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

• Published in: Journal of molecular and cellular cardiology 2011-09, Vol.51 (3), p.370-380
• Main Authors: Turrell, Helen E, Rodrigo, Glenn C, Norman, Robert I, Dickens, Martin, Standen, Nicholas B
• Format: Article
• Language: English
• Subjects: Cardiovascular
• ISSN: 0022-2828
• DOI: 10.1016/j.yjmcc.2011.06.015

Abstract Preconditioning of hearts with the α1 -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 ε and δ (PKCε and PKCδ), AMP-activated protein kinase (AMPK), p38 MAPK (p38) and sarcolemmal ATP-sensitive potassium ( sarc KATP ) 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 sarc KATP 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 PKCε and PKCδ, and transient activation of AMPK, which was dependent upon activation of PKCδ but not PKCε. P38 was also activated by phenylephrine preconditioning and this was blocked by inhibitors of PKCε, PKCδ or AMPK. Inhibition of PKCδ, AMPK or p38 was sufficient to prevent the increase in current, suggesting that these kinases are involved in modulation of sarc KATP channel current by phenylephrine preconditioning. However, whilst inhibition of AMPK and p38 prevented the protection from phenylephrine preconditioning, PKCδ inhibition paradoxically had no effect. The increase in sarc KATP current induced by phenylephrine preconditioning requires PKCδ, AMPK and p38 and may contribute to the observed improvement in contractile recovery.