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J Thorac Cardiovasc Surg 2005;130:371-377
© 2005 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Pretreatment with an adenosine A1 receptor agonist and lidocaine: A possible alternative to myocardial ischemic preconditioning

Department of Physiology and Pharmacology, School of Biomedical Sciences, James Cook University, Queensland, Australia

Received for publication August 2, 2004; revisions received December 15, 2004; accepted for publication December 23, 2004.

^_* Address for reprints: Geoffrey P. Dobson, PhD, Department of Physiology and Pharmacology, Molecular Science Building, James Cook University, Townsville, Queensland 4811, Australia (Email: geoffrey.dobson{at}jcu.edu.au).

OBJECTIVE: The heart possesses an extraordinary ability to remember short episodes of sublethal ischemia and reperfusion (angina), which protects the myocardium and coronary vasculature from a subsequent lethal insult, a phenomenon known as ischemic preconditioning. A therapeutic goal for more than 2 decades has been to develop a pharmacologic mimetic comparable with ischemic preconditioning. Our aim was to investigate the preconditioning effect of a new combinatorial therapy targeting adenosine A1 receptors and voltage-dependent sodium fast channels in the in vivo rat model of regional ischemia.

METHODS: Ischemia-reperfusion was achieved by placing a reversible tie around the left coronary artery in anesthetized and ventilated Sprague-Dawley rats (n = 37). Rats were randomly assigned to 1 of 5 groups: (1) saline control (n = 13); (2) ischemic preconditioning (n = 6); (3) lidocaine only (608 µg · kg^–1 ·min^–1, n = 5); (4) adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA; 5 µg/kg, n = 7); and (5) CCPA plus lidocaine (n = 6). Ischemic preconditioning was achieved by using 3 cycles of ischemia and reperfusion lasting 3 minutes each. Lidocaine was infused continuously 5 minutes before and throughout 30 minutes of ischemia and ceased at reperfusion. A bolus of CCPA was infused 5 minutes before ligation along with a constant infusion of lidocaine (as above). All animals were reperfused for 120 minutes for infarct size measurement.

RESULTS: Fifty-four percent of saline control rats, 17% of ischemic preconditioning-treated rats, and 29% of CCPA-treated rats died during ischemia from ventricular fibrillation. Infarct size of saline control animals was 61% ± 5%. Pretreating with CCPA and lidocaine infusion resulted in no deaths, no severe arrhythmias, and significant infarct size reduction compared with that seen in saline control animals (P < .05). Remarkably, infarct size reduction in CCPA plus lidocaine-treated rats (12% ± 4%) was equivalent to that achieved with ischemic preconditioning (11% ± 3%), whereas infarct size in rats undergoing CCPA-only and lidocaine-only treatments was 42% ± 7% and 60% ± 6%, respectively. Although CCPA plus lidocaine treatment reduced heart rate, mean arterial pressure, and systolic pressure during ischemia, no correlation was found between these variables and infarct size reduction.

CONCLUSION: We conclude that activating adenosine A1 receptor subtype with CCPA and concomitantly modulating sodium fast channels with lidocaine was comparable with ischemic preconditioning and might offer a new therapeutic window to minimize myocardial damage during surgical ischemia and reperfusion.

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