Abstract
Introduction This study sought to investigate the mechanisms of relaxation induced by the (nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) stimulators 3-[5′-hydroxymethyl-2′-furyl]-1-benzylindazole (YC-1) in human mesenteric arteries relaxed and precontracted with 1 μmol/L 5-hydroxytryptamine (serotonin). Material and methods Human mesenteric arteries obtained during kidney retrieval were preserved in the same conditions as transplanted kidneys. All experiments were performed after reperfusion with Krebs buffer in 37°C and 100% oxygen exposure. Results In endothelium-intact rings, YC-1 (0.001 to 30 mmol/L) caused concentration-dependent relaxation (pEC 50: 6.59 ± 0.12), which shifted to the right in endothelium-denuded rings. The sGC inhibitor 1 H- [1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ 10 mmol/L) partially attenuated the maximal responses to YC-1 (E max = 51.30% ± 3.70%; n = 6) and displaced its curve to the right in intact and denuded vessels. Both, the NO synthesis inhibitor N-nitro-L-arginine methyl ester (100 mmol/L) and the NO scavenger carboxy-2-[4-carboxyphenyl]-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (100 mmol/L) significantly reduced YC-1 relaxation. The sodium pump inhibitor ouabain (1μmol/L) produced a greater decrease in the vasodilator response of YC-1 (E max = 18.7% ± 4.55%; n = 9). ODQ (10 μmol/L) plus 1 μmol/L ouabain abolished the relaxant response of YC-1 (E max = 9.4% ± 2.94%, n = 9). Conclusions This study demonstrated that sodium pump stimulation by YC-1 as an additional mechanism of sGC activation independent of cGMP relaxed human mesenteric artery, including blockade of Ca 2+ influx. Furthermore, this study suggested an ability of NO to mediate relaxation of resistance-like arteries through the activation of soluble guanylate cyclase and K + channels.
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