Vascular affinity of trandolapril.
This article discusses the pharmacologic basis on which trandolapril exhibits a more potent and longer-lasting antihypertensive effect than its chemical prototype enalapril. Our studies have shown that 1) trandolapril and its active metabolite trandolaprilat are more lipophilic than enalapril and its active diacid enalaprilat; 2) trandolaprilat is three times more potent than enalaprilat in vitro; and 3) trandolapril is 10 times more effective and longer-acting than enalapril in lowering the blood pressure of spontaneously hypertensive rats. The long duration of action of trandolapril can be attributed to its long-lasting inhibition of the vascular tissue angiotensin converting enzyme (ACE). The long action onto the vascular tissue ACE may be due to the high lipophilicity of trandolapril which may increase its tissue penetration and its elimination half-life from the tissue, and the unique nature of the vascular tissue which, unlike the other tissues, does not respond to trandolapril with the induction of de novo ACE that may counteract the ACE inhibition. These data imply that trandolapril is a potent ACE inhibitor with distinctively long action, which might be a result of its vascular tissue affinity and the lack of any ACE inducing ability of the vascular tissue.
Miyazaki
M
M
Department of Pharmacology, Osaka Medical College, Takatsuki, Japan.
Kawamoto
T
T
Okunishi
H
H
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects*; D004656:Enalapril / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D050356:Lipid Metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D007211:Indoles; C052035:trandolapril; D004656:Enalapril