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(Circulation. 2006;114:I-308 – I-313.)
© 2006 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Protein Kinase C Isoform Activation and Endothelin-1 Mediated Defects in Myocyte Contractility After Cardioplegic Arrest and Reperfusion

Rupak Mukherjee, PhD; Kimberly A. Apple, MD; Christina E. Squires, BS; Brooke S. Kaplan, BS; Julie E. McLean, BS; Stuart M. Saunders, BS; Robert E. Stroud, MS; Francis G. Spinale, MD, PhD

From the Division of Cardiothoracic Surgery Research, Medical University of South Carolina, and Ralph H. Johnson Veteran’s Administration Medical Center, Charleston, SC.

Correspondence to Rupak Mukherjee, Cardiothoracic Surgery, 770 MUSC Complex, Suite 625, Medical University of South Carolina, Charleston, SC 29425. E-mail mukherr{at}musc.edu

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 (PKC) isoforms, which can cause differential intracellular events. The goal of this study was to determine which PKC 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°C), and CA: (2 hours/4°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 PKC 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 &35% from normothermia (P<0.05), which was further reduced with ET-1. PKC-Beta-II or PKC-Gamma inhibition increased PERSHORT from ET-1/CA as well as CA only (P<0.05). CA prolonged T50 by &19% from normothermia (P<0.05) and was further prolonged with ET-1. Inhibition of the classical PKC isoforms reduced T50 from ET-1/CA (P<0.05). Inhibition of novel PKC isoforms did not yield similar effects on either PERSHORT or T50 with ET-1/CA.

Conclusions— Inhibition of the classical PKC 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.

Key Words: active relaxation • cardioplegia • endothelin • kinases • myocyte contractility