Abstract 1443: Angiotensin Ii Type 2 Receptor-dependent Dilation Is Reduced In Type Ii Diabetes Due To Cox-2 Generated Thromboxane A2 And Reactive Oxygen Species

The role of angiotensin II type 2 receptors (AT2R) is not fully understood, especially in vascular diseases. Although its vasodilatory and antitrophic properties are well accepted, in hypertensive rats AT2R stimulation induces vasoconstriction. Abnormalities in the renin-angiotensin system have a key role in cardiovascular disorders associated with the evolution of type II diabetes. Thus, we hypothesized that AT2R function might be altered in diabetic rats resistance arteries. Mesenteric resistance arteries (250 μm diameter) were isolated from type II diabetic Zucker (ZDF) and control rats (LZ) rats receiving the antioxidant tempol (16 mg/kg/day) or water for 3 weeks. Dilation to angiotensin II (due AT2R stimulation) in the presence of candesartan (angiotensin II type 1 receptor blocker) was studied in ring segment of arteries using a wire-myograph mesenteric wall force. AT2R induced endothelium and NO-dependent dilation in LZ (inhibited by L-NAME). It was not affected by cyclooxygenase (indomethacin) or reactive oxygen species (ROS) inhibition (TEMPOL). In ZDF rats AT2R-induced dilation was lower than in LZ rats and independent of NO (not inhibited by L-NAME). It was restored to control level after ROS (tempol) and cycloxygenase inhibition (indomethacin). Cycloxygenase-2 (NS398) and Thromboxane A2 receptor (SQ29548) inhibition also restored AT2R-dilation in ZDF rats to control (LZ) level. Cycloxygenase-2 and ROS were overexpressed (immuno-histological detection using confocal microscopy) in ZDF rats arteries. In ZDF rats chronically treated with the antioxydant Tempol (SOD mimetic) AT2R-induced dilation was equivalent to that in LZ (control) rats and it involved NO and cycloxygenase-2-derivatives in equivalent proportion (dilation inhibited in part by L-NAME and by NS398). In tempol-treated rats SQ29548 had no effect. We conclude that in type II diabetic rats AT2R induced dilation is reduced due to ROS and thromboxane A2-dependent vasoconstriction due to COX-2 activation. Chronic treatment of diabetic rats with tempol restored AT2R-dependent dilation through the suppression of ROS and TxA2 production. These findings might be important to consider in the choice of vasoactive drugs in diabetic patients.