Relaxant Effects of the Soluble Guanylate Cyclase Activator and NO Sensitizer YC-1 in Piglet Pulmonary Arteries

Abstract

Background: The indazole derivative YC-1 has been characterized as a nitric oxide (NO)-independent and heme dependent soluble guanylate cyclase (sGC) activator, which also sensitizes sGC to NO. Objective: To examine the effects of YC-1 on vascular relaxation in newborn and 2-week-old piglet pulmonary arteries. The effect of YC-1 on the relaxation induced by exogenous NO was also analyzed. Methods: Isolated rings from third branch pulmonary arteries and fifth–seventh-generation intrapulmonary arterioles were mounted in organ chambers for isometric tension recording. Arteries were precontracted with the thromboxane A₂ mimetic U46619. Results: YC-1 induced relaxation was greater in 2-week-old pulmonary arteries and was abolished by the sGC inhibitor ODQ (10 µM). YC-1 induced relaxation was similar in conduit pulmonary arteries and arterioles. In the 2-week-old conduit pulmonary arteries, the response to YC-1 was significantly reduced when the endothelium was removed or after incubation with the NO synthase inhibitor L-NAME (0.1 mM). YC-1 augmented NO-induced relaxation in 2-week-old but not in neonatal conduit pulmonary arteries. Conclusions: Our results indicate that YC-1 induced pulmonary vascular relaxation in conduit and resistance pulmonary arteries and these effects increased with postnatal age. In the 2-week-old conduit pulmonary arteries and besides being a direct activator of sGC, YC-1 produced endothelium-dependent relaxation and synergized with exogenous NO.