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Endothelin receptors in the failing and nonfailing human heart
K Pönicke1, M Vogelsang, M Heinroth
1Institut für Pharmakologie und Toxikologie, Universität Halle-Wittenberg, Halle, Germany.
Insights
The cardiac endothelin-A (ETA) receptor system is functionally unchanged in chronic heart failure (CHF) patients. This study found that ETA receptors in the human heart are important for signaling, but their responsiveness is not altered in CHF.
Area of Science:
- Cardiovascular Physiology
- Molecular Pharmacology
- Receptor Biology
Background:
- Elevated plasma endothelin-1 (ET-1) levels are observed in patients with chronic heart failure (CHF).
- The potential alteration of the cardiac endothelin (ET) receptor system in CHF patients requires investigation.
Purpose of the Study:
- To investigate the functional characteristics and density of the cardiac ET-receptor system in patients with end-stage CHF compared to non-failing hearts (NFH).
- To determine if the ET-receptor system's responsiveness is altered in the human heart during CHF.
Main Methods:
- Assessed ET-evoked inositol phosphate (IP) formation and ET-receptor density in right atrial and left ventricular tissues.
- Studied ET-induced inhibition of adenylyl cyclase activity in response to isoprenaline and forskolin.
- Utilized [125I]ET-1 binding assays and measured left ventricular Gq/11 protein levels.
Main Results:
- ET-1 concentration-dependently increased IP formation in both NFH and CHF hearts via ET(A)-receptor stimulation, with no difference in potency or efficacy.
- ET(A)-receptor stimulation inhibited adenylyl cyclase in right atria but not left ventricles of NFH and CHF hearts, with similar potency and efficacy.
- No significant differences were found in ET(A)-receptor density or Gq/11 protein levels between NFH and CHF hearts.
Conclusions:
- Both ET(A) and ET(B) receptors coexist in the human heart, but only ET(A) receptors are functionally significant.
- In the human heart, ET(A) receptors mediate IP formation in both atria and ventricles, and inhibit adenylyl cyclase in atria.
- The functional responsiveness of the cardiac ET(A)-receptor system remains unaltered in end-stage chronic heart failure.
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 Gq/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.