Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1

Abstract

The inwardly rectifying K(+) channel Kir6.1 forms K(+) channels by coupling with a sulfonylurea receptor in reconstituted systems, but the physiological roles of Kir6.1-containing K(+) channels have not been determined. We report here that mice lacking the gene encoding Kir6.1 (known as Kcnj8) have a high rate of sudden death associated with spontaneous ST elevation followed by atrioventricular block as seen on an electrocardiogram. The K(+) channel opener pinacidil did not induce K(+) currents in vascular smooth-muscle cells of Kir6.1-null mice, and there was no vasodilation response to pinacidil. The administration of methylergometrine, a vasoconstrictive agent, elicited ST elevation followed by cardiac death in Kir6.1-null mice but not in wild-type mice, indicating a phenotype characterized by hypercontractility of coronary arteries and resembling Prinzmetal (or variant) angina in humans. The Kir6.1-containing K(+) channel is critical in the regulation of vascular tonus, especially in the coronary arteries, and its disruption may cause Prinzmetal angina.

Distribution of Kir6.0 and SUR2 ATP-sensitive potassium channel subunits in isolated ventricular myocytes

“…In summary, this study provides direct immunological evidence from confocal microscopy and subcellular fractionation followed by Western blotting for distinct 30 The major effect of Kir6.1 knockout in these mice was an increased susceptibility to spontaneous coronary spasm leading to a lethal atrioventricular block, resembling a Prinzmetal angina in humans. This condition was associated with defects in vascular sarcolemmal K ATP channels, rather than their cardiac counterparts.…”

“…This condition was associated with defects in vascular sarcolemmal K ATP channels, rather than their cardiac counterparts. 30 In view of these results and reservations concerning the use of flavoprotein fluorescence to monitor mitoK ATP channel activity [12][13][14] , the confirmation of the presence and potential rôle of a cardiac mitoK ATP channel remains elusive.…”

Potent and selective activation of the pancreatic beta-cell type K ATP channel by two novel diazoxide analogues

“…The beta-cell K ATP channel is composed of Kir6.2 and SUR1 [8,9], the cardiac type of Kir6.2 and SUR2A [10], and the vascular smooth muscle type of Kir6.1 and SUR2B [11]. It is believed that Kir6.2 and SUR2B make up some smooth muscle K ATP channels [12], and that both Kir6.2/SUR1 and Kir6.2/SUR2B combinations are found in neurones [13].…”

Potassium channels in the sinoatrial node and their role in heart rate control

“…There are reasons to believe that pacemaker function may also be influenced by K ATP channels containing the Kir6.1 subunit. Mice with global genetic deletion of Kir6.1 develop SAN failure and also heart block which leads to sudden death [93,96]. In our own studies we have studied mice with selective deletion of Kir6.1 in vascular smooth muscle or endothelium [93,97].…”