Synergistic modulation of ATP-sensitive K+ currents by protein kinase C and adenosine: Implications for ischemic preconditioning

Yongge Liu, Wei Dong Gao, Brian O'Rourke, Eduardo Marban

Research output: Contribution to journalArticle

Abstract

Ischemic preconditioning has been shown to involve the activation of adenosine receptors, protein kinase C (PKC), and ATP sensitive K+ (K(ATP)) channels. We investigated the effects of PKC activation and adenosine on K(ATP) current (I(KATP))) and action potentials in isolated rabbit ventricular myocytes. Responses to pinacidil (100 to 400 μmol/L), an opener of K(ATP) channels, were markedly increased by preexposure to the PKC activator phorbol 12-myristate 13-acetate (PMA, 100 nmol/L). I(KATP) measured at 0 mV was increased by PMA pretreatment from 0.55±0.32 to 3.25±0.47 nA (n=6, P<.01). We next determined whether PKC activation abbreviates the time required to turn on I(KATP) during metabolic inhibition (MI). In control cells in which MI was induced by 2 mmol/L cyanide and 0 glucose, I(KATP) developed after an average of 15.1±2.4 minutes (n=8). Ten-minute pretreatment with PMA alone (PMA+MI) did not significantly alter this latency (11.9±2.0 minutes, n=8). Since adenosine receptor activation has been shown to play an important role in the preconditioning response, two groups of myocytes were studied with adenosine (10 μmol/L) included during MI. Without PMA, adenosine alone (MI+Ado) did not affect the latency to develop I(KATP) (12.3±1.5 minutes, n=8). However, if cells were pretreated with PMA and then subjected to MI in the presence of adenosine (PMA+MI+Ado), the latency was greatly shortened to 5.5±1.6 minutes (n=8; P<.02 versus MI, PMA+MI, and MI+Ado groups). This effect could not bc reproduced by an inactive phorbol but was completely abolished by the adenosine receptor antagonist 8-(p- sulfophenyl)-theophylline. The opening of K(ATP) channels may be cardioprotective because of the abbreviation of action potential duration (APD) during ischemia. Therefore, we tested whether PKC activation could modify the time course of APD shortening during MI. Consistent with the ionic current measurements, PMA pretreatment significantly accelerated APD shortening, but only when adenosine (10 μmol/L) was included during MI. The effects were not attributable to accelerated ATP consumption: PMA pretreatment did not alter the time required to induce rigor during MI, whether or not adenosine was included. Our results indicate that PKC activation increases the I(KATP) induced by pinacidil or by MI. The latter effect requires concomitant adenosine receptor activation. The synergistic modulation of I(KATP) by PKC and adenosine provides an explicit basis for current paradigms of ischemic preconditioning.

Original languageEnglish (US)
Pages (from-to)443-454
Number of pages12
JournalCirculation research
Volume78
Issue number3
DOIs
StatePublished - Mar 1996

Keywords

  • ATP-sensitive
  • K current
  • adenosine
  • ischemic preconditioning
  • pinacidil
  • protein kinase C

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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