Hypercapnic Acidosis Activates K _ATP Channels in Vascular Smooth Muscles

Abstract

Abstract-ATP-sensitive K ϩ channels (K ATP ) couple intermediary metabolism to cellular activity, and may play a role in the autoregulation of vascular tones. Such a regulation requires cellular mechanisms for sensing O 2 , CO 2 , and pH. Our recent studies have shown that the pancreatic K ATP isoform (Kir6.2/SUR1) is regulated by CO 2 /pH. To identify the vascular K ATP isoform(s) and elucidate its response to hypercapnic acidosis, we performed these studies on vascular smooth myocytes (VSMs). Whole-cell and single-channel currents were studied on VSMs acutely dissociated from mesenteric arteries and HEK293 cells expressing Kir6.1/SUR2B. Hypercapnic acidosis activated an inward rectifier current that was K ϩ -selective and sensitive to levcromakalim and glibenclamide with unitary conductance of Ϸ35pS. The maximal activation occurred at pH 6.5 to 6.8, and the current was inhibited at pH 6.2 to 5.9. The cloned Kir6.1/SUR2B channel responded to hypercapnia and intracellular acidification in an almost identical pattern to the VSM current. In situ hybridization histochemistry revealed expression of Kir6.1/SUR2B mRNAs in mesenteric arteries. Hypercapnia produced vasodilation of the isolated and perfused mesenteric arteries. Pharmacological interference of the K ATP channels greatly eliminated the hypercapnic vasodilation. These results thus indicate that the Kir6.1/SUR2B channel is a critical player in the regulation of vascular tones during hypercapnic acidosis. Although these K ϩ channels are sensitive to ATP, studies have shown that they are also modulated by other nucleotides and phospholipids. [3][4][5][6][7][8][9] Previous studies have shown that K ATP channels in myocardium and insulin-secreting cell line are activated by intracellular acidification. 10,11 Similar activation was observed in the cloned pancreatic K ATP isoform (Kir6.2/ SUR1) during hypercapnic acidosis. [12][13][14][15] The regulation of K ATP by protons is particularly significant, because pH alterations occur in a large variety of physiological and pathophysiological conditions and are more frequently seen than sole energy depletion.The pH sensitivity may allow the K ATP channels to play a role in autoregulation of vascular tones. Experimental evidence suggests that the K ATP channels may be involved in reactive hyperemia, as sulfonylurea blocks hyperemic vasodilation. 16,17 The autoregulation occurs in most tissues including the heart and brain in which it underlies the cardioprotective effect of ischemic preconditioning and the activitydependent regulation of cerebral circulation. 18 -21 The reactive hyperemia is produced by hypoxia, hypercapnia, acidosis, and accumulation of other metabolic products in local tissues.Because under most physiological and pathophysiological conditions, ATP levels may not readily drop to submillimolar concentrations in cells to activate K ATP channels, 1,2 demonstration of the CO 2 /pH sensitivity of the K ATP channels becomes critical for understanding the molecular basis of the autoregulation of vascular to...

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Hypercapnia-Induced Cerebral Hyperperfusion: An Underrecognized Clinical Entity

“…5,6,30,31 Animal studies have shown hypercapnia activates K ATP channels in vascular smooth muscle, causing vasodilation. 32 Animal models have also suggested that nitric oxide plays a role in hypercapnic vasodilation. 2,30 However, human studies have shown that hypercapnia acts independently of nitric oxide to produce elevated CBF.…”

Localization of Sulfonylurea Receptor Subunits, SUR2A and SUR2B, in Rat Heart

“…SUR2A is prominent in cardiomyocytes (Chutkow et al 1996;Inagaki et al 1996), whereas RT-PCR of SUR2B has revealed its ubiquitous distribution in various cells and tissues including cardiomyocytes (Isomoto et al 1996) and rat vascular smooth muscle (Wang et al 2003). Until now, there have been no unequivocal data establishing the precise cellular localization of SUR2A and SUR2B subunits in cardiac myocytes.…”