Regulation of the endothelin-1 transmembrane signaling pathway: the potential role of agonist-induced desensitization in the coronary artery of the rapid ventricular pacing-overdrive dog model of heart failure.
This study examined the potential role of ET-1 and the contribution of protein kinase C (PKC) in the desensitization of the ET-1 transmembrane signaling pathway in the left circumflex coronary artery (CCA) of a dog model of congestive heart failure (CHF). In the CCA of the rapid ventricular pacing-overdrive dog model of CHF, elevated plasma endothelin levels were associated with a decrease in the basal accumulation of inositol phosphates and ET-1 mediated activation of phosphatidylinositol (PI) turnover (P < 0.05). To assess whether elevated plasma ET-1 levels may have contributed to the diminished ET-1 responsiveness in the heart failure dogs, ET-1 generation of inositol phosphates was measured following a one hour pretreatment of normal coronary artery rings with 0.1 nM ET-1. As compared to non-treated rings, ET-1 pretreatment resulted in a 33% decrease of ET-1 (10 nM) production of inositol phosphates. To evaluate the role of PKC in this process, normal coronary rings pretreated for a period of one hour with the phorbol ester, phorbol 12-myristate 13-acetate (PMA, 1 microM), resulted in a similar attenuation (36%) of ET-1 production of inositol phosphates. In the presence of the protein kinase C inhibitor staurosporine, both the agonist and phorbol ester induced decreases in ET-1 mediated PI turnover were reversed. Staurosporine even potentiated (75%) ET-1 induced PI turnover despite ET-1 and PMA pretreatments. These results suggest that agonist-induced desensitization of ET-1 mediated PI turnover can occur and is at least one of the possible mechanisms contributing to the desensitization of the ET-1 transmembrane signaling pathway in the pacing-overdrive model of heart failure in the dog.
Calderone
A
A
Faculté de Médecine, Dépt. de Physiologie, Université de Montréal, Quebec, Canada.
Rouleau
J L
JL
de Champlain
J
J
Bélichard
P
P
Stewart
D J
DJ
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000378:metabolism; D003331:Coronary Vessels / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D016232:Endothelins / Q000378:metabolism* / Q000494:pharmacology; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011863:Radioimmunoassay; D017466:Receptors, Endothelin / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism
D000470:Alkaloids; D016232:Endothelins; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D017466:Receptors, Endothelin; D011493:Protein Kinase C; D010738:Type C Phospholipases; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate