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

Abstract

1 The relaxant responses of S-nitroso-L-cysteine (CysNO), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), S-nitroso-N-acetyl-L-cysteine (SNAG) 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 trains) of non-adrenergic non-cholinergic (NANG) 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 (106-1 0-4 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, N-nitro-L-arginine (L-NOARG, 3 x 10-4 M) had no influence.4 In the presence of LY 83583 (10-`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 CysNO-induced relaxations was prevented by superoxide dismutase (SOD, 1000 u ml-'). 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 10-5M SNAP were significantly decreased. The reduction of the response to the other Snitrosothiols was not significant. 6 The combination of nitrate tolerance and 10-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-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.

Blockade of nitrergic transmission by hydroquinone, hydroxocobalamin and carboxy‐PTIO in bovine retractor penis: role of superoxide anion

“…Specifically, they show that nitrergic neurotransmission in the BRP can be blocked by agents that either destroy (superoxide anion generating systems) or scavenge (hydroxocobalamin and carboxy-PTIO) NO. Consequently, although it is perhaps possible that the neurotransmitter in this tissue is an NO-releasing substance (Gibson et al, 1992;Barbier & Lefebvre, 1994;Rand & Li, 1995a), we have thus far no reason to suspect that it is anything other than NO per se. Whether the release of an NOadduct as neurotransmitter in the rat anococcygeus accounts for the inability of hydroxocobalamin (Rajanayagam et al, 1993) and carboxy-PTIO (Rand & Li, 1995b) to block nitrergic transmission in this tissue remains to be determined.…”

“…Some have considered the possibility that the neurotransmitter is an NO-releasing molecule such as an S-nitrosothiol (Gibson et al, 1992;Barbier & Lefebvre, 1994;Rand & Li, 1995a). Others have suggested the neurotransmitter is indeed NO but that, on theoretical grounds, the long diffusion pathway of exogenously added NO compared with endogenously released NO, renders the former more susceptible to inactivation (Wood & Garthwaite, 1994).…”

Effect of thiol modulators and Cu/Zn superoxide dismutase inhibition on nitrergic relaxations in the rat gastric fundus

“…However, in different studies that were carried out in a variety of tissues, the exact identity of the nitrergic NANC neurotransmitter was questioned. A number of pharmacological compounds had a different effect on responses to authentic NO and on responses to NANC nerve stimulation (Gillespie & Sheng, 1990;Hobbs et al, 1991;Barbier & Lefebvre, 1992;Jenkinson et al, 1995;Lilley & Gibson, 1995;Rand & Li, 1995), suggesting that the nitrergic NANC neurotransmitter is not free NO but an NO-releasing compound such as a nitrosothiol (Gibson et al, 1992;Thornbury et al, 1991;Kerr et al, 1992;Kitamura et al, 1993;Barbier & Lefebvre, 1994;Liu et al, 1994). An alter-native explanation for this differential effect is that the nitrergic neurotransmitter is free NO which is protected from breakdown by tissue antioxidants such as superoxide dismutase (SOD), which scavenges superoxide radicals.…”

Rebound Contraction by Nitric Oxide in the Longitudinal Muscle of Porcine Gastric Fundus

“…CysNO was prepared according to the modified method of Barbier and Lefevbre (9). Briefly, the same volume of acidified NaNO2 (200 mM in 1 N HCl, pH<2) and Lcysteine (200 mM in distilled water) were mixed together under 4°C.…”