THE PRECLINICAL BASIS OF THE THERAPEUTIC EVALUATION OF LOSARTAN

Angiotensin II receptor antagonists: Losartan (DuP 753, MK-954) is the prototype of a new class of orally active, non-peptide angiotensin II receptor antagonists able to inhibit the renin-angiotensin system spe cifically and selectively without the agonistic effects of the peptide receptor antagonists, e.g. saralasin, or the bradykinin-potentiating effects of the angiotensin converting enzyme (ACE) inhibitors. Preclin ical pharmacology: The preclinical pharmacology of angiotensin II rece ptor blockade is exemplified by the experience with losartan. Over 120 0 abstracts and papers have been published from studies in which losar tan has been used to explore the role of angiotensin II in a wide rang e of normal and pathological states. Losartan has also proved useful i n further defining the heterogeneity of angiotensin II receptors. Acco rding to current nomenclature, losartan represents the prototype antag onist of the angiotensin II type-1 (AT(1)) receptor family (AT(1a) and AT(1b)) and does not possess significant affinity for the so-called A T(2) receptor. Virtually all of the known actions of angiotensin Il, e .g. those defined by angiotensin II itself, saralasin, ACE inhibitors or renin inhibitors, are blocked by losartan, emphasizing the major ro le of AT(1) receptors in mediating the responses of angiotensin II. Al though the AT(2) receptor has now been cloned, the function of this re ceptor remains poorly understood. Preclinical studies with losartan: P reclinical studies with losartan have suggested that this agent produc es inhibition of the renin-angiotensin system comparable to that of AC E (and renin) inhibitors, without the bradykinin-potentiating effects. In several models of experimental and genetic hypertension losartan h as proved to be an orally effective antihypertensive agent with a long duration of action and similar efficacy to that of ACE and renin inhi bitors. In animal models of renal disease losartan significantly decre ases proteinuria, provides protection against diabetic glomerulopathy and increases survival in stroke-prone spontaneously hypertensive rats . A growing number of experimental studies have also shown that losart an inhibits neointimal proliferation and markedly reduces or prevents cardiovascular hypertrophy/remodeling and cardiac failure mediated by activation of the renin-angiotensin system. Non-peptide AT(1) receptor antagonists have added another dimension to the arsenal of drugs mani pulating the renin-angiotensin system. These agents do not have the ex perimental limitations of the peptide antagonists and ACE inhibitors. Conclusions: Losartan, the first potent and specific AT(1) receptor an tagonist, is orally active with a long duration of action and therefor e has potential for treatment of chronic diseases, such as hypertensio n and heart failure.