend and showed only a decrease in B at reperfusion. Pretreatment with 1 μmol/l verapamil completely prevented the changes which were observed for [H]-(+)-PN 200-110. Pretreatment with a low, vasodilating concentration (30 nmol/l) of nifedipine displayed selective protection against the extra reduction in B which was observed during reperfusion. It is concluded that calcium antagonists show protection against the ischaemia-induced loss of dihydropyridine binding sites in relation to their negative inotropic, energy-saving activity. Furthermore, nifedipine at low, vasodilating but not negative inotropic concentrations protects against further reperfusion-induced injury, which protection may be related to an improved flow during reperfusion. [ABSTRACT FROM AUTHOR]

The effects of the stereoisomers and the racemate of the calcium agonist BAY K 8644 and the calcium antagonist nifedipine were studied on the Langendorff-perfused rat heart, subjected to 30 min of global ischaemia. The results show that (-)- and (+/-)-BAY K 8644 induced a strong positive inotropic effect at 100 and 1000 nmol/l and a vasoconstricting effect which was most prominent at 1 and 10 nmol/l, respectively. At higher concentrations the flow reduction was inverted to a flow increase, closely related to the positive inotropic activity. The inotropic status induced by the agonist before the onset of ischaemia was reflected in an accelerated development of the diastolic contracture during ischaemia. During the reperfusion, a complex triphasic effect on the recovery was found, in which probably positive inotropism, vasoconstriction, metabolic and mechanical factors are involved. The (+)-enantiomer of BAY K 8644 behaved as a weak calcium antagonist showing merely vasodilatation, which accelerated the recovery from the ischaemic contracture at reperfusion. The calcium antagonistic, vasodilating effects of the (+)-enantiomer were expressed in the racemate only during the reperfusion phase, where it took an intermediate position between the effects of the (-)- and (+)-enantiomer. In contrast, nifedipine, at negative inotropic - energy saving - concentrations, diminished the height and delayed the development of the energy deprivation-induced left ventricular diastolic contracture during ischaemia. The time needed for recovery from the contracture during reperfusion was significantly shortened already at a 100 times lower, vasodilating concentration of nifedipine.