Endothelin and increased contractility in adult rat ventricular myocytes. Role of intracellular alkalosis induced by activation of the protein kinase C-dependent Na(+)-H+ exchanger

URN to cite this document:

urn:nbn:de:bvb:355-epub-220557 Copy

DOI to cite this document:

10.5283/epub.22055 Copy

Krämer, Bernhard K. ; Smith, T. W. ; Kelly, R. A.

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Date of publication of this fulltext: 09 Sep 2011 14:39

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Details

Item type:	Article
Journal or Publication Title:	Circulation research
Publisher:	Lippincott, Williams & Wilkins
Volume:	68
Number of Issue or Book Chapter:	1
Page Range:	pp. 269-279
Date:	1991
Institutions:	UNSPECIFIED
Identification Number:	Value Type 1845855 PubMed ID
Classification:	Notation Type Alkalosis/metabolism MESH Ammonium Chloride/pharmacology MESH Animals MESH Carrier Proteins/metabolism MESH Endothelins/physiology MESH Heart Ventricles MESH Hydrogen-Ion Concentration MESH Intracellular Membranes/metabolism MESH Myocardial Contraction MESH Myocardium/cytology MESH Ouabain/pharmacology MESH Protein Kinase C/pharmacology MESH Rats MESH Sodium-Hydrogen Antiporter MESH
Dewey Decimal Classification:	600 Technology > 610 Medical sciences Medicine
Status:	Published
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Unknown
Item ID:	22055

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Abstract

Endothelin, a 21-amino acid vasoactive peptide, is among the most potent positively inotropic agents yet described in mammalian heart. Having demonstrated that endothelin's inotropic effect is due, in part, to an apparent sensitization of cardiac myofilaments to intracellular calcium, we determined whether this could be due to a rise in intracellular pH (pHi). In isolated adult rat ventricular ...

Abstract

Endothelin, a 21-amino acid vasoactive peptide, is among the most potent positively inotropic agents yet described in mammalian heart. Having demonstrated that endothelin's inotropic effect is due, in part, to an apparent sensitization of cardiac myofilaments to intracellular calcium, we determined whether this could be due to a rise in intracellular pH (pHi). In isolated adult rat ventricular cells loaded with the H(+)-selective fluorescent probe BCECF, 100 pM endothelin increased contractile amplitude to 190 +/- 26% of baseline and pHi by 0.08 +/- 0.02 (n = 8), whereas 1 nM endothelin increased pHi by 0.13 +/- 0.03 with little further increase in contractility. Amiloride (10(-4)M) prevented the increase in pHi in response to endothelin and reduced the inotropic response by 45%, although the inotropic effect could be readily restored by subsequent NH4Cl-induced alkalinization. Similarly, inhibitors of protein kinase C (H-7 and sphingosine) diminished or abolished the rise in pHi after endothelin superfusion while causing a decline in its inotropic effect comparable with that observed with amiloride. Pretreatment with pertussis toxin, which we have demonstrated results in complete ADP-ribosylation of the alpha-subunits of Go and Gi GTP-binding proteins and abolition of endothelin's positive inotropic effect, only partially reduced the intracellular alkalinization induced by the peptide, suggesting a complex signal transduction mechanism. Thus, the positive inotropic action of endothelin is due in part to stimulation of the sarcolemmal Na(+)-H+ exchanger by a protein kinase C-mediated pathway, resulting in a rise in pHi and sensitization of cardiac myofilaments to intracellular Ca2+.

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