Roxadustat has beneficial effects on the vascular tone of the rat thoracic aorta.

Abstract

Roxadustat, an agent for renal anemia, may have beneficial effects on the cardiovascular system, but its direct effects on the vasculature system have not been clarified. Therefore, in this study, the effect of roxadustat on vascular tone was examined using rat thoracic aortas and superior mesenteric arteries according to the organ chamber method. Roxadustat relaxed the thoracic aorta in the presence or absence of vascular endothelium, but the degree of vascular relaxation was attenuated by endothelium denudation, indicating that the majority of vasorelaxation caused by roxadustat is endothelium-dependent. Pretreatment with a nitric oxide (NO) synthase inhibitor (i.e., NG-nitro-L-arginine-methyl ester), a soluble guanylate cyclase (sGC) inhibitor (i.e., 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxaline-1-one), and a bradykinin B2 receptor inhibitor (i.e., icatibant) significantly weakened roxadustat-induced vasorelaxation. In addition, roxadustat treatment of endothelium intact vascular rings increased mildly NO metabolites. When the direct effects of roxadustat on vascular smooth muscle were examined, various selective potassium channel inhibitors markedly diminished roxadustat-induced vasorelaxation in vascular endothelium-denuded rings. Moreover, roxadustat significantly inhibited angiotensin Ⅱ- and phenylephrine-induced vasocontraction, regardless of the presence of vascular endothelium. Not only the thoracic aorta, roxadustat relaxed the superior mesenteric artery, a smaller vessel. These results suggest that roxadustat-induced vasorelaxation of the thoracic aorta involves activation of endothelial NO synthase through bradykinin B2 receptors and the subsequent NO/sGC pathway. Furthermore, roxadustat probably inhibited vasocontraction by activating potassium channel opening.