Interaction of hypoxanthine/xanthine oxidase with nitrergic relaxation in the porcine gastric fundus

The influence of hypoxanthine (HX)/xanthine oxidase (XO) on short‐term [electrical field stimulation (EFS; 4 Hz) for 10 s and 3 min; bolus of exogenous NO (10 −5   M )] and long‐term [EFS (4 Hz) and continuous NO‐infusion for 20 min] nitrergic relaxations was investigated in circular muscle strips of the pig gastric fundus. HX (3×10 −4   M ) / XO (64 mu ml −1 ) did not affect EFS for 10 s and 3 min; the short‐lasting relaxation in response to a bolus of exogenous NO (10 −5   M ) was changed into a biphasic relaxation with a small and short first phase followed by a larger and prolonged second phase. Cu/Zn superoxide dismutase (Cu/Zn SOD; 1000 u ml −1 ) and uricase (100 mu ml −1 ) respectively enhanced the amplitude of the first phase and diminished the amplitude of the second phase. Ascorbate (5×10 −4   M ) and bilirubin (2×10 −4   M ) prevented the prolonged component. Exposure to HX/XO during long‐term EFS elicited a complete, stable reversal of relaxation starting after a delay. During continuous NO‐infusion, HX/XO induced an immediate, complete but transient reversal. The antioxidants bilirubin, ascorbate, α‐tocopherol, urate, glutathione and Cu/Zn SOD, the hydrogen peroxide degrading enzyme catalase, the hydroxyl radical scavengers dimethylsulphoxide and mannitol, and the cofactor flavin adenine dinucleotide did not influence the reversal induced by HX/XO during either EFS or NO‐infusion. The cell‐permeable manganese SOD mimetic EUK‐8 modified the stable reversal during long‐term EFS into a transient one. The results suggest that a nitrated uric acid derivative is responsible for the prolonged second phase in the relaxation to a bolus of exogenous NO in the presence of HX/XO. The exact underlying mechanism of the reversal induced by HX/XO during sustained relaxation remains unclear.British Journal of Pharmacology (2000) 130 , 359–366; doi: 10.1038/sj.bjp.0703317