Antihypertensive mechanism of alacepril. Effects of its metabolites on the peripheral sympathetic nervous system.
To elucidate the antihypertensive mechanisms of alacepril (DU-1219), the drug itself and its metabolites, desacetylalacepril (DU-1227) and captopril, were examined both in vitro and in vivo for their effects on the sympathetic nerve which innervates the peripheral vessels. 1. In isolated perfused mesenteric preparations from spontaneously hypertensive rats (SHR, DU-1227 (10(-6)-10(-5) mol/l) attenuated dose-dependently the increases in perfusion pressure and in norepinephrine (NE) overflow which were induced by electrical stimulation of periarterial sympathetic nerves (15 Hz). Captopril (10(-6)-10(-5) mol/l) caused a similar attenuation, though to a lesser degree, of the perfusion pressure but did not inhibit the increase in NE overflow. 2. The sympatho-inhibitory effect of DU-1227 in the above experiment was shown to be caused by DU-1227 per se, since no captopril was detected in either the perfusate or tissues perfused with DU-1227. 3. In pithed SHR, alacepril (3 mg/kg) caused as potent an inhibitory effect as captopril (3 mg/kg) on the pressor response to the electrical sympathetic nerve stimulation (3 Hz) at an oral dose about half as that of captopril on the molar basis. The effect of alacepril tended to last longer than that of captopril. However, at higher oral dose levels, the inhibitory effect of alacepril (30 mg/kg) was of the similar extent to that of captopril (30 mg/kg). 4. In pithed SHR which had received bilateral nephrectomy 2 to 8 h previously, alacepril (30 mg/kg p.o.) significantly attenuated the vasopressor response induced by electrical stimulation (1-30 Hz) 1 and 3 h after administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Minato
H
H
Department of Pharmacology, Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Hosoki
K
K
Hayashi
K
K
Sawayama
T
T
Kadokawa
T
T
Hashimoto
M
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents; D002216:Captopril / Q000031:analogs & derivatives* / Q000494:pharmacology; D004558:Electric Stimulation; D004656:Enalapril / Q000494:pharmacology; D008297:Male; D009392:Nephrectomy; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D013564:Sympathetic Nervous System / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004656:Enalapril; D002216:Captopril; C046835:alacepril; D009638:Norepinephrine