Modulatory effect of imetit, a histamine H3 receptor agonist, on C-fibers, cholinergic fibers and mast cells in rabbit lungs in vitro.

The pharmacological mechanisms involved in the interactions between C-fibers, cholinergic fibers and mast cells were investigated in tracheally perfused rabbit lungs by measuring the simultaneous release of substance P and histamine in lung effluents. The amounts of substance P and histamine released in lung superfusates were measured by radioimmunoassay (RIA) after administration of capsaicin and carbachol. Capsaicin (10(-4) M) induced a simultaneous increase in substance P (273 +/- 56% of baseline) and histamine (460 +/- 138%) release. Similarly, carbachol (10(-4) M) caused an increase in the release of both substance P (367 +/- 111%) and histamine (1379 +/- 351%). The effect of capsaicin was prevented by pretreating the lungs with the tachykinin NK1 receptor antagonist SR 140333 (10(-7) M), and atropine (10(-6) M). SR 140333 prevented the carbachol-induced release of substance P but not of histamine. Exogenous substance P induced an increase in histamine release (136 +/- 7%) which was significantly greater in lungs perfused with the neutral endopeptidase inhibitor, thiorphan (10(-5) M) (272 +/- 35%). This effect was prevented by atropine (10(-6) M). Pretreatment of lungs with imetit (5 x 10(-8) M), a selective H3 receptor agonist, prevented the capsaicin-induced release of both mediators. Imetit also blocked the carbachol-induced release of substance P but not of histamine. Exogenous substance P-evoked histamine release was inhibited by imetit. Therefore, it can be concluded that substance P released through the action of capsaicin can activate cholinergic fibers, leading to cholinoceptor stimulation with subsequent activation of C-fibers and mast cells. While the presence of presynaptic H3 receptors modulating substance P-induced acetylcholine release was only surmised, the existence of modulating histamine H3 receptors on C-fibers was confirmed.

Short-term Toxicity of Various Pharmacological Agents on the In Vitro Nitrification Process in a Simple Closed Aquatic System.

During the treatment of fish diseases, drugs which inhibit the nitrification process can cause acute ammonia toxicity. The same phenomenon can occur when fish are put into a tank without active cultures of nitrifying bacteria. The purpose of this study was to quantify the inhibitory effects of 15 pharmacological agents, which are often used as therapeutic agents in ichthyopathology, on ammonia removal and nitrate production in a simple closed aquatic system. The experiments were conducted in polyethylene bags containing activated biofilters and synthetic water solutions, held in a water bath. Ammonia was added to initiate the nitrification process, and graded concentrations of various pharmacological agents were added. The effects of the pharmacological agents on in vitro nitrification were assessed by monitoring ammonia and nitrate concentrations compared to controls with no added agents, for 24 hours. Graded concentrations of ampicillin (Albipen®), chloramine T, enrofloxacin (Baytril®), erythromycin, levamisole, methylene blue and polymyxin B induced dose-dependent inhibitions of ammonia removal and nitrate production. The corresponding linear regression curves showed high correlation coefficients and were highly significant (p < 0.05). The addition of chloramphenicol, copper (II ) sulphate, kanamycin disulphate, malachite green, neomycin sulphate, potassium penicillin G, tetracycline and a mixture of trimethoprim and sulphadoxin (Duoprim™) had no significant effects on the nitrification process. A significant dose-related inhibition of nitrate production, but not of ammonia oxidation, was observed with enrofloxacin. The significant correlation (r = 0.940; p < 0.001) between the degrees of inhibition of ammonia oxidation and nitrate production for the various inhibitory pharmacological agents has also been calculated, with a view to validating this method. The data presented suggest that separate tank facilities for hospitalisation or quarantine are necessary when treating diseased fish with ampicillin, enrofloxacin, chloramine T, erythromycin, levamisole, methylene blue or polymyxin B, in order to avoid ammonia poisoning.

Relationship between parathion and paraoxon toxicokinetics, lung metabolic activity, and cholinesterase inhibition in guinea pig and rabbit lungs.

Kinetic parameters of parathion and paraoxon uptake were determined in isolated and perfused rabbit and guinea pig lungs. They were related to organophosphate-induced lung cholinesterase inhibition. A single pass procedure was used to perfuse the lungs with an artificial medium perfusate containing paraoxon or parathion. The paraoxon and parathion concentrations were determined in the effluents collected at chosen intervals over an 18-min period beginning at the start of perfusion. Three inflowing concentrations (1 nmol/ml, 10 nmol/ml, and 20 nmol/ml) were tested in guinea pig lungs and one (10 nmol/ml) in rabbit lungs. Cholinesterase activity was determined at time 0 and at the end of the experiment. The lungs abundantly extracted paraoxon and parathion over the perfusion period. The extraction ratio was consistently greater in guinea pig than in rabbit lungs. The uptake velocity varied biexponentially in time, suggesting the existence of two compartments. Initial uptake velocities (A, B) and slopes (alpha and beta) were calculated for both compartments. In guinea pigs, A, B and A + B increased proportionally to the supply rate of paraoxon and parathion while a and b remained constant. No significant difference was observed between parathion and paraoxon uptake kinetics. Parameter B was the only one to differ significantly between the two species (rabbits: 8.19 +/- 1.53 for parathion and 6.85 +/- 1.26 for paraoxon; guinea pigs: 12.75 +/- 0.88 for parathion and 15.02 +/- 3.84 for paraoxon). In the lungs of both species, there was a linear relation between y, the percentage of cholinesterase inhibition induced by either organophosphate, and X, the total amount of drug taken up by the lung tissue (in nmol/g/18 min). The following equations were obtained: y = 0.128 x + 0.979 (R2 = 0.89, p < 0.001 for paraoxon); y = 0.120 x - 6.57 (R2 = 0.82, p < 0.005 for parathion). No difference was observed between the two organophosphates. After treatment with the cytochrome P450 inhibitor piperonyl butoxide, the above relations ceased to apply, but this treatment did not influence the kinetics of paraoxon and parathion uptake. The IC50 value calculated for paraoxon, i.e., the paraoxon concentration required to produce 50% inhibition of lung cholinesterase activity, was similar for guinea pigs (2.22 10(-7) +/- 0.22 M) and rabbits (2.36 10(-7) +/- 0.24 M). In conclusion, the biexponential evolution of the velocity of paraoxon and parathion uptake by the lungs thus demonstrates the presence of two pools. The lower extraction ratios calculated for rabbit lungs reflect the lower initial uptake velocity of the second compartment. In the range of concentrations investigated in guinea pigs, no saturable mechanism could be demonstrated for paraoxon and parathion. Cytochrome P450-related lung metabolic activity, through which parathion is converted to paraoxon, appears as a major step in parathion-induced lung cholinesterase inhibition, although it does not appear to affect parathion toxicokinetics.

Effects of age, sex and breed on antipyrine disposition in calves.

In domestic animals relatively little is known about the functions of hepatic microsomal enzymes and their role in biotransformation. In this study, antipyrine was used to assess microsomal oxidative function and particularly to determine the effect of age, sex and breed on drug metabolising enzymes. At birth, the elimination rate of antipyrine was very low as reflected by a half-life of 24 hours. The first two months of life were characterised by a steady decrease of antipyrine half-life values of three to four hours being reached at six months. The decrease observed during early life was not identical in the two breeds used in this experiment. By six months the Friesian calves eliminated antipyrine twice as fast as the Blue White Belgian (BWB) breed: 2.1 +/- 0.3 hours and 4.9 +/- 0.3 hours, respectively. The BWB breed is characterised by muscular hypertrophy and by a relative imbalance in muscle:body ratio. The apparent volume of distribution of antipyrine did not vary with age, sex and breed. No differences in antipyrine clearance were found between male and female calves.

Antipyrine disposition in calves. I. Effects of some drugs.

The influence of four drugs on antipyrine pharmacokinetic parameters was studied after 3 h, 2 and 6 days in 32 Friesian calves. Dexamethasone phosphate and griseofulvin led to increased antipyrine elimination. The effect of dexamethasone remained significant 2 and 6 days later. The rate of antipyrine elimination was markedly but transiently depressed by chloramphenicol and oxytetracycline. The apparent volume of antipyrine distribution remained unaltered during treatment.

Clinical and experimental modifications of plasma iron and zinc concentrations in cattle.

Plasma iron and zinc concentrations were studied in pyrexic cattle or in cattle experimentally infected with infectious bovine rhinotracheitis virus or Escherichia coli endotoxin. Plasma iron and zinc levels tended to decline in the animals given endotoxin and in the pyrexic cattle, but the plasma iron level was only modified after experimental infectious bovine rhinotracheitis infection. These changes were not always related to pyrexia. Plasma iron and zinc concentrations taken together may be used as an indicator of infection.