General pharmacology of the non-sulfhydryl angiotensin converting enzyme inhibitor N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline.
The effects of N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline (AB-47, CAS 120008-53-9), an orally active angiotensin converting enzyme inhibitor, on the central nervous, respiratory and cardiovascular, autonomic systems, isolated smooth muscles and other functions were investigated in various experimental animals. AB-47 had no effect on central nervous, autonomic systems and isolated smooth muscles. AB-47 (10 and 30 micrograms/kg i.v.) significantly lowered femoral blood pressure without affecting respiration and heart rate in anesthetized rats. However, AB-47 had no effect on the contractile tension of mammalian isolated atrium and aorta. AB-47 had no effect on gastrointestinal transit in mice. Very slight injury of gastric mucosa was observed 4 h after the oral administration of AB-47 in rats but AB-47 did not damage the small intestinal mucosa. AB-47 had no effect on the contraction of rat phrenic nerve-diaphragm preparation induced by electrical stimulation. AB-47 did not affect the incidence of acetic acid-induces writhings. AB-47 potentiated carrageenan-induced hind paw edema in rats. The potentiation of edema may be due to an accumulation of bradykinin induced by the inhibition of angiotensin converting enzyme (ACE), because ACE is the identical enzyme with kinase II. The pretreatment of AB-47 for 7 days (1, 3, 10 mg/kg/d p.o.) inhibited the cardiac hypertrophy induced by isoproterenol (isoprenaline). This result suggests that the renin-angiotensin-aldosterone system directly or indirectly participates in the cardiac hypertrophy induced by isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)
Shirota
M
M
Central Research Laboratories, Asahi Breweries, Ltd., Tokyo, Japan.
Hayashi
M
M
Kajiwara
Y
Y
Kitabatake
K
K
Uruno
T
T
Kubota
K
K
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects; D006332:Cardiomegaly / Q000517:prevention & control; D002490:Central Nervous System / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007509:Irritants / Q000633:toxicity; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015656:Respiratory Mechanics / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D004151:Dipeptides; D007509:Irritants; C065126:N-(8-amino-1-carboxyoctyl)-alanyl-proline