title: Phenylephrine preconditioning involves modulation of cardiac sarcolemmal K(ATP) current by PKC delta, AMPK and p38 MAPK.
abstract: Preconditioning of hearts with the α(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 ε and δ (PKCε and PKCδ), 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 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 sarcK(ATP) 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 sarcK(ATP) current induced by phenylephrine preconditioning requires PKCδ, AMPK and p38 and may contribute to the observed improvement in contractile recovery.
authors: Department of Cell Physiology & Pharmacology, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors: Helen E
authors: HE
authors: Turrell
authors: Glenn C
authors: GC
authors: Rodrigo
authors: Robert I
authors: RI
authors: Norman
authors: Martin
authors: M
authors: Dickens
authors: Nicholas B
authors: NB
authors: Standen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012508:Sarcolemma / Q000187:drug effects* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D054086:KATP Channels; D010656:Phenylephrine; D017346:Protein Serine-Threonine Kinases; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases