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Ischemic preconditioning: differences in protection and susceptibility to blockade with single-cycle versus
1Research Institute, the Hospital for Sick Children, Department of Physiology, University of Toronto, Ontario, Canada. r.sandhu@utoronto.ca
Background:
We compared ischemic preconditioning (IP) induced with a single cycle of transient ischemia and reperfusion with that induced by multiple cycles in terms of (1) efficacy of protection against myocardial necrosis and (2) susceptibility to pharmacological blockade by inhibition of protein kinase C (PKC) or elevation of cAMP.
Methods And Results:
All rabbits were subjected to 30 minutes of regional ischemia and 90 minutes of reperfusion in vivo. IP was induced with either one or three cycles of 5-minute transient ischemia and 10-minute reperfusion given before the 30-minute ischemia. Drug-treated hearts received a bolus dose of one of the following just before the 30-minute ischemia: (1) the PKC inhibitor chelerythrine (3.8 mg/kg), (2) the PKC inhibitor polymyxin B (10 mg/kg), or (3) the cAMP-increasing agent NKH477 (45 microg/kg). IP induced with either one or three cycles of transient ischemia and reperfusion significantly protected the heart against infarction, although the extent of protection was significantly greater with three-cycle IP. Chelerythrine, polymyxin B, or NKH477 alone did not alter infarct size in control hearts, nor did they increase infarct size in hearts preconditioned with three-cycle IP. In contrast, when IP was induced with only a single cycle, all three of these drugs significantly increased infarct size above that of the untreated one-cycle IP group. However, infarct size in all three of these drug-treated one-cycle IP groups was still significantly lower than that in the corresponding drug-treated controls, indicating a partial block of IP.
Conclusions:
Three-cycle IP provided more effective protection against myocardial necrosis than one-cycle IP and was less susceptible to blockade by inhibitors of PKC or an agent that increases cAMP levels. However, single-cycle IP was only partially blocked by either inhibition of PKC or stimulation of cAMP production. Neither activation of the PKC pathway nor reduced formation of cAMP alone fully accounted for the necrosis protection by IP even when induced with only a single cycle of transient ischemia.