RENAL IMIDAZOLINE GUANIDINIUM RECEPTIVE SITE - A POTENTIAL TARGET FOR ANTIHYPERTENSIVE DRUGS

Imidazoline and guanidinium alpha2-adrenergic agonists such as clonidine and guanabenz are used as centrally mediating antihypertensive drugs. However, we showed that in human and rabbit kidney, this class of molecules recognizes not only alpha2-adrenergic receptors but also a previously unknown membrane protein, the imidazoline-guanidinium receptive site (IGRS). Through pharmacological and biochemical studies, we demonstrated that IGRS is recognized by imidazoline and guanidinium derivatives, insensitive to catecholamines, physically distinct from alpha2-adrenergic receptors, localized in the basolateral membranes and, mainly, in mitochondria, and regulated by K+ in vitro. Studies of Na+ and H+ fluxes in isolated cells from rabbit renal proximal tubule showed that alpha2-adrenergic receptors and IGRS are involved in stimulation and inhibition, respectively, of Na+/H+ antiporter. These opposite ways of regulating of Na+/H+ antiporter by alpha2-adrenergic receptors and IGRS could be therapeutically relevant. Depending on their preferential interaction for either of the binding sites, imidazoline and guanidinium derivatives could be responsible for sodium retention (alpha2-adrenergic effect) or an increase in sodium excretion (IGRS effect). In the future, the relative affinity for alpha2-adrenergic receptors or IGRS should be taken into account when considering the therapeutical and side effects of imidazoline and guanidinium antihypertensive drugs.