Review of the molecular pharmacology of Losartan and its possible relevance to stroke prevention in patients with hypertension

BACKGROUND: The Losartan Intervention For End-point reduction in hypertension (LIFE) study found that a losartan-based regimen, compared with an atenolol-based regimen, resulted in a significantly lower risk of stroke in hypertensive patients with left ventricular hypertrophy, despite similar reductions in blood pressure. OBJECTIVE: The purpose of this review was to examine the molecular and pharmacologic mechanisms that may be associated with the different outcomes observed in the LIFE study. METHODS: A PubMed/MEDLINE search of English-language articles (1990 to February 2006) with the terms angiotensin II antagonists or AIIAs or angiotensin receptor blockers or losartan or atenolol or beta blocker and terms including, but not limited to, atherosclerosis, left ventricular hypertrophy, carotid artery hypertrophy, fatty streaks, atrial fibrillation, arrhythmias, endothelial function, myocyte hypertrophy, myocardial fibrosis, platelet aggregation, tissue factor, plasminogen activator inhibitor-1, PAI-1, anti-inflammatory, uric acid, or oxidative stress. RESULTS: Losartan's significant effect on stroke may be related to several possible mechanisms that are independent of blood-pressure reductions. These include improvements in endothelial function and vascular structure; decreases in vascular oxidative stress; reductions in left ventricular hypertrophy, reductions in myocardial fibrosis, or both; and modulation of atherosclerotic disease progression. Although some of these effects may be shared by other angiotensin II receptor antagonists (AIIAs), and perhaps other anti-hypertensive classes (eg, angiotensin-converting enzyme inhibitors), the ability of losartan to lower serum uric acid levels-a proposed independent risk factor for cardiovascular disease-appears to be a molecule-specific effect. Alternative explanations of the results of the LIFE study have also been hypothesized, including inappropriate choice of atenolol as an active comparator and differences in central pulse pressures between study groups. CONCLUSIONS: This review of the literature suggests that losartan (and perhaps other AIIAs) may possess a number of properties, independent of its antihypertensive effects, that may be associated with decreased vulnerability of the plaque, myocardium, and blood