251. Glibenclamide inhibits thromboxane-mediated vasoconstriction by thromboxane receptor blockade.
- Author
-
Pfister SL, Pratt PE, Kurian J, and Campbell WB
- Subjects
- 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid pharmacology, Adenosine Triphosphate physiology, Animals, Aorta, Thoracic drug effects, Aorta, Thoracic physiology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cattle, Coronary Vessels drug effects, Coronary Vessels physiology, Fatty Acids, Unsaturated pharmacology, In Vitro Techniques, Male, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular physiology, Potassium Channels drug effects, Potassium Channels physiology, Prostaglandin Endoperoxides, Synthetic pharmacology, Rabbits, Radioligand Assay, Receptors, Thromboxane metabolism, Thromboxane A2 pharmacology, Thromboxane A2 physiology, Glyburide pharmacology, Receptors, Thromboxane antagonists & inhibitors, Thromboxane A2 analogs & derivatives, Vasoconstriction drug effects, Vasoconstrictor Agents pharmacology
- Abstract
Because sulfonylureas, such as glibenclamide, are used to treat Type 2 diabetes and because this disease is associated with various cardiovascular complications that may be mediated by thromboxane (TX), this study was designed to characterize the role of glibenclamide on TX-mediated contractions in isolated ring segments of bovine coronary arteries and rabbit aortas. A series of TXA(2) analogs [9,11 Dideoxy-9alpha, 11alpha-methanoepoxy prostaglandin F(2alpha) (U46619), [1S-(1alpha, 2beta(5Z),3alpha(1E, 3R*),4alpha)]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo [2.2.1]heptan-2-yl]-5-heptenoic acid (I-BOP), carbocyclic TXA(2) (CTA(2)) and 9,11-dideoxy-9alpha,11alpha-epoxymethano prostaglandin F(2alpha) (U44069)], endothelin and phenylephrine contracted both types of blood vessels. Glibenclamide (10 microM) inhibited the contraction to each of the TX agonists but had no effect on endothelin- or phenylephrine-induced contractions. We hypothesized that this effect was due to a direct effect to block the vascular smooth muscle cell TX receptor. Receptor binding studies were performed in rabbit vascular smooth muscle cells and indicated that glibenclamide (10 microM) inhibited (125)I-BOP binding by more than 80%. The inhibition constants or K(i) for glibenclamide was 0.53 microM. These studies provide the first evidence that the ability of glibenclamide to inhibit TX-mediated contractions occurs independent of the vascular K(ATP) channel and is, instead, mediated by the blockade of the vascular TX receptor.
- Published
- 2004
- Full Text
- View/download PDF