Effects of sulfonylureas on K ATP channel-dependent vasodilation

Abstract

Introduction: Sulfonylureas are widely prescribed for the treatment of type 2 diabetes. Their therapeutic efficacy resides in the ability to bind to sulfonylurea receptors (SURs) present on the β-cell plasma membrane, to close the ATP-regulated potassium (K ATP) channel, and thereby to enhance glucose-stimulated insulin secretion. These receptors are also found in a wide variety of extra-pancreatic tissues such as brain, peripheral nerves, heart, and vascular smooth muscle where they contribute to the regulation of the vascular tone. Objective: The objective of the present study was to determine the potency of three sulfonylureas, glibenclamide, gliclazide, and glimepiride, in antagonizing the vasorelaxant action of diazoxide, an ATP-regulated K + channel (K ATP) opener, in vivo, using the hamster cheek pouch preparation and evaluating the changes in mean internal diameter and blood flow of arterioles and venules. Material and methods: Cheek pouches of anesthetized male hamsters superfused with a HEPES-supported HCO 3 −-buffered saline solution were placed under an intravital microscope coupled to a closed-circuit TV system. All substances were applied topically. Measurements: Mean arteriolar and venular internal diameters using an image shearing device, red blood cell (RBC) velocity by the dual-slit photometric technique and microvessel volume flow was calculated from diameters and RBC velocities. Results: The numbers are given in order, first diameter and then flow, always for the highest concentration of diazoxide tested, by itself or in combination with a given sulfonylurea: (1) diazoxide, used in doses of 0.01, 1, and 100 μM, elicited a dose-dependent dilation and flow increase in arterioles [increase of 52.1% ( P<.01) and 41.2% ( P<.01)] and venules [37.9% ( P<.05) and 57.6% ( P<.01)]; (2) glibenclamide (0.81 μM)+diazoxide 29.3% ( P=.172) and 25.0% ( P=.064) for arterioles and 8% ( P=.654) and 3.7% ( P=.769) for venules; (3) gliclazide (12 μM)+diazoxide 51.0% ( P<.01) and 46.7% ( P<.01) for arterioles and 59.0% ( P<.01) and 45.2% ( P<.01) for venules; (4) glimepiride (0.82 μM)+diazoxide 22.8% ( P=.228) and 12.5% ( P=.305) for arterioles and 15.6% ( P=.415) and 16.0% ( P=.291) for venules. Conclusion: These results suggest that, in contrast to glibenclamide and glimepiride, therapeutic concentrations of gliclazide produce no cross-reactivity with smooth muscle cell K ATP channels in the microvessels of the hamster cheek pouch. Previous studies have confirmed these results in isolated aortic rings of rats and guinea pigs.