Abstract 65: Cyclooxygenase-2 is a Source of Oxidative Stress in Small Arteries From Patients With Essential Hypertension or Pheochromocytoma
Essential hypertensive patients (EH) shows a reduced NO availability secondary to reactive oxygen species (ROS) generation. Cyclooxygenase (COX) is a source of ROS. An impaired endothelial function in patients with pheochromocytoma (Pheo) was also described. In this study we assessed the role of COX-1 or COX-2 as determinants of endothelial dysfunction in isolated small resistance arteries taken from EH (n=7, age 49.0±14), Pheo patients (n=7, age 47.1±17) vs control subjects (NT, n=7, age 48.1±9) during a surgical laparoscopic procedure. Small arteries were dissected and investigated on a pressurized micromyograph. Endothelium-dependent vasodilation (VD) was assessed by acetylcholine infusion (Ach, 0.001-100 μM), which was repeated under the NO synthase inhibitor L-NAME (100μM), SC-560 (1 μM, COX-1 inhibitor) or DuP 697 (1 μM, COX-2 inhibitor). Vascular ROS generation was measured by fluorescent dihydroethidium (DHE). EH and Pheo showed elevated BP levels (153/100 and 150/96 mmHg, respectively) vs NT (120/81 mmHg). In NT, maximal VD to ACh (95.1±1.8%) was blunted by L-NAME (61.2±3.4%; inhibitory effect: 33.9±2.1%; P<0.001), and unmodified by SC-560 (94.0±1.1%) or DuP (94.9±0.8%). In EH, VD to ACh was blunted vs NT (58.8±2.5%; P<0.001), resistant to L-NAME (56.2±1.8%; 2.6±0.7% inhibition), not affected by SC-560 (56.9±0.9%) but enhanced (P<0.01) by DuP (80.2±2.1%), which also restored the inhibition of L-NAME on ACh (51.7±1.7%; 28.5±3.7% inhibition). Similarly, in Pheo, VD to ACh was blunted vs NT (60.2±2.6%; P<0.001), slightly sensitive to L-NAME (52.7±2.3%; 7.6±2.9% inhibition; P<0.001 vs NT), not affected by SC-560 (53.9±0.9%) but potentiated (P<0.01) by DuP (78.6±2.2%), which also restored the inhibitory effect of L-NAME on ACh (54.8±2.1%; 23.9±1.7% inhibition). DHE analysis revealed an increased ROS production in EH (stained area: 23±4%) and Pheo (26.5±5%) vs NT (9.2±2%). In both EH and Pheo, ROS excess was attenuated (P<0.01) by incubation with COX-2 inhibitor (EH: 13±3%; Pheo: 14±4%), being unaffected by COX-1 inhibitor (EH: 21.5±2%; Pheo: 25.2±3.5%). In small resistance vessels from EH and Pheo patients, COX-2 participates on reducing NO availability. COX-2 might represent a main source of ROS generation in both clinical conditions.
- © 2012 by American Heart Association, Inc.