Impaired hypoxic coronary vasodilation and ATP-sensitive potassium channel function: a manifestation of diabetic microangiopathy in humans?

Hypoxic coronary vasodilation contributes to the maintenance of oxygen supply to the working heart during increased metabolic demand. Mechanisms of hypoxic coronary dilation have been studied extensively and differ considerably depending upon the species and experimental model. In isolated coronary vessels, several mechanisms have been implicated either alone or in combination, including release of vasodilatory factors (ie, nitric oxide, prostaglandins, and adenosine), activation of ATP-sensitive potassium (KATP) channels and Ca -activated K channels, and inhibition of voltage-gated Ca channels.1–5 To date, however, relatively few studies have been conducted in human blood vessels. Furthermore, whereas most prior studies have examined hypoxic dilation in conduit coronary arteries, coronary microvessels ( 150 m in diameter) are considered to be the principal regulators of coronary blood flow in response to metabolic stress.6 Thus, despite extensive studies conducted over the past several decades, surprisingly little is known about mechanisms of hypoxic coronary microvascular dilation in humans, and how it might be altered in disease states. In this issue of Circulation Research, Miura and colleagues7 provide evidence that hypoxic dilation of human coronary microvessels is mediated primarily by activation of KATP channels in vascular smooth muscle cells (SMCs), independent of the endothelium. Moreover, they report that both hypoxic dilation and vasodilation induced by the KATP opener aprikalim are attenuated in microvessels from patients with diabetes mellitus, suggesting impaired KATP function. These findings provide new insight into mechanisms of coronary vasoregulation in humans, and they suggest that impaired microvascular KATP channel function might contribute to increased cardiovascular morbidity and mortality in patients with diabetes. KATP channels are distributed in a variety of tissues, including cardiomyocytes, SMCs, skeletal muscle, and pancreatic -cells.8 These octameric channels are composed of four inwardly rectifying potassium channel subunits (Kir) and four regulatory sulfonylurea receptor subunits (SUR). Channel complexes composed of less than 8 subunits are retained in the endoplasmic reticulum and thus cannot be targeted to the cell membrane.9 Two different KIR (KIR6.1 and KIR6.2) and SUR (SUR1 and SUR2) gene products have been identified to make up KATP channels. Splice variants of SUR2 (SUR2A and SUR2B) further add to the structural diversity of KATP channels. The molecular structure of KATP channels varies depending upon the species and tissue and is an important determinant of channel function, including sensitivity to ATP, nucleotide diphosphates, and potassium channel openers (KCO). Channel activity may also be regulated by posttranslational modification (ie, glycosylation, phosphorylation, and inositol phosphate metabolism). A characteristic feature of KATP channels is inhibition by sulfonylurea compounds such as glibenclamide.8 Recently, Farouque et al10 demonstrated that intracoronary infusion of glibenclamide reduced resting coronary blood flow in humans, suggesting that KATP channels contribute to basal regulation of the coronary circulation. In coronary arterioles from the right atrial appendages of humans (the same vessels used in the present study), nicorandil, a nonselective KCO compound, was demonstrated to induce vasodilation that was unaffected by methylene blue but markedly attenuated by glibenclamide, consistent with activation of KATP channels.11 The study by Miura et al7 confirms and extend these findings by demonstrating that dilation to aprikalim, a selective KCO, is markedly attenuated by glibenclamide, but unaffected by removal of the endothelium or by inhibitors of nitric oxide synthase or cyclooxygenase. These findings confirm that KATP channels are functionally expressed in human coronary microvessels and indicate that aprikalim acts directly on these channels to produce microvascular dilation. The authors also provide evidence that Kir6.1 and SUR2B are expressed in human coronary microvessels. Deletion of Kir6.1 in mice was recently shown to induce coronary vasospasm and to block vasodilatory responses to KCO in vivo and in vitro, implying that this subunit is a constituent of coronary vascular SMC KATP channels.12 Also, deletion of SUR2 resulted in increased blood pressure in mice.13 Among the SUR2 variants, SUR2B is thought to be the most prevalent in vascular SMCs.14 Interestingly, coexpression of Kir6.1 and SUR2B formed a channel that was not sensitive to inhibition by ATP, although the channel was robustly activated by nucleotide diphosphates and KCO, and it was inhibited by glibenclamide.15 Thus, the channel is perhaps The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Internal Medicine, Cardiovascular Division, University of Iowa College of Medicine, and VA Medical Center, Iowa City, Iowa. Correspondence to Neal L. Weintraub, MD, Dept of Internal Medicine, Cardiovascular Division, University of Iowa College of Medicine, 200 Hawkins Dr, E329 GH, Iowa City, IA 52242. E-mail [email protected] (Circ Res. 2003;92:127-129.) © 2003 American Heart Association, Inc.