Effects of a Soluble Guanylate Cyclase Stimulator Riociguat on Contractility of Isolated Pulmonary Artery and Hemodynamics of U46619-Induced Pulmonary Hypertension in Dogs

SIMPLE SUMMARY: Pulmonary hypertension (PH) is a progressive and refractory vascular disease in both dogs and humans. The soluble guanylate cyclase stimulator riociguat is a relatively novel pulmonary vasodilator used for the treatment of PH in human medicine. Although riociguat may have beneficial effects in the treatment of PH in dogs, there is a lack of basic studies on its clinical application in veterinary medicine. Thus, the aim of this study was to examine the effects of riociguat on the contractility of an isolated canine pulmonary artery (PA) and the hemodynamics of acute PH model dogs. In an isolated canine PA, riociguat endothelium independently increased cyclic guanosine-3′,5′-monophosphate (cGMP) levels and reduced vasocontractile endothelin-1-induced contraction. Moreover, riociguat inhibited the increased pulmonary vascular resistance and elevated PA pressure in thromboxane A2 analog U46619-induced PH model dogs. In contrast, riociguat had no effect on basal systemic arterial pressure. These results suggest that riociguat can inhibit the elevation of PA pressure through PA relaxation via an endothelium-independent increase in cGMP levels in dogs with PH. Riociguat may be a novel and safe therapeutic agent for the treatment of PH in veterinary medicine. ABSTRACT: Soluble guanylate cyclase (sGC) stimulator riociguat is a relatively novel therapeutic agent for pulmonary hypertension (PH) in human medicine. Riociguat induces endothelium-independent pulmonary artery (PA) relaxation by directly activating the sGC-cyclic guanosine-3′,5′-monophosphate (cGMP) pathway in muscle cells. Although riociguat may be effective in the treatment of dogs with refractory PH, basic studies on its clinical application in veterinary medicine are lacking. The present study aimed to explore the effects of riociguat on the contractility of an isolated canine PA and the hemodynamics of dogs with acute PH. In an isolated endothelium-denuded canine PA, the effects of riociguat on endothelin (ET)-1-induced contraction and cGMP levels were investigated using the Magnus method and ELISA, respectively. The effect of riociguat on the hemodynamics of the thromboxane A2 analog U46619-induced PH model dog was examined by invasive catheterization. Riociguat increased cGMP levels and reduced ET-1-induced contraction of the isolated PA. Riociguat inhibited the U46619-induced elevation of PA pressure and pulmonary vascular resistance and increased cardiac output, but it had no effect on basal systemic blood pressure. These results demonstrate for the first time that riociguat can inhibit the elevation of PA pressure through PA relaxation via an endothelium-independent increase in cGMP in dogs with PH.