Effects of local mechanical stimulation on coronary artery endothelial function and angiotensin II type 1 receptor in pressure or flow-overload

Abstract

This study investigates the effect of local mechanical stimulation induced by pressure or flow-overload in right coronary artery (RCA) angiotensin II type 1 (AT1) receptor-mediated endothelial dysfunction in swine models of aortic or pulmonary artery banding. A total of 36 pigs (37 ± 7 kg) were studied. The RCA was exposed to pressure-overload by aortic banding (n = 6) or blood flow-overload by pulmonary artery banding (n = 6) for 4 weeks, and sham-operated animals served as controls (n = 6). The RCA of 18 pigs were exposed to acute ex-vivo pressure-overload. The effects of local mechanical stimuli on AT1 receptor were determined by external cuff. Aortic banding caused RCA pressure-overload of 118 ± 11 mmHg in comparison with 79 ± 9 mmHg for sham controls. The cross-sectional area of the RCA lumen increased 27.9% (from 8.09 ± 0.89 to 10.3 ± 0.96 mm) when the blood flow increased by 80% (from 23.8 ± 4.3 to 44.3 ± 7.2 ml/min) in the 4-week pulmonary artery banding period. Both pressure and flow-overload resulted in the up-regulation of expression and activation of AT1 receptor. An increased production of reactive oxygen species (ROS) and endothelium dysfunction were observed in the RCA. The acute inhibition of AT1 receptor and NADPH oxidase partially restored the endothelial function. The endothelial dysfunction and activation of AT1 receptor was also realized in ex-vivo pressure-overload of normal RCA. An external cuff inhibited the increase in activation of AT1 receptor and preserved endothelial function in ex-vivo pressure-overload which implicates local wall mechanical stimulation as opposed to pressure. Local mechanical stimulation activates the AT1 receptor which likely mediates ROS production and endothelial dysfunction in RCA.