YC‐1 potentiates nitric oxide‐induced relaxation in guinea‐pig trachea

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Abstract
The effects of YC‐1 (3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzylindazole) on tension, levels of cyclic GMP and cyclic AMP were investigated in guinea‐pig trachea. We especially studied the combined effect of YC‐1 with exogenous or endogenous nitric oxide on these parameters. YC‐1 at the concentration 3 or 10 μM, which caused only minor effect by itself, elicited concentration‐dependent potentiation of sodium nitroprusside (SNP)‐induced tracheal relaxation. This relaxation of YC‐1 with SNP was reversed by ODQ. Relaxant responses to electric field stimulation (EFS) in the presence of indomethacin, atropine, guanethidine, α‐chymotrypsin and histamine were also markedly increased by YC‐1 (10 μM). In the presence of L‐NAME or ODQ, the relaxant effects to EFS were attenuated and the following addition of YC‐1 did not further enhance relaxation. YC‐1 (10 μM) or SNP (0.3 μM) alone did not induce significant elevation of cyclic GMP levels in the presence of IBMX, whereas simultaneous application of both compounds markedly elevated the cyclic GMP accumulation. In contrast, the cyclic AMP levels were not altered even at the combination of YC‐1 and SNP. Additionally, YC‐1 also affected cyclic GMP metabolism, since it inhibited the activity of phosphodiesterase type V in human platelets. YC‐1 (30 μM) did not scavenge superoxide anion and had no effect on the removal of superoxide anion by superoxide dismutase in a xanthine/xanthine oxidase system. In conclusion, these results indicate that although YC‐1 elicits negligible relaxation of guinea‐pig trachea by itself, it can potentiate the relaxant responses of exogenous or endogenous NO. This synergistic response of YC‐1 is via the elevation of cyclic GMP contents. British Journal of Pharmacology (1999) 128, 577–584; doi:10.1038/sj.bjp.0702830

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