Calcium antagonists and hypothermia: the temperature dependency of the negative inotropic and anti-ischemic properties of verapamil in the isolated rat heart.

Using an isolated rat heart preparation under both aerobic and ischemic conditions we have characterized the temperature dependency of the slow calcium channel-blocking drug verapamil. In the first series of studies, isolated working rat hearts were subjected to global ischemia at 37 degrees, 34 degrees, 31 degrees, 29 degrees, 27 degrees, 25 degrees, and 20 degrees C. The duration of ischemic arrest was adjusted so that in the control group the postischemic recovery of function (aortic flow) was approximately 50% of its preischemic value. Ischemic times were therefore 35, 50, 55, 60, 80, 100, and 130 min, respectively. In all cases hearts were subjected to 3 min preischemic infusion with St. Thomas' cardioplegic solution with or without added verapamil (1.1 mumol/liter). At 37 degrees C verapamil increased recovery by 36.6 +/- 4.8%; this increased to 57.4 +/- 6.0% at 34 degrees C. Below 34 degrees C, however, additional protection was progressively lost, so that at 27 degrees C or below verapamil contributed no significant additional protection. In separate aerobic perfusion studies with paced Langendorff-prepared hearts with intraventricular balloons, verapamil (0.2 mumol/liter) was shown to depress pressure development by up to 76% at 37 degrees C; this increased to 92% at 34 degrees C, but thereafter the drug's negative inotropic effects declined, so that at 24 degrees C and below there was no significant difference in developed pressure between the control and drug-treated groups. On the basis of these and other studies, the argument is advanced that by some mechanism common to both hypothermia and verapamil, the anti-ischemic and negative inotropic effects of verapamil are rendered redundant under conditions of hypothermia.