Isoflurane sensitizes the cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel to pinacidil

Abstract

Background: Cardioprotective effects of isoflurane are partially mediated by the sarcolemmal adenosine triphosphate-sensitive potassium (sarcKATP) channel. The authors tested the hypothesis that isoflurane sensitizes sarCKATP channels to a potassium channel opener, pinacidil, via adenosine- and phospholipid-mediated pathways. Methods: Activation by pinacidil of the KATP current (IKATP) was monitored in guinea pig ventricular myocytes at 0.5 and 5 mM intracellular ATP in the whole cell configuration of the patch clamp technique. The sensitization effect was evaluated by pretreating each myocyte with isoflurane (0.57 ± 0.04 mM) before application of pinacidil (5 μM) in the continued presence of the anesthetic. To investigate whether intracellular signaling pathways may be involved in isoflurane sensitization, the authors used the adenosine receptor antagonist theophylline (100 μM) and the phosphatidylinositol kinase inhibitor wortmannin (100 μM). Results: The density of pinacidil-activated IKATP was higher at 0.5 mM ATP (20.7 ± 3.2 pA/pF) than at 5 mM ATP (2.0 ± 0.3 pA/pF). At 0.5 mM ATP, pretreatment with isoflurane caused an increase in density of pinacidil-activated IKATP (42.4 ± 6.2 pA/pF) and accelerated the rate of current activation (from 5.4 ± 1.2 to 39.0 ± 7.9 pA · pF-1 · min-1). Theophylline attenuated current activation by pinacidil (9.4 ± 3.9 pA/pF) and abolished the sensitization effect of isoflurane on IKATP (10.0 ± 2.5 pA/pF). Wortmannin did not alter pinacidil activation of IKATP (13.2 ± 1.7 pA/pF) but prevented sensitization by isoflurane (15.8 ± 4.5 pA/pF). Conclusions: These results suggest that isoflurane increases sensitivity of cardiac sarcKATP channels to the potassium channel opener pinacidil. Blockade of adenosine receptors or phosphatidylinositol kinases abolishes the sensitization effect, suggesting that the adenosine and phospholipid signaling pathways may be involved in the actions by isoflurane.