Angiotensin-II biochemistry and physiology: Update on angiotensin-II receptor blockers

Based on the knowledge of the importance of the RAS in cardiovascular physiology, a new class of antihypertensive agents, the AII-receptor antagonists has been developed and studied in animals and humans. These agents, like ACEIs, reduce vasoconstriction, aldosterone secretion, and proteinuria, but have a much lower incidence of cough and angioedema, and have been shown to effectively lower blood pressure clinically. Clinical trials are under way to further evaluate their effectiveness in the regression of LVH, improvement of cardiac function, and reduction of proteinuria and cardiovascular events. Many of these compounds may find applications in other areas of human physiology. In particular, AT2 receptor function remains to be elucidated. This may be especially important in the brain since receptor knockout models in mice show definite behavioral alterations (104,118), and the cognitive effects of intracerebral AII infusion appear to be mediated by both AT1 and AT2 receptor subtypes (24). Similarly, the AT2 receptor may play a role in uterine growth and vascularization in preparation for pregnancy (19), while locally produced AII has been postulated to play a part in intraovarian paracrine/autocrine control of ovulation (269). The presence of AII receptors in the liver has long been recognized. Recent evidence indicates that AII may have an impact on liver glucose output (191), and the AT1 receptor antagonist ICI D8731 prevents downregulation of the GLUT4 transporter in rat heart, observations that suggest possible targeting of AII receptors aimed at ameliorating the diabetic state. Thus, much investigative work still needs to be accomplished to understand the workings of the RAS and the usefulness of these new nonpeptide AII receptor antagonists in various pathophysiologic states.