Endothelin Receptors in the Failing and Nonfailing Human Heart

Abstract

Background —In patients with chronic heart failure (CHF), plasma endothelin-1 (ET-1) levels are increased. We studied whether the cardiac ET-receptor system is altered in CHF patients. Methods and Results —We assessed ET-evoked inositol phosphate (IP) formation in slices from right atria and left ventricles from 6 potential heart transplant donors (NFH) and 15 patients with end-stage CHF; in membranes from the same tissues, we studied ET-induced inhibition of isoprenaline- and forskolin-stimulated adenylyl cyclase and ET-receptor density. ET (10 −9 to 10 −6 mol/L, ET-1 >>> ET-3) increased IP formation in right atria and left ventricles through ET A -receptor stimulation in a concentration-dependent manner; no difference in potency or efficacy between NFH and CHF hearts was observed. ET-1 (10 −10 to 10 −6 mol/L), via ET A -receptor stimulation, inhibited isoprenaline- and forskolin-stimulated adenylyl cyclase in right atria but not in left ventricles, whereas carbachol inhibited adenylyl cyclase in both tissues; again, the potency and efficacy of ET- or carbachol-induced adenylyl cyclase inhibition was not different between NFH and CHF hearts. [ 125 I]ET-1 binding revealed the coexistence of ET A and ET B receptors in both tissues; however, the density of ET A receptors was not significantly different between NFH and CHF hearts. Finally, the immunodetectable amount of left ventricular G q/11 protein did not differ between NFH and CHF hearts. Conclusions —In the human heart, ET A and ET B receptors coexist; however, only ET A receptors are of functional importance. In right atria, ET A receptors couple to IP formation and inhibition of adenylyl cyclase; in left ventricles, they couple only to IP formation. In end-stage CHF, the functional responsiveness of the cardiac ET A -receptor system is not altered.