PHARMACOLOGY OF LOSARTAN, AN ANGIOTENSIN-II RECEPTOR ANTAGONIST, IN ANIMAL-MODELS OF HYPERTENSION

Background: Clinical experience with angiotensin converting enzyme (AC E) inhibitors has shown that inhibition of the renin-angiotensin syste m is effective therapy for hypertension and heart failure. Losartan (D uP 753, MK 954, cozaar) is the first non-peptidic drug that inhibits t he renin-angiotensin system by selectively blocking the interaction of angiotensin II with its receptor. Differences between losartan and AC E inhibitors: Pharmacological differences between ACE inhibitors and l osartan could affect comparative efficacy and/or safety. In addition t o angiotensin I, ACE has other substrates (e.g. kinins). Blocking the metabolism of kinins with ACE inhibitors could be beneficial (e.g. vas odilation) and/or elicit side effects (e.g. cough) which will not be p roduced by losartan. Non-ACE pathways of angiotensin II formation have been described (e.g. angiotensin convertase) which may limit the abil ity of ACE inhibitors to prevent formation of angiotensin II in all ti ssues. Losartan blocks angiotensin II responses irrespective of the ro ute or site of angiotensin II formation. Two binding sites for angiote nsin II are widely accepted, AT(1) and AT(2). Losartan blocks only AT( 1) sites while ACE inhibitors functionally black angiotensin II intera ction with both sites. Since the physiological role for AT(2) sites is unknown, the relevance of this difference between ACE inhibitors and losartan is questionable. Hypertension: In animal models of hypertensi on, the efficacy of losartan is equivalent to the efficacy of ACE inhi bitors. In animal models that reflect complications of hypertension, s uch as kidney dysfunction, cardiac and vascular hypertrophy and stroke , losartan and ACE inhibitors are also equally effective. From these r esults, kinin potentiation and lack of inhibition of angiotensin I con vertase do not lead to differences in pharmacological efficacy between ACE inhibitors and losartan. Therefore, with respect to therapeutic e fficacy, results in animal models indicate that losartan will display the beneficial pharmacology of ACE inhibitors without the detrimental side effects attributed to kinin potentiation.