Protective effects of AE0047, a novel calcium antagonist, on incidence of stroke and hemodynamic disturbances in stroke-prone spontaneously hypertensive rats.
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)
Shinyama
H
H
Central Research Laboratory, Green Cross Corporation, Osaka, Japan.
Nagai
H
H
Kawamura
T
T
Narita
Y
Y
Uchida
T
T
Watanabe
M
M
Kagitani
Y
Y
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002561:Cerebrovascular Disorders / Q000517:prevention & control*; D004095:Dihydropyridines / Q000494:pharmacology* / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C064970:AE0047