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Right arrow Cardiac - pharmacology
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Right arrow Transplantation - heart

J Thorac Cardiovasc Surg 2008;136:1586-1592
© 2008 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

A Rho-kinase inhibitor improves cardiac function after 24-hour heart preservation

Mariko Kobayashi, MD, Yoshihisa Tanoue, MD*, Masataka Eto, MD, Hironori Baba, MD, Satoshi Kimura, MD, Shinichiro Oda, MD, Kenichiro Taniguchi, MD, Ryuji Tominaga, MD

Department of Cardiovascular Surgery, Kyushu University, Fukuoka, Japan

Received for publication May 3, 2008; revisions received July 9, 2008; accepted for publication July 26, 2008.

* Address for reprints: Yoshihisa Tanoue, MD, Department of Cardiovascular Surgery, Kyushu University, 3-1-1 Maidashi Higashi-ku Fukuoka, 812-8582, Japan. (Email: tanoue{at}heart.med.kyushu-u.ac.jp).

Objective: The Rho-kinase signaling pathway is associated with coronary vasculopathy and myocardial dysfunction after cardiac transplantation. This study evaluated whether using a Rho-kinase inhibitor during allograft storage could limit early endothelial dysfunction and improve myocardial performance after reperfusion.

Methods: This experiment was performed with an isolated working rabbit heart model and a support rabbit. Donor hearts (control group, n = 8) were arrested with an extracellular type of cardioplegia, preserved with University of Wisconsin solution, and then immersed in University of Wisconsin solution for 24 hours (1°C). The Rho-kinase inhibitor (Rho-kinase inhibitor group, n = 8) was administrated in the cardioplegic solution, the preservation University of Wisconsin solution, and the storage University of Wisconsin solution. Left ventricular performance was evaluated from the modified Frank–Starling curve in the working mode. Coronary blood flow and donor heart rate were measured in Langendorff mode. Effective evaluation of the Rho-kinase inhibitor was inferred from phosphorylated myosin light chain. The expression of endothelial nitric oxide synthase mRNA was analyzed to assess endothelial function.

Results: The Frank–Starling curve showed a significant left and upward shift in the Rho-kinase inhibitor group compared with the control group (P < .05). The coronary blood flow and heart rate in the Rho-kinase inhibitor group at 120 minutes was significantly higher than in the control group (P < .05). Phosphorylated myosin light chain was significantly suppressed in the Rho-kinase inhibitor group (P < .05). Endothelial nitric oxide synthase mRNA levels in the Rho-kinase inhibitor group increased 4-fold relative to those seen in the control group.

Conclusions: Treatment with Rho-kinase inhibitor during allograft harvest and storage enhanced coronary blood flow and ventricular recovery through nitric oxide–dependent endothelial protection after reperfusion. Rho-kinase inhibitor could help prevent early myocardial dysfunction after transplantation.

Abbreviations and Acronyms CBF = coronary blood flow; CKMB = creatine kinase–MB; Ct = cycle threshold; eNOS = endothelial nitric oxide synthase; LAP = left atrial pressure; LV = left ventricular; MLC = myosin light chain; NO = nitric oxide; p-MLC = phosphorylated myosin light chain; RKI = Rho-kinase inhibitor; TUNEL = terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling; UW = University of Wisconsin






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