The inotropic response to endothelin-1 differs significantly between isolated ventricular myocytes and intact papillary muscles in rabbits, likely due to integrated regulatory mechanisms involving noncardiac cells in the myocardium.
Isolated myocyte ET-1 responses may overestimate potency in intact myocardium; leaves open non-myocyte modulation of endothelin inotropy.
Endothelin-1 (ET-1) increased cell shortening and Ca2+ transients over the concentration of 3 x 10(-11) M to 10(-9) M with EC50 of 8.3 x 10(-11) M in rabbit single ventricular myocytes. Thus ET-1 was approximately 60 times more potent in single myocytes than in papillary muscles (EC50 = 5.1 x 10(-9) M) of the same species. In single myocytes, ET-1 at 10(-8) M elicited an inhibitory response that counteracted the facilitatory response: the concentration-response curve (CRC) for ET-1 was bell shaped. The ET(A)-receptor antagonist BQ-485 shifted CRC for ET-1 to the right in parallel; however, the facilitatory response to 10(-8) M ET-1 was markedly enhanced by BQ-485 and also by the ET(B) antagonist BQ-788. The ET(A)/ET(B) antagonist TAK-044 abolished the ET-1-induced response. These findings indicate that the response to ET-1 of single myocytes is different from that of papillary muscles in concentration dependence, characteristics of the response, and susceptibility to ET-receptor antagonists. Anomalous pharmacological characteristics of ET-1-induced response in rabbit papillary muscles may be due to integrated regulatory mechanisms that may involve also various types of noncardiac cell in ventricular myocardium.
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Talukder et al. (2001) studied this question.
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