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Cimetidine inhibits nitric oxide associated nitrate production in a soft‐tissue inflammation model in the horse
Author(s) -
R. P. Hunter,
Charles R. Short,
Jill J. McClure,
Catherine Koch,
Michael L. Keowen,
Jan L. VanSteenhouse,
Azra Dees
Publication year - 1999
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1046/j.1365-2885.1999.00196.x
Subject(s) - nitric oxide , nitrate , cimetidine , horse , inflammation , medicine , pharmacology , chemistry , biology , organic chemistry , paleontology
Cimetidine (CIM) is an H 2 ‐receptor antagonist that has been used in racehorses in an attempt to reduce the occurrence of stress‐related gastric ulceration. It has also been shown to produce several useful effects other than its gastric acid suppression properties. Further, it is a well documented antagonist of cytochrome P‐450 (CYP) mediated oxygenation reactions. Nitric oxide (NO), a recently discovered mediator or modifier of numerous physiological functions, is generated by several forms of nitric oxide synthase (NOS), one of which is inducible (iNOS). Inducible NOS, expressed in neutrophils and macrophages as part of the inflammatory response to noxious stimuli, contains both a CYP and a CYP reductase domain. Because of the similarity of structure of iNOS and CYP, it was decided to determine whether CIM could reduce NO production, using a carrageenan inflammation model in the horse. Two experiments were conducted. In Trial 1, six female Thoroughbred horses each had three tissue chambers inserted subcutaneously on the sides of the neck. The study was divided into three treatments: 0.9% NaCl (NaCl), CIM (3 mg/kg), and aminoguanidine (AG; 25 mg/kg), an inhibitor of iNOS. Each mare received three i.v. injections 12 h apart prior to instillation of 1 mL of carrageenan into the test chamber. Blood and tissue chamber fluid (TCF) were collected serially. Concentrations of NO 3 − (the major metabolite of NO), albumin, total protein, CIM and AG were measured and complete cell counts and differentials were conducted. Trial 2 also used six female Thoroughbred horses implanted with at least two tissue chambers inserted subcutaneously on the sides of the neck. The study was divided into two treatments: NaCl (0.9%) and CIM (6 mg/kg). Each mare received seven i.v. injections of either NaCl or CIM 8 h apart prior to instillation of 1 mL of carrageenan into the test chamber. Blood and TCF were collected serially as before, and analysed for NO 3 − and CIM content. Areas under the curve ( AUC ) of the different parameters were calculated for the periods of –1–1, –1–3 and –1–7 days (Trial 1) and –2–1 for Trial 2. Absolute values were also compared at 4, 8 and 12 h postcarrageenan. Saline treatment did not reduce the elevated concentrations of NO 3 − in either plasma or TCF. Plasma, test chamber and control chamber NO 3 − concentrations rose from 0 to 12 h, and were very similar in all three sampled fluids. Cimetidine significantly ( P 0.05) decreased NO 3 − production in plasma over the periods of –1–1, –1–3, and –1–7 days post inflammation when compared to NaCl treatment in Trial 1. Aminoguanidine and CIM decreased NO 3 − production in TCF for the periods –1–1, 1–3, and –1–7 days post inflammation in Trial 1 and –2–1 for Trial 2. Both CIM and AG also significantly reduced NO 3 − concentrations in plasma and TCF at 12 h postinitiation (Trials 1 and 2). Thus CIM, at the doses studied, was capable of reducing NO 3 − concentrations in this model as effectively as AG, a relatively specific inhibitor of iNOS activity.