Guanylyl Cyclase Activator Improves Endothelial Function by Decreasing Superoxide Anion Concentration

Abstract

Introduction: Soluble guanylyl cyclase (sGC) activation in vascular smooth muscle has the potential to induce vasodilation. Chronic sGC activation enhanced vascular function in the congestive heart failure animal model. Therefore, sGC activation can lead to vasodilation and improvement in endothelial function. Objective: To investigate whether the selective sGC activator can revert the endothelial dysfunction and investigate the mechanism of action. Methods: Wistar rats were split into two groups: normotensive (2K) and hypertensive rats (2K-1C). Intact aortic rings were placed in a myograph and incubated with 0.1 µM ataciguat for 30 min. Cumulative concentration-effect curves were generated for acetylcholine (Ach) to assess endothelial function. The pD2 and maximum relaxant effect (Emax) were measured to Ach. In endothelial cell culture, superoxide anion (O2•−) was detected by using fluorescent probes, including DHE and lucigenin. Results: Ataciguat improved the relaxation induced by acetylcholine in 2K-1C (pD2: 6.99 ± 0.08, n = 6) compared to the control (pD2: 6.43 ± 0.07, n = 6, p < 0.05). The aortic rings were also improved from 2K (pD2: 7.04 ± 0.13, n = 6) compared to the control (pD2: 6.59 ± 0.07, n = 6, p < 0.05). Moreover, Emax was improved by ataciguat treatment in the 2K-1C aorta (Emax: 81.0 ± 1.0; n = 6), and 2K aorta (Emax: 92.98 ± 1.83; n = 6), compared to the control (Emax 2K-1C: 52.14 ± 2.16, n = 6; and Emax 2K: 76.07 ± 4.35, n = 6, p < 0.05). In endothelial cell culture, treatment with ataciguat (0.1, 1, and 10 µM) resulted in a reduction of the superoxide anion formation induced by angiotensin II. Conclusions: Our findings indicated that ataciguat effectively enhanced endothelial function through the inactivation of superoxide anions.