Isoflurane decreases ATP sensitivity of guinea pig cardiac sarcolemmal KATP channel at reduced intracellular pH

Abstract

Background: Volatile anesthetics can protect the myocardium against ischemic injury by opening the adenosine triphosphate (ATP)-sensitive potassium (KATP) channels. However, direct evidence for anesthetic-channel interaction is still limited, and little is known about the role KATP channel modulators play in this effect. Because pH is one of the regulators of KATP channels, the authors tested the hypothesis that intracellular pH (pHi) modulates the direct interaction of isoflurane with the cardiac KATP channel. Methods: The effects of isoflurane on sarcolemmal KATP channels were investigated at pHi 7.4 and pHi 6.8 in excised inside-out membrane patches from ventricular myocytes of guinea pig hearts. Results: At pHi 7.4, intracellular ATP (1-1,000 μM) inhibited KATP channels and decreased channel open probability (Po) in a concentration-dependent manner with an IC50 of 8 ± 1.5 μM, and isoflurane (0.5 mM) either had no effect or decreased channel activity. Lowering pHi from 7.4 to 6.8 enhanced channel opening by increasing Po and reduced channel sensitivity to ATP, with IC50 shifting from 8 ± 1.2 to 45 ± 5.6 μM. When applied to the channels activated at pHi 6.8, isoflurane (0.5 mM) increased Po and further reduced ATP sensitivity, shifting IC50 to 110 ± 10.0 μM. Conclusions: Changes in pHi appear to modulate isoflurane interaction with the cardiac KATP channel. At pHi 6.8, which itself facilitates channel opening, isoflurane enhances channel activity by increasing Po and reduces sensitivity to inhibition by ATP without changing the unitary amplitude of single channel current or the conductance. These results support the hypothesis of direct isoflurane-KATP channel interaction that may play a role in cardioprotection by volatile anesthetics.