Endothelin receptors in the failing and nonfailing human heart

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 (IF) formation ill slices from light atria and left ventricles from G potential heart transplant donors (NFH) and lj 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-receptors density. ET (10(-9) to 10(-6) mol/L, ET-I >>> ET-3) increased IP formation in right atria and left ventricles through ETA-receptor stimulation in a concentration-dependent manner; no difference ill potency or efficacy between NFH and CHF hearts was observed, ET-1 (10(-10) to 10(-6) mol/L), via ETA-receptor stimulation, inhibited isoprenaline- and forskolin-stimulated adenylyl cyclase ill right atria but not in left ventricles, whereas carbachol inhibited adenylyl cyclase ill both tissues again, the potency and efficacy of ET-or carbachol-induced adenylyl cyclase inhibition was not different between NFH and CHF hearts, [I-125]ET-1 binding revealed the coexistence of ETA and ETB receptors in both tissues; however, the density of ETA 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, ETA and ETB receptors coexist, however, only ETA receptors are of functional importance. In light atria, ETA 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 ETA-receptor system is not altered.