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(Circulation. 1998;97:744-751.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Endothelin Receptors in the Failing and Nonfailing Human Heart

Klaus Pönicke, PhD; Magdalene Vogelsang; Moritz Heinroth; Karin Becker, PhD; Oliver Zolk, MD; Michael Böhm, MD; Hans-Reinhard Zerkowski, MD; ; Otto-Erich Brodde, PhD

From the Institut für Pharmakologie und Toxikologie (K.P., M.H., K.B., O.-E.B.) und Klinik für Herz- und Thorax-Chirurgie (H.-R.Z.), Universität Halle-Wittenberg, Halle, Germany; Abteilung für Nieren- und Hochdruckkrankheiten (M.V.), Zentrum für Innere Medizin, Universität Essen, Essen, Germany; and Klinik III für Innere Medizin der Universität zu Köln (O.Z., M.B.), Köln, Germany.

Correspondence to Professor Dr Otto-Erich Brodde, Institut für Pharmakologie und Toxikologie, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Str 4, D-06097 Halle/Saale, Germany.

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. [¹²⁵I]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.

Key Words: endothelin • heart failure • receptors • inositol phosphates

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