The pharmacokinetics of flunixin meglumine was determined after its multiple (altogether 4 doses at 24-hours intervals) intravenous administration at a dose of 2.2 mg/kg body weight in six mature clinically healthy heifers. Plasma flunixin and its metabolite 5-hydroxyflunixin concentrations were analyzed with high-pressure liquid chromatography using an assay with a lower limit detection of 0.03 μg/ml for both substances. Plasma concentrations versus time curves were described by a two compartment open model. Mean plasma flunixin concentrations were similar on day 1 and 4, and than rapidly decreased (within 2 hours) from initial concentrations higher than 10 μg/ml to the concentrations lower than 1 μg/ml. The distribution phase of flunixin was short (t05α = 0.29 ± 0.16 and 0.18 ± 0.04 on day 1 and 4, respectively) and the elimination phase was more prolonged (t05ß = 3.30 + 0.60 and 3.26 + 0.22 on day 1 and 4, respectively). The mean residence time of flunixin was similar on day 1 (1.83 ± 0.83) and 4 (1.88 + 0.46), and for 5-hydroxyflunixin this parameter was insignificantly (P > 0.05) higher on day 1 (5.49 ± 2.22) as compared to that found on day 4 (3.99 ± 2.17). The clearance of flunixin was similar on both examined days (0.23 ± 0.12 on day 1 and 0.31 ± 0.15 on day 4), and for 5-hydroxyflunixin was insignificantly (P > 0.05) lower on day 1 (2.37 ± 1.21) as compared to that determined on day 4 (3.23 ± 1.06). Our data indicate that multiple administration of flunixin did not alter significantly the parent drug and its metabolite concentrations in plasma, however may cause some small changes in pharmacokinetic parameters.
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Effects of Ap4A and NAD - precursor of adenosine, on renal plasma flow (RPF), glomerular filtration rate (GFR) and urine excretion were determined in the anaesthetised rats. Infusion of Ap4A or NAD (i.v., bolus - 1 µmol/kg followed by 10 nmol/min/kg) decreased RPF and GFR (by 30 and 40%, respectively). In spite of GFR reduction during Ap4A infusion, the significant increase in sodium excretion and urine flow was noticed: fractional sodium (FENa) and urine excretion (FEurine) rose 15-fold and 2.5-fold in comparision with the control value, respectively. In contrast to Ap4A, NAD-induced decrease in GFR was associated with parallel decrease in sodium and urine excretion, thus the FENa and FEurine did not significantly change. Pre-treatment with adenosine deaminase (adenosine degrading enzyme, 2 U/min/kg) or theophylline (P1-receptors antagonist, 0.2 mmol/min/kg) ceased responses to NAD, wherease Ap4A-induced changes were not affected. Pre-treatment with suramin (P2-receptors antagonist, (i.v., bolus - 12 mg/kg followed by 1.2 mg/min/kg) completely abolished the renal effects of Ap4A. We conclude that Ap4A may exert specific action on renal function. It acts different from NAD that modified renal function through its hydrolysis product - adenosine. Ap4A might reduce glomerular filtration rate and evoke natriuresis and diuresis, and its effects are probably mediated through stimulation of P2-receptors.
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Melatonin occurs in large amounts in the intestinal mucosa and is released during a meal. Recent studies of ours reveal that exogenous melatonin evokes the in vivo secretion of protein and amylase from the rat parotid gland. The aim of the present study was to investigate the effect of melatonin on the protein synthesis of the parotid gland of pentobarbitone-anaesthetised rats as estimated by the rate of incorporation of [3H]leucine into trichloroacetic acid-insoluble material of the gland. Compared with the parotid protein synthesis (set at 100%) of those rats exposed to an intravenous infusion of melatonin (25 mg/kg during 1 hour), under muscarinic and - and ß-adrenoceptor blockade, the synthesis in the corresponding glands of saline-treated control rats was less (by 25%). The synthesis was also less when the melatonin administration was combined with the melatonin 2-preferring receptor antagonist luzindole (24%), the non-selective nitric oxide synthase inhibitor L-NAME (18%) and the neuronal nitric oxide synthase inhibitor N-PLA (21%). Almost all the melatonin receptor-mediated effect was due to nitric oxide generation via the activity of neuronal type nitric oxide synthase. The present findings lend further weight to the idea that salivary glandular activity associated with food intake is hormonally influenced and they also suggest clinical implications for melatonin in the treatment of xerostomia. Since melatonin is known to exert anti-inflammatory actions in the oral cavity, the stimulatory effect of melatonin may include the synthesis of proteins of importance for the oral defence.
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The nutritional and physiological roles of amino acid (AA)s have been investigated for individual organs. In the current study, we focused on the dynamics of glutamate and transport systems in the pancreas. We employed original procedures to obtain rat pancreatic juice (PJ) subjected to intravenous administration of alanyl-glutamine (AG) for AA analysis. The pancreatic expressions of the transporters were evaluated by immunohistochemistry. We found that glutamate was secreted into the PJ in the basal state. The intravenous administration of AG increased the concentration and total amount of glutamate excreted into the PJ. In terms of the transport systems, L-type AA transporter (LAT1) was identified exclusively in the islet cells. Glutamate transporter 1 (GLT1), glutamate-aspartate transporter (GLAST), vesicular glutamate transporter 1 (VGUT1) and cystine/glutamic acid transporter (xCT) were found in the islet cells. xCT was identified in the duct cells as well, but was not accompanied by the expression of 4F2 heavy chain (4F2hc) staining in the islets and the acinar cells, similar to neutral AA transporter (ASCT2) or b0,+-type AA transporter 1(BAT1). Excitatory AA transporter (EAAC) was identified only in the acinar cells. Glutamate was exclusively found in the acinar cells. We revealed the novel dynamics of glutamate in the rat PJ. The glutamate secretion into the PJ was augmented by plasma glutamine, indicating the de novo metabolisms of glutamate, together with the local expression of the related transporters.
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