Inhibition of cyclooxygenase-2 causes a decrease in coronary flow in diabetic mice. The possible role of PGE2 and dysfunctional vasodilation mediated by prostacyclin receptor.
Several lines of evidence suggest that cyclooxygenase-2 (COX-2) activity can have a beneficial role in the maintenance of vascular tone of the blood vessels in diabetes. Specifically, the increased production of prostacyclin (PGI2) and prostaglandin E2 (PGE2), mediated by COX-2, has been suggested to compensate for decreased synthesis of nitric oxide (NO). The study investigates whether inhibition of COX-2 may reduce the coronary flow in diabetic animals and may also lead to decreased synthesis of prostaglandins. Mice aged 18-20 weeks were used for the study: those with leptin receptor deficiency (db/db) served as a model of diabetes while heterozygous (db/+) mice served as controls. Coronary flow was measured by the Langendorff method, and prostaglandin synthesis by myocardia was assayed in heart perfusates. COX-2 inhibition was found to reduce basal coronary flow in db/db mice but had no effect in db/+ mice. Secretion of PGE2 was found to be higher in db/db mice, while prostacyclin synthesis did not differ. COX-2 inhibition decreased production of both prostaglandins to similar levels in both groups. The use of ONO-1301, a specific agonist for the prostacyclin receptor revealed that vasodilating responses mediated by the receptor were impaired in db/db mice. The expression levels of the receptor in cardiac tissue did not differ between the groups. It is concluded that the increased COX-2 contribution to vasodilation in diabetic animals appears to be partially a result of increased COX-2-dependent synthesis of PGE2 and also may be caused by impaired vasodilation mediated by the prostacyclin receptor.
Department of Haemostasis and Haemostatic Disorders, Chair of Biomedical Sciences, Medical University of Lodz, Lodz, 92-215, Poland, tomasz.przygodzki@umed.lodz.pl.
Tomasz
T
Przygodzki
Marcin
M
Talar
Patrycja
P
Przygodzka
Cezary
C
Watala
D000818:Animals; D003331:Coronary Vessels / Q000503:physiopathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology*; D015232:Dinoprostone / Q000502:physiology*; D011464:Epoprostenol / Q000502:physiology; D008297:Male; D008820:Mice, Obese; D009578:Nitrobenzenes / Q000494:pharmacology*; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014664:Vasodilation
D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; C491910:Ptgir protein, mouse; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D011464:Epoprostenol; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone