CURRENT STATUS OF PUTATIVE IMIDAZOLINE (I1) RECEPTORS AND RENAL MECHANISMS IN RELATION TO THEIR ANTIHYPERTENSIVE THERAPEUTIC POTENTIAL

Abstract

1. A 'second generation' of centrally acting antihypertensive agents has recently been developed. Unlike the 'first generation' of these agents (e.g. alpha-methyldopa, clonidine, guanabenz), which act predominantly by an agonist action at a alpha 2-adrenoceptors, these agents (e.g. rilmenidine, moxonidine) are believed to exert their antihypertensive effects chiefly by an interaction at putative imidazoline (I) receptors of the I1-type, and so have a reduced profile of alpha 2-adrenoceptor-mediated side effects. There is also evidence from studies in experimental animals that activation of I1-receptors mediates a natriuretic effect. This review evaluates the evidence that they mediate renal effects different from those of alpha 2-adrenoceptors that could contribute to their long-term efficacy. 2. Data from binding studies suggest that I1-binding sites are heterogeneous. There is conflicting evidence concerning whether any of these binding sites are truly receptors. Indeed, the best evidence for the existence of I1-receptors comes from in vivo experiments indicating that imidazoline compounds act at non-adrenoceptor receptive sites in the central nervous system to reduce sympathetic drive and blood pressure. 3. There are a wide range of potential sites and mechanisms through which centrally acting antihypertensive agents can affect renal function, including actions mediated within the central nervous system, heart, systemic circulation and within the kidneys themselves. 'First generation' centrally acting antihypertensive agents cause diuresis and natriuresis in rats, while in dogs and humans a diuresis is often seen with variable effects on sodium excretion. 4. Evidence from studies in anaesthetized rats indicates that rilmenidine and moxonidine can promote sodium excretion by interacting with both central nervous system and renal putative I1-receptors. This does not appear to necessarily be the case in other species. At this time there are few or no published data from clinical studies to suggest that 'second generation' centrally acting antihypertensive agents affect salt and water balance differently from 'first generation' agents.