ENDOTHELIN RECEPTORS IN THE FAILING AND NONFAILING HUMAN HEART

Background-In patients with chronic heart failure (CHF), plasma endoth elin-1 (ET-1) levels are increased, We studied whether the cardiac ET- receptor system is altered in CHF patients. Methods and Results-We ass essed ET-evoked inositol phosphate (IF) formation ill slices from ligh t atria and left ventricles from G potential heart transplant donors ( NFH) and lj patients with end-stage CHF; in membranes from the same ti ssues, we studied ET-induced inhibition of isoprenaline- and forskolin -stimulated adenylyl cyclase and ET-receptors density. ET (10(-9) to 1 0(-6) mol/L, ET-I >>> ET-3) increased IP formation in right atria and left ventricles through ETA-receptor stimulation in a concentration-de pendent 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-recep tor stimulation, inhibited isoprenaline- and forskolin-stimulated aden ylyl cyclase ill right atria but not in left ventricles, whereas carba chol inhibited adenylyl cyclase ill both tissues again, the potency an d 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, th e density of ETA receptors was not significantly different between NFH and CHF hearts. Finally, the immunodetectable amount of left ventricu lar G(q/11) protein did not differ between NFH and CHF hearts. Conclus ions-In the human heart, ETA and ETB receptors coexist, however, only ETA receptors are of functional importance. In light atria, ETA recept ors couple to IP formation and inhibition of adenylyl cyclase; in left ventricles, they couple only to IP formation. In end-stage CHF, the f unctional responsiveness of the cardiac ETA-receptor system is not alt ered.