1 The in¯uence of several antioxidants (bilirubin, urate, ascorbate, a-tocopherol, glutathione (GSH), Cu/Zn superoxide dismutase (SOD) and the manganese SOD mimic EUK-8) on nitrergic relaxations induced by either exogenous nitric oxide (NO; 10 75 M) or electrical ®eld stimulation (4 Hz; 10 s and 3 min) was studied in the pig gastric fundus. 2 Ascorbate (5610 74 M), a-tocopherol (4610 74 M), SOD (300 ± 1000 u ml 71 ) and EUK-8 (3610 74 M) did not in¯uence the relaxations to exogenous NO. In the presence of GSH (5610 74 M), the short-lasting relaxation to NO became biphasic, potentiated and prolonged. Urate (4610 74 M) and bilirubin (2610 74 M) also potentiated the relaxant e ect of NO. None of the antioxidants in¯uenced the electrically evoked relaxations. 3 6-Anilino-5,8-quinolinedione (LY83583; 10 75 M) had no in¯uence on nitrergic nerve stimulation but nearly abolished the relaxant response to exogenous NO. Urate and GSH completely prevented this inhibitory e ect, while it was partially reversed by SOD and bilirubin. Ascorbate, a-tocopherol and EUK-8 were without e ect. 4 Hydroquinone (10 74 M) did not a ect the electrically induced nitrergic relaxations, but markedly reduced NO-induced relaxations. The inhibition of exogenous NO by hydroquinone was completely prevented by urate and GSH. SOD and ascorbate a orded partial protection, while bilirubin, EUK-8 and a-tocopherol were ine ective. 5 Hydroxocobalamin (10 74 M) inhibited relaxations to NO by 50%, but not the electrically induced responses. Full protection versus this inhibitory e ect was obtained with urate, GSH and atocopherol. 6 These results strengthen the hypothesis that several endogenous antioxidant defense mechanisms, enzymatic as well as non-enzymatic, might play a role in the nitrergic neurotransmission process.

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Olmesartan, a well-known and powerful antihypertensive drug, was first described to cause enteropathy in 2012. A possible mechanism may be inhibition of the intestinal immune suppressive effect of transforming growth factor-beta (TGF-β), with a consequential increase of intestinal T-cell inflammation. We present the case of a 60-year-old woman who developed large volume, watery diarrhoea with 8kg weight loss only two weeks after starting olmesartan 20mg daily with a secondary mild acute kidney insufficiency and hypokalaemia. Coeliac serology was negative. Endoscopy revealed no macroscopic lesions. Histology showed increased gastric, duodenal, ileal and colonic intraepithelial lymphocytes with partial duodenal villous atrophy, hence affecting the entire gastrointestinal tract. After cessation of olmesartan, symptoms improved within a week; therefore a diagnosis of olmesartan induced enteropathy was made. Extra immunohistochemical stains to further investigate the underlying pathophysiology were inconclusive.

1 The in¯uence of hypoxanthine (HX)/xanthine oxidase (XO) on short-term [electrical ®eld stimulation (EFS; 4 Hz) for 10 s and 3 min; bolus of exogenous NO (10 75 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. 2 HX (3610 74 M) / XO (64 mu ml 71 ) did not a ect EFS for 10 s and 3 min; the short-lasting relaxation in response to a bolus of exogenous NO (10 75 M) was changed into a biphasic relaxation with a small and short ®rst phase followed by a larger and prolonged second phase. Cu/Zn superoxide dismutase (Cu/Zn SOD; 1000 u ml 71 ) and uricase (100 mu ml 71 ) respectively enhanced the amplitude of the ®rst phase and diminished the amplitude of the second phase. Ascorbate (5610 74 M) and bilirubin (2610 74 M) prevented the prolonged component. 3 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. 4 The antioxidants bilirubin, ascorbate, a-tocopherol, urate, glutathione and Cu/Zn SOD, the hydrogen peroxide degrading enzyme catalase, the hydroxyl radical scavengers dimethylsulphoxide and mannitol, and the cofactor¯avin adenine dinucleotide did not in¯uence the reversal induced by HX/XO during either EFS or NO-infusion. The cell-permeable manganese SOD mimetic EUK-8 modi®ed the stable reversal during long-term EFS into a transient one.5 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.