To test for evidence of
stroke-preventive action, we initially examined the effect on
salt-loaded
stroke-prone spontaneously hypertensive rats of chronic treatment with 4-(4-benzhy-drylpiperazino)phenethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate dihydrochloride (
AE0047), a novel
calcium antagonist with slow onset and long-lasting hypotensive effect, and compared its efficacy with that of the
calcium antagonist
nicardipine and the
vasodilator hydralazine. We then used radioactive
microspheres to study the effects of these three agents on hemodynamic impairment to clarify the mechanism of the test
drug's putative preventive action. In a 12-week repeated-administration study using animals of initial age 9 weeks; all vehicle-treated subjects died within 37 days as a result of severe
hypertension and
stroke, whereas those treated with
AE0047, at doses of 1 or 3 mg/kg/day, remained free of
stroke and showed no signs of
hemorrhage, brain softening or the cerebrovascular lesions typical in this animal model. Significant suppression of the development of
hypertension was not noted at the lower of these doses nor at a
nicardipine dose of 10 mg/kg/day, which failed to prevent
stroke in most cases.
A 10-mg/kg/day dose of
hydralazine did suppress the development of
hypertension but failed to prevent death in half of all cases. In the hemodynamic study, 4-week treatment with
AE0047 averted the marked decreases in cardiac output and blood flow in the brain, heart, kidneys and adrenal glands observed in the control group, as well as the accompanying rise in total peripheral resistance before and after
stroke.(ABSTRACT TRUNCATED AT 250 WORDS)