To establish if the administration of
gallopamil, a derivative of
verapamil, protects heart muscle against the deleterious effect of
ischemia and subsequent reperfusion, rabbits were injected subcutaneously twice daily with 2 mg/kg of
Gallopamil for 5-6 days. The hearts were isolated and perfused with aerobic
Krebs-Henseleit buffer solution by the Langendorff method. The hearts were paced (180 b/min) and wall temperature was controlled.
Ischemia was induced by reducing coronary flow from 25 ml/min to 1 ml/min for 90 min and then the hearts were reperfused for 30 min. At the end of either the ischemic period or reperfusion, the hearts were assayed for
ATP, CP, and
calcium. Others were homogenized, their mitochondria harvested and monitored for oxidative phosphorylating and
ATP generating activity as well as
calcium content and uptake. The mechanical function of the hearts and
noradrenaline release was also measured. Hearts that were made ischemic gained
calcium, their endogenous stores of
ATP and CP were depleted, their mitochondria had reduced RCI and state 3 respiration and increased
calcium concentrations. During reperfusion tissue and mitochondrial
calcium was significantly increased, the capacity of mitochondria to use
oxygen for state 3 respiration was further impaired and their
ATP generating capacity reduced. Diastolic pressure increased and there was no recovery of developed pressure and important
noradrenaline release. Pretreatment with
gallopamil protected the mitochondria against the ischemically induced changes in RCI, state 3 respiration. There was also a less marked rise in tissue and mitochondrial
calcium and a reduced increase of diastolic pressure.
Gallopamil also diminished the effect of reperfusion on the
calcium accumulating activity of mitochondria and on the decline in the
ATP generating and
oxygen utilizing capacity of the mitochondria. The tissue levels of
ATP and CP were better maintained, and
noradrenaline release was reduced, the systolic pressure generating capacity was enhanced by the treatment with
gallopamil. These results are discussed in accordance with the hypothesis that this
drug protects heart muscle against the deleterious effects of
ischemia and reperfusion by ensuring that sufficient
ATP remains available to maintain homeostasis with respect to
calcium.