A key role for the subunit SUR2B in the preferential activation of vascular K_ATP channels by isoflurane

Abstract

Background and purpose: It has been postulated that isoflurane, a volatile anaesthetic, produces vasodilatation through activation of ATP-sensitive K þ (K ATP ) channels. However, there is no direct evidence for the activation of vascular K ATP channels by isoflurane. This study was conducted to examine the effect of isoflurane on vascular K ATP channels and compare it with that on cardiac K ATP channels. Experimental approach: Effects of isoflurane on K ATP channels were examined in aortic smooth muscle cells and cardiomyocytes of the mouse using patch clamp techniques. Effects of the anaesthetic on the K ATP channels with different combinations of the inward rectifier pore subunits (Kir6.1 and Kir6.2) and sulphonylurea receptor subunits (SUR2A and SUR2B) reconstituted in a heterologous expression system were also examined. Key results: Isoflurane increased the coronary flow in Langendorff-perfused mouse hearts in a concentration-dependent manner, which was abolished by 10 mM glibenclamide. In enzymically-dissociated aortic smooth muscle cells, isoflurane evoked a glibenclamide-sensitive current (i.e. K ATP current). In isolated mouse ventricular cells, however, isoflurane failed to evoke the K ATP current unless the K ATP current was preactivated by the K þ channel opener pinacidil. Although isoflurane readily activated the Kir6.1/SUR2B channels (vascular type), the volatile anesthetic could not activate the Kir6.2/SUR2A channels (cardiac type) expressed in HEK293 cells. Isoflurane activated a glibenclamide-sensitive current in HEK293 cells expressing Kir6.2/SUR2B channels. Conclusion and implications: Isoflurane activates K ATP channels in vascular smooth muscle cells and produces coronary vasodilation in mouse hearts. SUR2B may be important for the activation of vascular-type K ATP channels by isoflurane.

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

“…Volatile anesthetics such as halothane (819), isoflurane (203, 296, 447), and enflurane (296) cause coronary vasodilation that can be inhibited by glibenclamide. Similar results have been reported for volatile anesthetic-induced dilation of pial arterioles (637).…”

“…In isolated porcine coronary arterioles, isoflurane-induced dilation is endothelium dependent and can be inhibited by glibenclamide (457). However, isoflurane has been shown to activate K ATP channel currents in isolated vascular SMCs and that activation of K ATP channels by isoflurane requires SUR2B (447) and likely results from PKA-mediated phosphorylation of both K IR 6.1 and SUR2B subunits (1381). …”

Effects of Long-Duration Administration of 1% Isoflurane on Resting Cerebral Blood Flow and Default Mode Network in Macaque Monkeys

“…Isoflurane increases CBF in a dose-dependent manner by producing vasodilation through the ATP-sensitive K + channel activation (Fujita et al, 2006;Iida et al, 1998). The administration of isoflurane can last for hours in animals and patients.…”

Mechanisms Involved in Cardiac Sensitization by Volatile Anesthetics: General Applicability to Halogenated Hydrocarbons?

“…Another type of inward rectifier K + current is produced by the G protein-gated heterooligomeric GIRK1/GIRK4 channels in atrial myocytes (GIRK, G protein-gated inward rectifier K + channel); the basal current through these channels was enhanced, whereas muscarinic agonist-induced GIRK current was inhibited, both by low but clinically relevant concentrations of halothane (0.1-0.3 mmol/L; Weigl and Schreibmayer, 2001). A third type of inward rectifier K + current, however, the cardiac isoform of the ATPsensitive K + current, was not influenced by the volatile anesthetic isoflurane at a concentration of 1.36 mmol/L (Fujita et al, 2006).…”