Impaired Hypoxic Coronary Vasodilation and ATP-Sensitive Potassium Channel Function

Abstract

H ypoxic 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 (K ATP ) channels and Ca 2ϩ -activated K ϩ channels, and inhibition of voltage-gated Ca 2ϩ channels. [1][2][3][4][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 (Ͻ150 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 colleagues 7 provide evidence that hypoxic dilation of human coronary microvessels is mediated primarily by activation of K ATP channels in vascular smooth muscle cells (SMCs), independent of the endothelium. Moreover, they report that both hypoxic dilation and vasodilation induced by the K ATP opener aprikalim are attenuated in microvessels from patients with diabetes mellitus, suggesting impaired K ATP function. These findings provide new insight into mechanisms of coronary vasoregulation in humans, and they suggest that impaired microvascular K ATP channel function might contribute to increased cardiovascular morbidity and mortality in patients with diabetes.K ATP 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 K ATP channels. Splice variants of SUR2 (SUR2A and SUR2B) further add to the structural diversity of K ATP channels. The molecular structure of K ATP 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 K ATP channels is inhibition by sulfonylurea compounds such as glibenclamide. 8 Recently, Farouque et ...

The Opening of ATP-Sensitive K+ Channels Protects H9c2 Cardiac Cells Against the High Glucose-Induced Injury and Inflammation by Inhibiting the ROS-TLR4-Necroptosis Pathway

“…K ATP channels are important sensors and effecter of the metabolic status of cardiomyocytes and prominently involved in the regulation of insulin secretion [17, 18], cardioprotection [1-3] and cellular adaptation to stress, such as oxidation stress [3]. Several reports have shown the relationship between dysfunction in K ATP channel gating and diabetes [17].…”

“…Several reports have shown the relationship between dysfunction in K ATP channel gating and diabetes [17]. A previous study reported that nicorandil, a mitochondrial K ATP channel opener, protects from diabetes through inhibition of the production of ROS in the streptozotocin-treated rats [52].…”

“…In addition, the opening of K ATP channels also contributes to the regulation of cardiac mitochondrial function [14] and cardioprotection induced by ischemic preconditioning [14-16]. Noteworthily, several reports have shown a correlation between dysfunction in the K ATP channel gating and insulin secretory disorder [17, 18], such as neonatal diabetes [18]. Additionally, a previous study has indicated diabetes mellitus (DM) is associated with the dysfunction of cardiovascular K ATP channels [17].…”

“…Noteworthily, several reports have shown a correlation between dysfunction in the K ATP channel gating and insulin secretory disorder [17, 18], such as neonatal diabetes [18]. Additionally, a previous study has indicated diabetes mellitus (DM) is associated with the dysfunction of cardiovascular K ATP channels [17]. More recently, we have demonstrated that high glucose (35 mM glucose, HG) significantly decreases the expression level of K ATP channels and that the opening of K ATP channels protects against the HG-induced injuries, including over-production of reactive oxygen species (ROS) in H9c2 cardiac cells [7].…”

Naringin protects cardiomyocytes against hyperglycemia-induced injuries in vitro and in vivo

“…In addition, accumulating evidence has revealed that DM has been associated with dysfunction of the cardiovascular K ATP channels (Weintraub 2003). Hyperglycemia and DM impair vasodilation mediated by K ATP channels in human vascular smooth muscle cells (Miura et al 2003, Kinoshita et al 2004, Kinoshita et al 2006.…”