Pharmacology of idrapril: a new class of angiotensin converting enzyme inhibitors.
Idrapril is the prototype of a new chemical class of angiotensin converting enzyme (ACE) inhibitors, the hydroxamic non-amino acid derivatives. Idrapril strongly inhibited rat and human plasma ACE and rabbit lung ACE (IC50: 7-12 nM) as well as the pressor response induced by angiotensin I in anesthetized rats (ED50: 63 nmol/kg i.v.). Idrapril (0.04-23 mumol/kg i.v.) lowered the blood pressure dose dependently, up to 20-35%, in different models of hypertension (sodium-depleted spontaneously hypertensive rat, two-kidney-one-clip renal hypertensive rat, and aortic-coarctated rat), its profile being similar to that of captopril in terms of potency and efficacy. Idrapril and captopril reduced the blood pressure and potentiated substance P-induced bronchoconstriction in the guinea pig to the same extent, suggesting a similar degree of ACE inhibition in the circulation. However, idrapril potentiated capsaicin-induced bronchoconstriction (a model that has been related to the liability of ACE inhibitors to produce cough in patients) less effectively than captopril. We conclude that effective ACE inhibition in vitro and in vivo can be obtained with this novel class of compounds.
Subissi
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A
Department of Pharmacology, Laboratori Guidotti S.p.A., Pisa, Italy.
Criscuoli
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M
Sardelli
G
G
Guelfi
M
M
Giachetti
A
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D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D016084:Bronchoconstriction / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology*; D002216:Captopril / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood*; D051381:Rats; D011918:Rats, Inbred SHR; D013373:Substance P / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D003509:Cyclohexanecarboxylic Acids; D006898:Hydroxylamines; C076966:idrapril; D013373:Substance P; D000803:Angiotensin I; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D002211:Capsaicin