Effects of Tolbutamide on Vascular ATP-Sensitive Potassium Channels in Humans

Abstract

Sulfonylurea (SU) derivatives exert their hypoglycemic effect by blockade of adenosine-5′-triphosphate-sensitive potassium (K^ATP) channels in the beta cell of the pancreas. Interestingly, K_ATP channels also occur in the cardiovascular system, where they are thought to play an important role in cardioprotective mechanisms against ischemia. We have recently shown that the classical second generation SU-derivative glibenclamide is able to block vascular K_ATP channels in man, whereas the newly developed second generation derivative glimepiride was devoid of this property. The aim of this study was to determine whether the first generation SU derivative tolbutamide has K_ATP channel blocking properties in humans. In a group of 12 healthy male non-smoking volunteers, we investigated whether therapeutic concentrations of tolbutamide were able to inhibit the forearm vasodilation in response to the infusion of the K_ATP channel opening drug diazoxide into the brachial artery. Changes in forearm blood flow were recorded by venous occlusion mercury-in-silastic strain-gauge plethysmography. Diazoxide alone increased the forearm blood flow ratio dose-dependently by ultimately 691 ± 198%. A second diazoxide infusion in the presence of tolbutamide revealed a comparable vasodilator response with a percentage increase in forearm blood flow ratio of ultimately 542 ± 111%. This response did not differ from the vasodilator response to diazoxide alone. The present study shows that therapeutic concentrations of tolbutamide are not able to attenuate the vasodilation caused by the K_ATP channel opener diazoxide in man. When compared with published data on second generation SU-derivatives, tolbutamide shows an intermediate position between glibenclamide (with significant blockade of vascular K_ATP channels) versus glimepiride (with no blockade at all). It remains to be determined whether these acute effects of SU derivatives on pharmacological opening of forearm vascular K_ATP channels can be extrapolated to the chronic effects of these drugs on ischemia-mediated opening of myocardial K_ATP channels during treatment of NIDDM patients.

Key words

Tolbutamide - Glibenclamide - Glimepiride - Diazoxide - Forearm Blood Flow - Cardioprotection - Sulfonylurea Derivatives - Potassium Channels - Vascular