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Treatment of the animals, including the housing and experimental procedures, was in accordance with Russian and European Union guidelines on the use of animals in research (European Communities Council Directive 86/609/ECC). Protocols were approved by the Ethics Committee of the Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences. At the time of the experiment, conscious rats were placed into individual cages with a wire floor, through which urine was collected into a funnel and then a test tube. Diuresis was recorded as spontaneous urination. Individual urine samples were collected for 4?h. To determine urine concentrations of cAMP and cGMP, the collected samples were aliquoted and stored at ?20��C before analysis. selleck Urine aliquots, used for PGE2 determination, were mixed with indomethacin (10?��g/mL sample) before storage at ?20��C. Blood samples were obtained from the carotid artery under Nembutal anaesthesia (6?mL/kg, i.p., of 0.75% Nembutal; Olainfarm, Olaine, Latvia) in control and water-loaded rats (n?=?10 in each group). After this procedure, anaesthetized GPX4 rats were killed by decapitation. Exenatide was dissolved in a 0.9% NaCl solution at concentrations of 0.05, 0.15, 0.5, 1.5, or 5.0?nmol/mL and was injected in a volume of 1?mL/kg, i.m., in control and water-loaded rats (n?=?10 per cohort). Water load was introduced orally or intraperitoneally, simultaneously with intramuscular injection of exenatide at a dose of 0.15 or 1.5?nmol/kg Osimertinib in vivo (n?=?10 per cohort). Oral water load, equal to 1%, 2% or 5% of bodyweight, was administered by gavage (10, 20 or 50?mL/kg, p.o.). Intraperitoneal water loading consisted of the administration of a hypotonic NaCl solution (50?mL/kg of 0.6% NaCl, i.p.) that is known to induce water diuresis.[18] Blood samples were obtained from caudal blood vessels under ether anaesthesia in control rats (n?=?10) and in groups of water-loaded rats (50?mL/kg, p.o.) at different times (30, 45 and 60?min) after intramuscular injection of 0.15?nmol/kg exenatide (n?=?6, 7 and 7, respectively) or physiological saline (n?=?10, 9 and 10, respectively). To elucidate the mechanism of the hydrouretic effect of exenatide, arginine vasopressin (AVP), the cyclo-oxygenase inhibitor diclofenac and GLP-1 and V2 receptor antagonists were used (Table?1). The GLP-1 receptor antagonist exendin-(9�C39), the V2 receptor antagonist [d(CH2)51,D-Ile2,Ile4,Arg8]-vasopressin (Bachem, Bubendorf, Switzerland) and AVP (Sigma-Aldrich, St. Louis, MO, USA) were dissolved in 0.9% NaCl solution. Diclofenac solution (25?mg/mL; Hemofarm, Vr?ac, Serbia) was diluted 1?:?1 with physiological saline before injection to give a concentration of 12.5?mg/mL. Exenatide and the GLP-1 receptor antagonist exendin-(9�C39) were synthesized at the Faculty of Chemistry of St Petersburg State University under the guidance of Professor Mikhail I Titov.