Pharmacology of renal endothelin receptors.

Endothelin (ET)-1 is the major isoform in the human kidney where it interacts with two G protein-coupled receptors, ET(A) and ET(B). It contains high densities of ET receptors, but in contrast to most other peripheral organs, the majority (70%) are of the ET(B) subtype and largely have a differential distribution to ET(A) receptors within renal cells, thus mediating contrasting physiological and pathophysiological actions. ET-1 remains the most potent constrictor of human-isolated vessels, including those of the kidney which are particularly sensitive to the actions of this peptide. The pharmacological response is unusual in being sustained for a considerable period of time and slow to wash out. Smooth muscle cells of the renal vasculature mainly express ET(A) receptors, and ET(A)-selective antagonists fully block these constrictor responses. The vascular endothelium only expresses ET(B) receptors. ET-1 also acts in an autocrine or paracrine manner, and binds to ET(B) receptors to stimulate the release of vasodilators. ET-1 is unusual amongst the mammalian bioactive peptides in possessing two disulphide bridges, conferring resistance to enzymatic degradation. However, the plasma half-life of ET-1 is surprisingly short as a result of the second major function of endothelial ET(B) receptors in removing ET-1 from the circulation, mainly in the kidneys and lungs. Thus, ET(B) receptors have a critical role in protecting target organs such as the heart and may limit the detrimental vasoconstrictor effect caused by upregulation of ET-1 associated with disease. Inhibition of the renal medullary ET(B) system causes sodium retention because of its role in systemic fluid and electrolyte homeostasis. ET(A)/ET(B) antagonists would be expected to block the beneficial vasodilatory, clearing, and natriuretic actions of ET(B) receptors. Since many of the deleterious actions of ET-1, vasoconstriction, mesangial cell proliferation, and inflammation occur mainly via ET(A) receptors, selective ET(A) blockade may be more beneficial in renal disease.