Influence of S-nitrosothiols and nitrate tolerance in the rat gastric fundus

1. The relaxant responses of S-nitroso-L-cysteine (CysNO), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), S-nitroso-N-acetyl-L-cysteine (SNAC) and S-nitrosoglutathione (GSNO) in the rat gastric fundus (forestomach) were studied and compared to the relaxant responses obtained in response to nitric oxide (NO) and electrical field stimulation (EFS, 10 s strains) of non-adrenergic non-cholinergic (NANC) nerves. 2. CysNO (10(-7)-3 x 10(-4) M) caused transient relaxation of the precontracted rat gastric fundus, comparable to the response to NO (10(-6)-10(-4) M) and EFS. SNAP, SNAC and GSNO elicited more sustained relaxations. 3. The cyclic GMP-specific phosphodiesterase inhibitor, zaprinast (3 x 10(-5) M) increased the relaxant effect of CysNO, SNAP and GSNO while the NO-synthase inhibitor, NG-nitro-L-arginine (L-NOARG, 3 x 10(-4) M) had no influence. 4. In the presence of LY 83583 (10(-5) M), which releases superoxide anions, the relaxant response to NO and CysNO was decreased, whereas that to all other stimuli was unaltered. The inhibitory effect of LY 83583 on CsNO-induced relaxations was prevented by superoxide dismutase (SOD, 1000 u ml-1). 5. Tissues incubated for 1 h with 5.5 x 10(-4) M nitroglycerin (GTN) became tolerant to GTN. In this condition, the relaxant response to 10(-5) M NO was maintained, while the relaxations by EFS (8 Hz) and 3 x 10(-5) M SNAP were significantly decreased. The reduction of the response to the other S-nitrosothiols was not significant. 6. The combination of nitrate tolerance and 10-5 M LY 83583 caused a significantly larger inhibition of the relaxant response to EFS (8 Hz) than nitrate tolerance alone. The combination of LY 83583 and GTN tolerance reduced the relaxant effect of 10-5 M NO to a similar extent to LY 83583 alone, while the relaxant response to 10-4 M GTN was reduced to the same extent as after 1 h exposure to 5.5 x 10-4 M GTN alone.7. It is concluded that S-nitrosothiols potently relax the rat gastric fundus, possibly by a cyclic GMP-dependent mechanism and S-nitrosothiols such as SNAC and GSNO may be involved in NANC neurotransmission.