Effects of sulfonylureas on K(ATP) channel-dependent vasodilation.
BACKGROUND
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 beta-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.


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.


METHODS
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 microM, 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 microM)+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 microM)+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 microM)+diazoxide 22.8% (P=.228) and 12.5% (P=.305) for arterioles and 15.6% (P=.415) and 16.0% (P=.291) for venules.


CONCLUSIONS
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.
Cyrino
Fatima Z G A
FZ
Laboratório de Pesquisas em Microcirculaçāo, Pavilhão Reitor Haroldo Lisboa da Cunha, térreo, Universidade do Estado do Rio de Janeiro, Rua São Francisco Xavier, 524 20550-013, Rio de Janeiro, RJ, Brazil
Bottino
Daniel A
DA
Coelho
Flavio C
FC
Ravel
Denis
D
Bouskela
Eliete
E
D000255:Adenosine Triphosphate / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects*; D006224:Cricetinae; D003981:Diazoxide / Q000494:pharmacology; D004347:Drug Interactions; D005907:Gliclazide / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D008297:Male; D008647:Mesocricetus; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D007004:Hypoglycemic Agents; D015221:Potassium Channels; D013453:Sulfonylurea Compounds; D014665:Vasodilator Agents; C057619:glimepiride; D000255:Adenosine Triphosphate; D005907:Gliclazide; D003981:Diazoxide; D005905:Glyburide