Cerebrovascular, biochemical, and cytoprotective effects of isradipine in laboratory animals

Abstract

Dose-response curves of isradipine for blood pressure, total peripheral conductance, and regional cerebral conductances and blood flows were obtained in anesthetized cats and rabbits using the microsphere method. Cerebrovascular effects occurred at lower doses than systemic effects, and the effective duration was longer in the brain than in the periphery. In a rat model of embolic stroke (unilateral occlusion of the middle cerebral artery), isradipine has been shown to have cytoprotective efficacy (Sauter A, Rudin M: Stroke 1986; 17: 1228–1234; Rudin M, Sauter A, Wiederhold K-H: Therapie 1987; 42: 477–481; Sauter A, Rudin M, Wiederhold K-H: Neurochem Pathol 1989 [in press]). Using this model, dose-response curves for infarct size, measured by magnetic resonance imaging, and biochemical markers of infarction were obtained for various calcium antagonists. Isradipine showed the biggest improvements (50 to 60 percent at 2.5 mg/kg subcutaneously), followed by nimodipine (30 to 40 percent at 5 mg/kg subcutaneously), nitrendipine (30 to 40 percent at 10 mg/kg subcutaneously), darodipine (20 to 30 percent at 10 mg/kg subcutaneously), and nicardipine (10 percent at 10 mg/kg subcutaneously). It is concluded that isradipine differs in both efficacy and potency from the other calcium antagonists tested. The effects of isradipine, nimodipine, and darodipine on cerebral blood flow were further investigated in this model using the [ 14C]iodoantipyrine method. Despite systemic hypertension, cerebral blood flow was dose dependently increased in the normal and ischemic hemispheres. Isradipine elicited maximal improvements over a wider dose range than the other drugs tested (0.1 to 2.5 mg/kg), preferentially affecting cerebral blood flow in the ischemic areas, as further demonstrated using autoradiographic techniques. These effects are in good, quantitative agreement with the reductions in infarct size, observed by magnetic resonance imaging and histology, emphasizing the importance of cerebrovascular mechanisms for cytoprotection in stroke. The concurrence between cat, rabbit, and rat experiments suggests that the findings may also apply to humans.