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CLINICAL STUDIES

Renal ischemia/reperfusion remotely improves myocardial energy metabolism during myocardial ischemia via adenosine receptors in rabbits: effects of "remote preconditioning"

Atsushi Takaoka, MD^a, Ichiro Nakae, MD, PhD^a, Kenichi Mitsunami, MD, PhD^*, Takahiro Yabe, MD, PhD^a, Shigehiro Morikawa, MD, PhD, Toshiro Inubushi, PhD and Masahiko Kinoshita, MD, PhD^a

^a First Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu 520-2192, Japan
^* Department of General Medicine, Medical Coordination Center, Shiga University of Medical Science, Seta, Otsu 520-2192, Japan
Molecular Neurobiology Research Center, Shiga University of Medical Science, Seta, Otsu 520-2192, Japan

Manuscript received May 19, 1998; revised manuscript received September 1, 1998, accepted October 2, 1998.

Reprint requests and correspondence: Dr. Atsushi Takaoka, First Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu 520-2192, Japan
taka5836{at}belle.shiga-med.ac.jp

Objectives

This study examined the changes in myocardial energy metabolism during myocardial ischemia after "remote preconditioning" and investigated the involvement of adenosine receptors in the mechanisms of this effect.

Background

Recent studies have indicated that a brief period of ischemia and reperfusion (ischemic preconditioning, PC) in a remote organ reduces myocardial infarct size (IS) protecting against subsequent sustained myocardial ischemia. However, the mechanisms of "remote PC" remain unclear. We assessed myocardial energy metabolism during sustained myocardial ischemia and reperfusion after renal PC (RPC), in comparison with that after myocardial PC (MPC) in open-chest rabbits. It has been established that adenosine receptors are involved in the mechanisms of MPC.

Methods

Rabbits that had been anesthetized with halothane were divided into six groups. The control (CNT) group underwent 40-min coronary occlusion followed by 120 min reperfusion. Before the procedure, the MPC group underwent an additional protocol of 5 min coronary artery occlusion and 20 min reperfusion, and the RPC group received a 10 min episode of renal artery occlusion and 20 min reperfusion. In additional experimental groups, 8 sulfophenyltheophylline (SPT, 10 mg/kg), an adenosine receptor inhibitor, was intravenously injected before the 40 min myocardial ischemia (SPT, MPC + SPT and RPC + SPT groups, respectively). Myocardial levels of phosphocreatine (PCr), ATP and intracellular pH (pHi) were measured by ³¹P-NMR spectroscopy.

Results

RPC and MPC delayed the decreases in ATP levels, preserved pHi during 40-min myocardial ischemia and resulted in better recovery of ATP and PCr during 120 min reperfusion compared with the controls. SPT abolished the improvement in myocardial energy metabolism and the reduction in myocardial IS caused by MPC or RPC. Myocardial IS in the CNT (n = 8), MPC (n = 9), RPC (n = 9), SPT (n = 6), MPC + SPT (n = 8) and RPC + SPT (n = 8) groups averaged 42.8 ± 3.5%, 18.2 ± 1.8%*, 19.6 ± 1.3%*, 44.9 ± 5.0%, 35.6 ± 2.7% and 34.8 ± 3.6% of the area at risk (*p < 0.05 vs. CNT), respectively.

Conclusions

PC in a remote organ, similar to MPC, improved myocardial energy metabolism during ischemia and reperfusion and reduced IS in vivo by an adenosine-dependent mechanism in rabbits.

Abbreviations and Acronyms   AAR = area at risk   CNT = control   2,3-DPG = 2, 3-diphosphoglyceric acid   IS = infarct size   MPC = myocardial ischemic preconditioning   PC = ischemic preconditioning   PCr = phosphocreatine   pHi = intracellular pH   RPC = renal ischemic preconditioning   SPT = 8-sulfophenyltheophylline

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