The preclinical basis of the therapeutic evaluation of losartan

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 specifically 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.

The preclinical pharmacology of angiotensin II receptor blockade is exemplified by the experience with losartan. Over 1200 abstracts and papers have been published from studies in which losartan has been used to explore the role of angiotensin II in a wide range of normal and pathological states. Losartan has also proved useful in further defining the heterogeneity of angiotensin II receptors. According to current nomenclature, losartan represents the prototype antagonist of the angiotensin II type 1 (AT1) receptor family (AT1a and AT1b) and does not possess significant affinity for the so-called AT2 receptor. Virtually all of the known actions of angiotensin II, e.g. those defined by angiotensin II itself, saralasin, ACE inhibitors or renin inhibitors, are blocked by losartan, emphasizing the major role of AT1 receptors in mediating the responses of angiotensin II. Although the AT2 receptor has now been cloned, the function of this receptor remains poorly understood.

Preclinical studies with losartan have suggested that this agent produces inhibition of the renin-angiotensin system comparable to that of ACE (and renin) inhibitors, without the bradykinin-potentiating effects. In several models of experimental and genetic hypertension losartan has proved to be an orally effective antihypertensive agent with a long duration of action and similar efficacy to that of ACE and renin inhibitors. In animal models of renal disease losartan significantly decreases 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 losartan inhibits neointimal proliferation and markedly reduces or prevents cardiovascular hypertrophy/remodeling and cardiac failure mediated by activation of the renin-angiotensin system. Non-peptide AT1 receptor antagonists have added another dimension to the arsenal of drugs manipulating the renin-angiotensin system. These agents do not have the experimental limitations of the peptide antagonists and ACE inhibitors.

Losartan, the first potent and specific AT1 receptor antagonist, is orally active with a long duration of action and therefore has potential for treatment of chronic diseases, such as hypertension and heart failure.