404 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 an 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-1on 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. Design/Methods: Isolated rings from third generation pulmonary arteries (outer diameter 500-1000 microm) and small distal pulmonary arteries (outer diameter 150–200 microm) were mounted in organ chambers for isometric tension recording. Arteries were precontracted with the thromboxane A2 mimetic U46619 (0.1 microM) Results: YC-1 induced a concentration-dependent relaxation that was significantly greater in 2 week-old pulmonary arteries and was abolished by the sGC inhibitor ODQ (10 microM). YC-1 induced relaxation was similar in conduit pulmonary arteries and arterioles. In the 2-week-old 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 (3 microM) augmented NO-induced relaxation in 2-week-old but not in neonatal pulmonary arteries. Conclusions: YC-1 induced pulmonary vascular relaxation in conduit and resistance pulmonary arteries and these effects increased with postnatal age. In the 2-week-old pulmonary arteries and besides its direct activator of sGC, YC-1 produced endothelium-dependent relaxation and synergized with exogenous NO.