We previously reported that acute intermittent
hypoxia (IH) confers delayed cardioprotection against a prolonged ischemic insult in the rat, via the involvement of
nitric oxide synthase and K(
ATP) channels. In the present study, we investigated the role of
protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K), stress activated
p38 MAP kinase (MAPK) and
extracellular signal-regulated kinase (ERK1/2) using selective inhibitors of these pathways. Adult male rats were exposed to 1-min cycles of IH (10% O(2), 40 s)/normoxia (21% O(2), 20 s) during 4 h or to normoxic cycles. 24 h later, isolated hearts were perfused in Langendorff mode and subjected to a 30-min global
ischemia followed by 120 min of reperfusion. Compared to normoxic conditions, IH significantly reduced
infarct size (22.2+/-2.4% vs. 33.8+/-2.6%, p<0.05), improved coronary flow and decreased the
contracture at reperfusion. When administered before sustained
ischemia,
chelerythrine (a PKC inhibitor) abolished both the IH-induced reduction in
infarct size (36.1+/-4.9%) and improvement in hemodynamic parameters. In contrast,
chelerythrine administration 10 min before IH, did not modify the delayed cardioprotective response. Similarly,
wortmannin (a PI3K inhibitor) administration 10 min before IH was unable to block the cardioprotective effects. However, administration of
SB203580 (a
p38 MAPK inhibitor) and
PD98059 (an Erk1/2 inhibitor), 30 min before IH abolished its delayed
infarct-sparing effect (32.2+/-3.4% and 33.9+/-2.9%, respectively). In addition, 24 h after IH, a significant increase in
p38 MAPK and Erk1/2 phosphorylation was observed by Western blot. These results suggest that the delayed preconditioning induced by intermittent
hypoxia does not involve the PI3K signalling pathway and that is mediated by PKC and triggered by
p38 MAPK and Erk1/2.