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Pretreatment with an adenosine A1 receptor agonist and a possible alternative to myocardial ischemic preconditioning

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Pretreatment with adenosine A1 receptor-agonist and lidocaine: a possible alternative to Myocardial Ischemic Preconditioning.

Sarah J. Canyon PhD and Geoffrey P. Dobson PhD
Department of Physiology and Pharmacology
School of Biomedical Sciences
James Cook University
Queensland Australia

Key words: adenosine, CCPA, A1 agonist, sodium channels, local anaesthetics, ischemia, preconditioning, infarction, heart

 

 Abstract

 

Objective:  The heart possesses an extraordinary ability to ‘remember’ short episodes of sublethal ischemia-reperfusion (angina) which protects the myocardium and coronary vasculature from a subsequent lethal insult, a phenomenon known as ischaemic preconditioning (IPC). A therapeutic goal for over two decades has been to develop a pharmacological mimetic comparable to IPC. 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 anaesthetised, ventilated Sprague-Dawley rats (n=37). Rats were randomly assigned to one of five groups: (1) Saline controls (n=13); (2) Ischemic preconditioning (IPC) (n=6); (3) Lidocaine only (LIDO, 608 ug/kg/min) (n=5); (4) Adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 5ug/kg) (n=7) (5) CCPA plus LIDO (n=6). IPC was achieved using 3x3 min cycles of ischemia/reperfusion. Lidocaine was infused continuously 5 min before and throughout 30 min ischemia, and ceased at reperfusion. A bolus of CCPA was infused 5 min before ligation along with a constant infusion of lidocaine (as above). All animals were reperfused for 120 min for infarct size measurement.

Results:  54% percent saline controls, 17% IPC, 29% CCPA-treated rats died during ischemia from ventricular fibrillation. Infarct size of saline-controls was 61±5%. Pretreating with CCPA and lidocaine infusion resulted in no deaths, no severe arrhythmias and significant infarct size reduction compared to saline-controls (P<0.05). Remarkably, infarct size reduction in CCPA plus LIDO treated rats (12±4%) was equivalent to ischemic preconditioning (11±3%) whereas infarct size CCPA-only and LIDO-only treatments was 42±7% and 60±6% respectively. While CCPA plus LIDO 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 and concomitantly modulating Na+ fast channels with lidocaine is comparable to IPC and may offer a new therapeutic window to minimise myocardial damage during surgical ischemia-reperfusion.