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.