Dual Signaling via Protein Kinase C and Phosphatidylinositol 3′-Kinase/Akt Contributes to Bradykinin B2Receptor-induced Cardioprotection in Guinea Pig Hearts

We investigated the role of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3-K) in the signaling mechanism of cardioprotection afforded by bradykinin (BK). Coronary-perfused guinea pig ventricular muscles were subjected to 20-min no-flow ischemia and 60-min reperfusion. Pretreatment for 5 min with BK (1 μ m) significantly improved the recovery of developed tension measured after 60 min of reperfusion (86.8±2.6%v 34.8±4.1% in control). Prior treatment with B2receptor antagonist HOE 140 completely abolished the protective effect of BK (37.0±7.6%). The protection was reduced by either PKC inhibitor chelerythrine (CH, 58.9±2.2%) or PI3-K inhibitor wortmannin (WM, 59.4±2.5%); however, the recovery of contractility was intermediate between the BK and control groups. Nevertheless, pretreatment with CH and WM together completely eliminated the protective effect of BK (38.9±4.2%). The mitochondrial ATP-sensitive K+(mitoKATP) channel blocker 5-hydroxydecanoate (5HD) significantly but partially inhibited the effect of BK (59.0±2.2%). Pretreatment with 5HD and CH together could not generate further inhibition (61.1±3.3%), while pretreatment with 5HD and WM together totally eliminated the protection (34.9±2.9%). We conclude that BK B2receptors can precondition guinea pig hearts via the dual activation of PKC and PI3-K. The mitoKATPchannels act as downstream targets of PKC, whereas PI3-K is not associated with mitoKATPchannels.