DISCOVERY OF LOSARTAN, THE FIRST ANGIOTENSIN-II RECEPTOR ANTAGONIST

The 'discovery' of losartan represents three separate discoveries: (1) losartan as the unique biphenyltetrazole molecule and the first of a new chemical class; (2) losartan as a tool to identify AT(1)-subtype r eceptors; and (3) losartan as a specific probe for exploring the multi ple roles of angiotensin II (Ang II) in normal physiology and patholog ic states. Losartan is the first nonpeptide orally active Ang II recep tor antagonist to reach clinical trials. Losartan was selected for its affinity for Ang II receptors, functional antagonism of Ang II, lack of agonist properties, and oral anti-hypertensive effects. Losartan ha s been widely used to define the distribution and function of AT recep tor subtypes. Although possible roles of the AT, subtype have been rep orted, virtually all of the known effects of Ang II are blocked by los artan. Specific AT(1), receptor blockade has been broadly compared wit h ACE inhibition. Possible differences on the basis of AT(1) selectivi ty, bradykinin potentiating effects and Ang II formed by non-ACE pathw ays are discussed. Losartan blocks the vascular constrictor effect of Ang II, the Ang II-induced aldosterone synthesis and/or release, and t he Ang II-induced cardiovascular 'growth' in vitro and in vivo. In var ious models of experimental hypertension, losartan prevents or reverse s the elevated blood pressure and the associated cardiovascular hypert rophy similar to ACE inhibitors. Likewise, in models of renal failure (for example reduced renal mass, puromycin, ochratoxin), losartan, lik e ACE inhibition, markedly reduced the elevation in blood pressure, pr oteinuria or sclerosis. In aortocaval shunt, coronary ligation and ven tricular pacing models of heart failure, losartan demonstrated a patho logical role for Ang II by reversing the associated haemodynamic findi ngs. In SHR-stroke prone, losartan dramatically increased survival whi le having a limited effect on blood pressure, suggesting a non-pressur e dependent effect of Ang II. These collective data show that Ang II e xerts complex pathological effects in experimental models of vascular, cardiac, renal and cerebral disease. The effectiveness of losartan in experimental models of heart failure supports its evaluation in clini cal trials with patients with heart failure.