[Antihypertensive effects of a novel calcium antagonist, AE0047, in various hypertensive models].
The antihypertensive effects of oral or intravenous administration of AE0047, a novel 1,4-dihydropyridine-type calcium antagonist, were investigated in spontaneously hypertensive rats (SHR/crj), one kidney-one clip renal hypertensive rats (RHR), deoxycorticosterone acetate (DOCA)-salt hypertensive rats (DHR) and two kidney-one clip renal hypertensive dogs (RHD). AE0047 (1, 3, 10 mg/kg, p.o.) caused a dose-related reduction of systolic blood pressure (SBP) with low reflex tachycardia in SHR/crj and RHR. The effect reached its maximum at 2-4 hr after administration and was sustained for a long time. In DHR, AE0047 (0.3, 1, 3 mg/kg, p.o.) similarly showed the antihypertensive effects at 2-7 hr with no significant changes in heart rates (HR). The doses (ED30) of AE0047 required to decrease SBP by 30% were 2.6, 3.4 and 0.68 mg/kg in SHR/crj, RHR and DHR, respectively. In RHD, and AE0047 capsule (GJ-0956: 4, 8, 16, 32 mg/body, p.o.) produced dose-dependent and long lasting effects with a transient and slight increase in HR. Furthermore, the intravenous administration of AE0047 (10, 30, 100 micrograms/kg) produced the antihypertensive action slowly, reached a plateau 10 min later and then maintained for many hours. In contrast, nitrendipine (3-100 mg/kg, p.o., 3-30 micrograms/kg, i.v.) and nicardipine (1-30 mg/kg, p.o., 3-30 micrograms/kg, i.v.) exhibited a similar potency to AE0047, but these maximal effects were produced at 1-2 hr and 0.5-1 min in the case of oral and intravenous administration, respectively, with a rapid recovery in the above hypertensive rats. These results indicate that AE0047 exhibits an antihypertensive effect with a slow onset and long-lasting profile.
Kido
H
H
Central Research Laboratories, Green Cross Corporation, Osaka, Japan.
Nishikawa
M
M
Hayashi
K
K
Kubo
Y
Y
Ohtaki
Y
Y
Fujino
Y
Y
Egi
Y
Y
Ebisu
H
H
Inoue
S
S
Yamanaga
K
K
Uchida
T
T
Nakamura
N
N
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003900:Desoxycorticosterone; D004095:Dihydropyridines / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D006977:Hypertension, Renal / Q000503:physiopathology; D007275:Injections, Intravenous; D009529:Nicardipine / Q000494:pharmacology; D009568:Nitrendipine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C064970:AE0047; D003900:Desoxycorticosterone; D009568:Nitrendipine; D009529:Nicardipine