ISSN:
1432-1912
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract The inhibitory potency of different classes of nitric oxide synthase (NOS) inhibitors (amino acid-based substances, guanidines, isothioureas, imidazoles and indazoles) versus peripheral neuronal NOS in the pig gastric fundus was investigated by studying their influence on electrically induced relaxations in non-adrenergic non-cholinergic conditions. Circular muscle strips were mounted for isotonic registration in the presence of atropine and guanethidine, and tone was raised with 5-hydroxytryptamine. Electrical field stimulation (40V, 0.1ms, 4Hz, 10s) induced short-lasting relaxations. The inhibitory effect of 1-phenylimidazole could not be evaluated because it nearly abolished the 5-hydroxytryptamine-induced tone of the tissues. 7-Nitroindazole, imidazole, 2-iminobiotin and aminoguanidine did not inhibit the electrically induced relaxations, while the other 9 substances tested were able to do so. The influence of the incubation period was tested by studying the inhibitory effect after incubation for 10 up to 60min. For NG-nitro-L-arginine methyl ester (L-NAME), NG-nitro-L-arginine (L-NNA), L-N5-(1-iminoethyl)-ornithine (L-NIO), L-N6-(1-iminoethyl)-lysine (L-NIL), S-methyl-L-thiocitrulline and S-isopropyl isothiourea there was a moderate increase in the inhibitory effect up to 30min of incubation so that they were incubated for 30min to study their inhibitory potency. For L-thiocitrulline, S-methyl isothiourea and S-ethyl isothiourea, an incubation period of 60min was used. The 9 substances concentration-dependently inhibited the electrically induced relaxations with a maximal inhibitory effect of approximately 80% except for S-methyl isothiourea (E max of 53%). The over all order of potency was: S-isopropyl isothiourea 〉 S-ethyl isothiourea ≥ S-methyl-L-thiocitrulline ≥ L-NNA 〉 L-NIO 〉 L-NAME 〉 S-methyl isothiourea 〉 L-thiocitrulline 〉 L-NIL. While the potency for S-isopropyl isothiourea (EC50: 3.1×10–5M, n=6) to S-methyl isothiourea (EC50: 11.5×10–5M, n=5) was in the same range, the potency of L-thiocitrulline and L-NIL was clearly lower. This study showed several compounds to be potent inhibitors of peripheral neuronal NOS in the pig gastric fundus while some compounds, that were reported to inhibit brain neuronal NOS were not effective. The EC50 values found for the effective substrates in this functional study may be a guideline for the concentrations required to evaluate the role of NO in NANC neurotransmission in gastrointestinal smooth muscle preparations.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/PL00005081
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