Guanylate cyclase activators influence reactivity of human mesenteric superior arteries retrieved and preserved in the same conditions as transplanted kidneys.

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 micromol/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 degrees 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 1H- [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 (1 micromol/L) produced a greater decrease in the vasodilator response of YC-1 (E(max) = 18.7% +/- 4.55%; n = 9). ODQ (10 micromol/L) plus 1 mumol/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.