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

Abstract

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.

Augmented oxidative stress and preserved vasoconstriction induced by hydrogen peroxide in coronary arteries in obesity: role of COX‐2

“…Firstly, the selective EP 4 receptor antagonist L1613982 significantly increased the contractile effect of H 2 O 2 in coronary arteries from obese but not from lean rats suggesting the involvement of PGE 2 in the COX-2-mediated endothelial relaxant effects . This was further supported by the enhanced coronary vasodilator effect found for the selective EP 4 receptor agonist TCS 2519 in OZR and confirmed by the augmented COX-2-mediated release of PGE 2 in coronary arteries from obese rats compared with the lean controls, as reported in diabetic mice (Przygodzki et al, 2015). Hence, COX-2 derived PGE 2 acting on vasorelaxant EP 4 receptors might have a protective role against oxidative damage induced by ROS in coronary arteries under conditions of obesity-associated insulin resistance, consistent with the protective role recently ascribed to the EP 4 receptor in obesity-related inflammation (Yasui et al, 2015) and with reports showing that VSM-specific EP 4 receptor deletion exacerbates oxidative and renal injury induced by angiotensin II in mice (Thibodeau et al, 2016).…”

“…These results support previous studies in our laboratory showing that an up‐regulation of COX‐2 was associated with the enhanced basal COX‐2‐mediated relaxation in coronary arteries from OZR (Sánchez et al , ). Also in type 2 diabetic patients (Szerafin et al , ) and mice (Przygodzki et al , ), COX‐2 inhibition reduced endothelium‐dependent relaxations of coronary arterioles and blunted basal coronary blood flow, respectively, suggesting an increased release of COX‐2‐derived vasodilator prostanoids likely to compensate for abnormal vascular function in the insulin resistant states of diabetes and obesity.…”

Cyclooxygenase 2 contributes to bradykinin-induced microvascular responses in peripheral arterioles after cardiopulmonary bypass

“…6,8,17,18 We have previously reported that CPB is associated with impairment of peripheral arteriolar endothelial function in patients after cardiac surgery. 10,11,14 In particular, the relaxation responses of skeletal muscle microvessels to endothelium-dependent and independent vasodilators, ADP, substance P and SNP were significantly decreased after CPB and cardiac surgery. 10,11,14 In the present study, we found that the relaxation response of the skeletal muscle arterioles to the endothelium-dependent vasodilator bradykinin was also impaired in patients after CPB and cardiac surgery.…”

“…10,11,14 In particular, the relaxation responses of skeletal muscle microvessels to endothelium-dependent and independent vasodilators, ADP, substance P and SNP were significantly decreased after CPB and cardiac surgery. 10,11,14 In the present study, we found that the relaxation response of the skeletal muscle arterioles to the endothelium-dependent vasodilator bradykinin was also impaired in patients after CPB and cardiac surgery. In this study, we observed that impaired relaxation response to bradykinin was more pronounced in the DM patients than the ND patients after CPB.…”

Comparison of oral non-steroidal anti-inflammatory drugs in cautery dehorned calves

“…Despite obtaining the image before other data were collected, to avoid confounding factors of handling, the change in ocular temperature was increased in placebo treated controls in comparison to those treated with an NSAID during the initial 24 h period. This effect may be a result of the activity of an NSAID to inhibit prostaglandin production potentially resulting in alterations of peripheral blood flow (Przygodzki et al, 2015).…”