Chronic administration of cyclooxygenase-2 inhibitors improves endothelial function in streptozotocin induced diabetic rats

Aly Abdelrahman, Yousuf Alsuleimani
Sultan Qaboos University, Muscat, Oman

The effect of cyclooxygenase (COX)-2 inhibitors on endothelial dysfunction in streptozotocin induced diabetic rats is not clear. In this study, we examined the effect of chronic administration of COX-2 inhibitors on blood pressure and endothelial function in streptozotocin induced diabetic rats

Three groups of Sprague-Dawley rats (300 – 350 g, n = 6) were used. The first group served as normoglycemic control, the second and third groups were rendered diabetic (blood glucose > 20 mmol/L) by an intraperitoneal injection of streptozotocin (60 mg/kg). The third group received the selective COX-2 inhibitor, nimesulide (20 mg/kg/day), orally by gavage for 4 weeks while the second group received only drinking water and served as diabetic control. At the end of the treatment period, the rats were anesthetized with urethane (1.2 g/kg). Cannulae, filled with heparinized normal saline, were inserted into the right carotid artery for the measurement of mean arterial pressure (MAP) and into the right jugular vein for the administration of drugs. An ultrasonic probe was placed around the descending aorta and connected to a flowmeter to measure hind limb blood flow. MAP, heart rate (HR) and hind limb blood flow (HLBF) were continuously monitored and displayed on a data acquisition system. This was followed by the injection of acetylcholine (0.1-0.8 μg/kg) and sodium nitroprusside (1-4 μg/kg)

Baseline MAP was significantly reduced in the control diabetic group (95 ± 4 mmHg) when compared to the normoglycemic control group (110 ± 3 mmHg). There were no significant differences in HR, HLBF between normoglycemic control and diabetic control rats. Hind limb vascular resistance (HLVR) was increased in diabetic rats. Nimesulide treatment did not cause any significant change in MAP, HR, HLBF and HLVR. Acetylcholine (Ach, endothelium-dependent vasodilator) and sodium nitroprusside (SNP, endothelium-independent vasodilator) induced dose-dependent increases in hind limb vascular conductance (HLVC) in control normoglycemic rats. These increases in HLVC were attenuated in diabetic control rats and nimesulide treatment partially reversed the attenuation of Ach induced increase in HLVC (Table 1)

aSignificant from normoglycemic control, P < 0.05. bsignificant from diabetic control, P < 0.05

In conclusion, chronic administration of the selective COX-2 inhibitor, nimesulide partially reversed endothelial dysfunction in streptozotocin induced diabetic rats. This suggests that COX-2 products might be involved in the pathogenesis of endothelial dysfunction in streptozotocin induced diabetic rats