Influence of bilirubin and other antioxidants on nitrergic relaxation in the pig gastric fundus.
1. The influence of several antioxidants (bilirubin, urate, ascorbate, alpha-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(-5) M) or electrical field stimulation (4 Hz; 10 s and 3 min) was studied in the pig gastric fundus. 2. Ascorbate (5x10(-4) M), alpha-tocopherol (4x10(-4) M), SOD (300 - 1000 u ml(-1)) and EUK-8 (3x10(-4) M) did not influence the relaxations to exogenous NO. In the presence of GSH (5x10(-4) M), the short-lasting relaxation to NO became biphasic, potentiated and prolonged. Urate (4x10(-4) M) and bilirubin (2x10(-4) M) also potentiated the relaxant effect of NO. None of the antioxidants influenced the electrically evoked relaxations. 3. 6-Anilino-5,8-quinolinedione (LY83583; 10(-5) M) had no influence on nitrergic nerve stimulation but nearly abolished the relaxant response to exogenous NO. Urate and GSH completely prevented this inhibitory effect, while it was partially reversed by SOD and bilirubin. Ascorbate, alpha-tocopherol and EUK-8 were without effect. 4. Hydroquinone (10(-4) M) did not affect 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 afforded partial protection, while bilirubin, EUK-8 and alpha-tocopherol were ineffective. 5. Hydroxocobalamin (10(-4) M) inhibited relaxations to NO by 50%, but not the electrically induced responses. Full protection versus this inhibitory effect was obtained with urate, GSH and alpha-tocopherol. 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.
Colpaert
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Heymans Institute of Pharmacology, University of Gent Medical School, De Pintelaan 185, B-9000 Gent, Belgium.
Lefebvre
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D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001663:Bilirubin / Q000494:pharmacology*; D001664:Biliverdine / Q000494:pharmacology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors; D005748:Gastric Fundus / Q000187:drug effects; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006397:Hematinics / Q000494:pharmacology; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006873:Hydroquinones / Q000494:pharmacology; D006879:Hydroxocobalamin / Q000494:pharmacology; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology*; D013270:Stomach / Q000187:drug effects*; D013552:Swine
D000634:Aminoquinolines; D000975:Antioxidants; D004791:Enzyme Inhibitors; D006397:Hematinics; D006873:Hydroquinones; D009569:Nitric Oxide; D006418:Heme; C041715:6-anilino-5,8-quinolinedione; D006419:Heme Oxygenase (Decyclizing); D006162:Guanylate Cyclase; D001664:Biliverdine; D006879:Hydroxocobalamin; D001663:Bilirubin