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Title of article :
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
Author/Authors :
Angelino Calderone، نويسنده , , Jean L. Rouleau، نويسنده , , Jacques de Champlain، نويسنده , , Pierre Bélichard، نويسنده , , Duncan J. Stewart، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 1993
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Abstract :
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 μM), 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.
Keywords :
heart failure , ET-1 receptor , Homologous desensitization , Plasma ET-1 , protein kinase C
Journal title :
Journal of Molecular and Cellular Cardiology
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