Antihypertensive effect of perindopril: experimental pharmacology.
This review of the pharmacological effects of perindopril based on data in the literature, consists of three approaches: i) demonstration of the antihypertensive effect; ii) characterization of converting enzyme inhibition; iii) understanding of the mechanisms of action. The antihypertensive effect of perindopril has been demonstrated in the spontaneously hypertensive rat and in renovascular hypertension (1 clip-2 kidney or 1 clip-1 kidney). Its intensity and duration are dose-dependent; they are increased in the presence of stimulation of the renin-angiotensin system (renovascular hypertension, sodium depletion). Peripheral vascular resistance is decreased, while cardiac output and heart rate are not increased. This vasodilatation is predominant in the renal vascular bed and is accompanied, in the salt and water restricted dog, by increased sodium excretion. These effects are accompanied by inhibition of the converting enzyme activity. In vitro, perindoprilat (the principal active diacid metabolite of perindopril) is a potent (IC50: 1.5 to 3.2 nM) and relatively specific competitive converting enzyme inhibitor. In vivo, perindopril competitively inhibits the pressor response to angiotensin I. Following a dose of 1 mg.kg-1, the plasma converting enzyme activity is significantly inhibited for 24 hours in the rat and for a longer period in the case of low-salt diet. In the spontaneously hypertensive rat, the antihypertensive effect of perindopril lasts longer than plasma converting enzyme inhibition. This dissociation of the pharmacological effects suggests a role of tissue converting enzyme inhibition, demonstrated in various tissues, including the rat kidney and aorta. Inhibition of the presynaptic effects of angiotensin II on the transmission of sympathetic impulses--demonstrated in pithed rats--and potentiation of the effects of bradykinin--observed in vitro and in vivo--may also be involved in the antihypertensive effect of perindopril.
Barthelmebs
M
M
Institut de Pharmacologie et de Médecine Expérimentale, URA DO589 CNRS, Strasbourg, France.
Devissaguet
M
M
Imbs
J L
JL
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents; D004285:Dogs; D006973:Hypertension / Q000188:drug therapy; D007211:Indoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects; D020913:Perindopril; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D007211:Indoles; D020913:Perindopril