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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 ETA-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 ETA-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 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
Gq/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 right 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.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Endothelin Receptors in the Failing and Nonfailing Human Heart
Key Words: endothelin • heart failure • receptors • inositol phosphates
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