Effects of the soluble guanylyl cyclase stimulator (sGC) BAY 41‐2272 on vascular tone and cyclic GMP levels in spontaneously hypertensive rats.

Abstract

OBJECTIVE This study aimed to investigate the vasomotor activity of BAY 41-2272 and its effects on cGMP levels in intact (E+) and denuded (E-) rings of mesenteric artery from normotensive (WKY) and hypertensive (SHR) rats. METHODS Rings were mounted in myographs and data were recorded in a PowerLab system. Cyclic GMP was measured using EIA kits. RESULTS In E+ rings, BAY 41-2272 (0.0001-1 μM) caused concentration-dependent relaxations with pEC50 values of 8.57 ± 0.06 (WKY) and 8.28 ± 0.09 (SHR). In E- rings, the curves for BAY 41–2272 were shifted to the right (WKY, 6-fold; SHR, 4-fold) in comparison to E+ preparations. The sGC inhibitor ODQ (10 μM) caused significant inhibition of BAY 41–2272-induced relaxations in WKY (E+, 6.98 ± 0.18; E-, 6.31 ± 0.27) and SHR (E+, 7.89 ± 0.12; E-, 7.16 ± 0.25). In E+ and E- rings, BAY 41–2272-induced relaxations were reduced by approximately 50% in all concentrations used. Relaxations to acetylcholine (ACh, 0.001–10 μM) in SHR rings were markedly potentiated by BAY 41–2272 (0.01–0.1 μM). BAY 41–2272 (0.1 μM) increased cGMP levels by 30- and 15-fold WKY and SHR rings, respectively, in an ODQ-sensitive manner. Levels of cGMP increased by 300- (WKY) and 35-fold (SHR) when BAY 41–2272 was co-incubated with SNP (1 μM). CONCLUSION These findings ascertained the functional and biochemical basis that BAY 41–2272 acts synergistically with NO in vessels from normotensive and hypertensive animals. Financial Support: HL-74167.