EFFECTS OF TOLBUTAMIDE ON VASCULAR ATP-SENSITIVE POTASSIUM CHANNELS IN HUMANS - COMPARISON WITH LITERATURE DATA ON GLIBENCLAMIDE AND GLIMEPIRIDE

Sulfonylurea (SU) derivatives exert their hypoglycemic effect by block ade of adenosine-5'-triphosphate-sensitive potassium (K-ATP) channels in the beta cell of the pancreas. Interestingly, K-ATP channels also o ccur in the cardiovascular system, where they are thought to play an i mportant role in cardioprotective mechanisms against ischemia. We have recently shown that the classical second generation SU-derivative gli benclamide is able to block vascular K-ATP channels in man, whereas th e newly developed second generation derivative glimepiride was devoid of this property, The aim of this study was to determine whether the f irst generation SU derivative tolbutamide has K-ATP channel blocking p roperties in humans. In a group of 12 healthy male non-smoking volunte ers, we investigated whether therapeutic concentrations of tolbutamide were able to inhibit the forearm vasodilation in response to the infu sion of the K-ATP channel opening drug diazoxide into the brachial art ery. Changes in forearm blood flow were recorded by venous occlusion m ercury-in-silastic strain-gauge plethysmography, Diazoxide alone incre ased the forearm blood flow ratio dose-dependently by ultimately 691 /- 198 %. A second diazoxide infusion in the presence of tolbutamide r evealed a comparable vasodilator response with a percentage increase i n forearm blood flow ratio of ultimately 542 +/- 111 %. This response did not differ from the vasodilator response to diazoxide alone. The p resent study shows that therapeutic concentrations of tolbutamide are not able to attenuate the vasodilation caused by the K-ATP channel ope ner diazoxide in man. When compared with published data on second gene ration SU-derivatives, tolbutamide shows an intermediate position betw een glibenclamide (with significant blockade of vascular K-ATP channel s) versus glimepiride (with no blockade at all). It remains to be dete rmined whether these acute effects of SU derivatives on pharmacologica l opening of forearm vascular K-ATP channels can be extrapolated to th e chronic effects of these drugs on ischemia-mediated opening of myoca rdial K-ATP channels during treatment of NIDDM patients.