Interaction of sulphonylurea derivatives with vascular ATP-sensitive potassium channels in humans.
Cardiovascular adenosine-5'-triphosphate-sensitive potassium (KATP) channels have been reported to play an important role in endogenous cardioprotective mechanisms. Sulphonylurea derivatives can inhibit these cardioprotective mechanisms in animal models. We investigated whether therapeutic concentrations of sulphonylurea derivatives can block vascular KATP channels in humans. The forearm vasodilator responses to administration of the specific KATP channel opener diazoxide into the brachial artery of healthy male volunteers were recorded by venous occlusion plethysmography. This procedure was repeated with concomitant intraarterial infusion of:1) the sulphonylurea derivative glibenclamide (0.33 or 3.3 micrograms. min-1. dl-1, both n = 12), 2) the new sulphonylurea derivative glimepiride (2.5 micrograms.min-1. dl-1, n = 12) or 3) placebo (n = 12). The effects of glibenclamide on the vasodilator responses to sodium nitroprusside were also studied (n = 12). Glibenclamide significantly inhibited the diazoxide-induced increase in forearm blood flow ratio (ANOVA with repeated measures: p < 0.01). During the highest diazoxide dose this ratio (mean +/- SEM) was lowered from 892 +/- 165 to 449 +/- 105%, and from 1044 +/- 248 to 663 +/- 114% by low- and high-dose glibenclamide, respectively. In contrast, neither glimepiride nor placebo attenuate diazoxide-induced vasodilation. Furthermore, glibenclamide did not affect nitroprusside-induced vasodilation. We conclude that therapeutic concentrations of the classical sulphonylurea derivative glibenclamide result in significant blockade of vascular KATP channels in humans. The newly developed glimepiride seems to be devoid of these properties.
Bijlstra
P J
PJ
Department of Internal Medicine, University Hospital Nijmegen, The Netherlands.
Lutterman
J A
JA
Russel
F G
FG
Thien
T
T
Smits
P
P
D000328:Adult; D000704:Analysis of Variance; D001794:Blood Pressure / Q000187:drug effects*; D003981:Diazoxide / Q000008:administration & dosage / Q000494:pharmacology*; D005542:Forearm / Q000098:blood supply; D005905:Glyburide / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007269:Injections, Intra-Arterial; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D015221:Potassium Channels; D013453:Sulfonylurea Compounds; D014665:Vasodilator Agents; D009599:Nitroprusside; C057619:glimepiride; D003981:Diazoxide; D005905:Glyburide