Protein kinase C isoform activation and endothelin-1 mediated defects in myocyte contractility after cardioplegic arrest and reperfusion.

BACKGROUND:Endothelin-1 (ET-1) is released after hyperkalemic cardioplegic arrest (CA) and reperfusion and may contribute to contractile dysfunction. ET-1 receptor transduction causes activation of protein kinase C isoforms, which can cause differential intracellular events. The goal of this study was to determine which isoforms contribute to myocyte contractile dysfunction with ET-1 and CA. METHODS AND RESULTS:Percent shortening (PERSHORT) and the time to 50% relaxation (T50) were measured in porcine (n =22) left ventricular myocytes, randomized (minimum: 30 cells/group) to normothermia: (cell media for 2 hours/37 degrees C), and CA: (2 hours/4 degrees C, 24 mEq K+ solution followed by reperfusion in cell media), ET-1/CA: (100 pM ET-1 during CA). Studies were performed in the presence and absence of duanyu1531 inhibitors (500 nM) against the classical (Beta-I, Beta-II, Gamma) and novel (Epsilon, Eta) isoforms (myocytes from a minimum of 3 pigs per inhibitor). CA reduced PERSHORT by approximately 35% from normothermia (P<0.05), which was further reduced with ET-1. or inhibition increased PERSHORT from ET-1/CA as well as CA only (P<0.05). CA prolonged T50 by approximately 19% from normothermia (P<0.05) and was further prolonged with ET-1. Inhibition of the classical duanyu1531 isoforms reduced T50 from ET-1/CA (P<0.05). Inhibition of novel duanyu1531 isoforms did not yield similar effects on either PERSHORT or T50 with ET-1/CA. CONCLUSIONS:Inhibition of the classical duanyu1531 isoforms relieved the negative inotropic and lusitropic effects of ET-1 after CA. These findings provide mechanistic support for developing targeted inhibitory strategies with respect to ET-1 signaling and myocyte contractile dysfunction with cardioplegic arrest and reperfusion.

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