Phenylephrine preconditioning involves modulation of cardiac sarcolemmal K-ATP current by PKC delta, AMPK and p38 MAPK

作者：Turrell Helen E; Rodrigo Glenn C; Norman Robert I; Dickens Martin^*; Standen Nicholas B

来源：Journal of Molecular and Cellular Cardiology, 2011, 51(3): 370-380.

DOI：10.1016/j.yjmcc.2011.06.015

• Phenylephrine
• Cardioprotection
• K-ATP channel
• PKC
• AMPK
• p38 MAPK

Preconditioning of hearts with the alpha(1)-adrenoceptor agonist phenylephrine decreases infarct size and increases the functional recovery of the heart following ischaemia-reperfusion. However, the cellular mechanisms responsible for this protection are not known. We investigated the role of protein kinase C epsilon and delta (PKC epsilon and PKC delta). AMP-activated protein kinase (AMPK), p38 MAPK (p38) and sarcolemmal ATP-sensitive potassium (sarcK(ATP)) channels in phenylephrine preconditioning using isolated rat ventricular myocytes. Preconditioning of ventricular myocytes with phenylephrine increased the recovery of contractile activity following metabolic inhibition and re-energisation from 30.1 +/- 1.9% to 66.5 +/- 5.2% (P<0.01) and increased the peak sarcK(ATP) current activated during metabolic inhibition from 32.1 +/- 1.8 pA/pF to 46.0 +/- 5.0 pA/pF (P < 0.05), which was required for protection. Phenylephrine preconditioning resulted in a sustained activation of PKC epsilon and PKC delta, and transient activation of AMPK, which was dependent upon activation of PKC delta but not PKC epsilon. P38 was also activated by phenylephrine preconditioning and this was blocked by inhibitors of PKC epsilon, PKC delta or AMPK. Inhibition of PKC delta, AMPK or p38 was sufficient to prevent the increase in current, suggesting that these kinases are involved in modulation of sarcK(ATP) channel current by phenylephrine preconditioning. However, whilst inhibition of AMPK and p38 prevented the protection from phenylephrine preconditioning, PKC delta inhibition paradoxically had no effect. The increase in sarcK(ATP) current induced by phenylephrine preconditioning requires PKC delta. AMPK and p38 and may contribute to the observed improvement in contractile recovery.

• 出版日期2011-9