What can angiotensin antagonists do that converting-enzyme inhibition can't: the case of post-angioplastic restenosis.
The introduction of nonpeptide angiotensin II antagonists in clinical use has necessarily led to comparison with the various and clinically established angiotensin converting enzyme inhibitors. In essence, losartan, the first approved angiotensin receptor antagonist, has a clinical profile highly similar to that of the converting-enzyme inhibitors, although much higher doses are required but with the advantage of no dry cough. On the other hand, the emergence of the concept of inverse agonism on other receptor systems has led to the search for pathological situations mediated through constitutive receptor activity as well as antagonists with inverse agonistic properties on the angiotensin receptor. Basic research on angiotensin peptide antagonists has led to the identification of molecular characteristics that produce antagonism. The combination of these characteristics then led to angiotensin antagonists that possessed a long in vivo duration of action. Studies with angiotensin converting enzyme inhibitors and nonpeptide antagonists on animal models of post-angioplastic restenosis revealed that both classes of compounds have similar partial efficacy on the inhibition of neointima formation. A peptide antagonist produced on the rat carotid model a complete inhibition of neointima formation. This increased efficacy is now tentatively attributed to potential inverse agonistic activity of this peptide antagonist. This concept would give angiotensin antagonists therapeutic opportunities where convertase inhibitors should be ineffective.
Pham
D
D
Department of Pharmacology, Faculty of Medicine, Université de Sherbrooke, Canada.
Laporte
S
S
Pérodin
J
J
Bourgeois
R
R
Escher
E
E
D000800:Angioplasty, Balloon; D000804:Angiotensin II / Q000031:analogs & derivatives; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D016893:Carotid Stenosis / Q000503:physiopathology / Q000517:prevention & control*; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000502:physiology; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000627:therapeutic use
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C070967:L 158809