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Histamine h3 receptors are involved in the regulation of gastric acid secretion in the dog
Pharmacological Research, til. 26, Supplement I, 1992
HISTAMINE H3 RECEPTORS ARE LNVOLVEDIN THE REGULATIONOF GASTRICACID SECRETIonIN THE DOG Giulio Soldani, Luigi Intorre, Grazia Mengozzi, Gabriella Coruzzi” & Giulio Berlaccini* Laboratory of Veterinary Pharmacology, University of Pisa & *Institute of Pharmacology, University of Parma, Parma, Italy It has been shown that histamine H3 receptor activation reduces gastric acid secretion in response to 2-deoxy D-glucose (ZDG), while Ieaving unaltered the hypersecretion induced by dimaprit and pentagastrin in the cat (1). In the present study six dogs chronically fitted with gastric fistulae were used. The selective H3 agonist (R) a-methylhistamine (0.15-0.3 PM/kg/h) or antagonist thioperamide (0.05-0.1 uM/kg/h) was infused for 60 mln under basal conditions or against gastric acid secretion (mEq H+i15 min) stimulated by 2DG (75 mg/kg i.v.). Plasma gastrin was determined by RIA. (R) a-methylhistamine did not induce any significant effect on gastric secretion and gastrin release under basal conditions; by contrast, thioperamide produced a significant increase on both gastric secretion and gastrin plasma levels (PiO.05 at 60 min). -4 dosedependent inhibition of acid secretion stimulated by ZDG, without any effect on gastrin plasma levels, was induced by (R) a-methylhistamine; this inhibitory effect was fully prevented by thioperamide. These results suggest that histamine H3 receptors are involved in the regulation of gastric acid secretion in the dog. 1) Coruzzi G, Bertaccini G, Schwartz JC, Naunyn-Schmiedeberg’s Arch Pharmacol (1991) 343:225.
EFFECTS OF ADR-932, A LONG-LASTING 5-HT, ANTAGONIST, ON BEZOLD-JARISCH REFLEX IN RATS AND CISPLATIN EMESIS IN DOGS. C. Arrigoni, M. Buonamici, A. Kozak*, M. Varasi* Farmitalia Carlo Erba, Preclinical Safety/General Pharmacology and *CNS/CV Department, Nerviano (MI), Italy. The activity of ADR-932 as 5-HT, antagonist and its duration of action were determined by the von Bezold-Jarisch reflex (B-Jr) test in anesthetized rats after i.v. and i.d. treatment; % inhibition of the decrease in heart rate was calculated from the responses to i.v. 5-HT (20 pg/kg) obtained before and after antagonist administration. At the time of peak effect, ADR-932 inhibited B-Jr with ED,& of 0.20 (i.v.) and 11.8 (i.d.) pg/kg. Two hours after i.v. and 8 hours after i.d. administration, ADR-932 (1 and 50 ug/kg respectively) was still able to inhibit significantly B-Jr. Antiemetic activity of ADR-932 was studied in dogs; the compound, given orally 60 min before cisplatin or i.v. 30 min before and 120 min after inhibited emesis with ED,,s of 8.1 (i-v.) and 29.1 (p.0.) cisplatin, w/kg Oral and i-v. activity of ADR-932 on gastric emptying was also studied in rats receiving a semi-solid meal containing 20 ion exchange resin beads. ADR-932 from 0.1 to 10 mgjkg, like After both oral and i.v routes, zacopride 1 mg/kg, increased gastric emptying from 150 to 300%. These results indicate that ADR-932 is a new, potent and long lasting 5-HT, antagonist in rats and dogs.
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HISTAMINE H3 RECEPTORS ARE LNVOLVEDIN THE REGULATIONOF GASTRICACID SECRETIonIN THE DOG Giulio Soldani, Luigi Intorre, Grazia Mengozzi, Gabriella Coruzzi” & Giulio Berlaccini* Laboratory of Veterinary Pharmacology, University of Pisa & *Institute of Pharmacology, University of Parma, Parma, Italy It has been shown that histamine H3 receptor activation reduces gastric acid secretion in response to 2-deoxy D-glucose (ZDG), while Ieaving unaltered the hypersecretion induced by dimaprit and pentagastrin in the cat (1). In the present study six dogs chronically fitted with gastric fistulae were used. The selective H3 agonist (R) a-methylhistamine (0.15-0.3 PM/kg/h) or antagonist thioperamide (0.05-0.1 uM/kg/h) was infused for 60 mln under basal conditions or against gastric acid secretion (mEq H+i15 min) stimulated by 2DG (75 mg/kg i.v.). Plasma gastrin was determined by RIA. (R) a-methylhistamine did not induce any significant effect on gastric secretion and gastrin release under basal conditions; by contrast, thioperamide produced a significant increase on both gastric secretion and gastrin plasma levels (PiO.05 at 60 min). -4 dosedependent inhibition of acid secretion stimulated by ZDG, without any effect on gastrin plasma levels, was induced by (R) a-methylhistamine; this inhibitory effect was fully prevented by thioperamide. These results suggest that histamine H3 receptors are involved in the regulation of gastric acid secretion in the dog. 1) Coruzzi G, Bertaccini G, Schwartz JC, Naunyn-Schmiedeberg’s Arch Pharmacol (1991) 343:225.
EFFECTS OF ADR-932, A LONG-LASTING 5-HT, ANTAGONIST, ON BEZOLD-JARISCH REFLEX IN RATS AND CISPLATIN EMESIS IN DOGS. C. Arrigoni, M. Buonamici, A. Kozak*, M. Varasi* Farmitalia Carlo Erba, Preclinical Safety/General Pharmacology and *CNS/CV Department, Nerviano (MI), Italy. The activity of ADR-932 as 5-HT, antagonist and its duration of action were determined by the von Bezold-Jarisch reflex (B-Jr) test in anesthetized rats after i.v. and i.d. treatment; % inhibition of the decrease in heart rate was calculated from the responses to i.v. 5-HT (20 pg/kg) obtained before and after antagonist administration. At the time of peak effect, ADR-932 inhibited B-Jr with ED,& of 0.20 (i.v.) and 11.8 (i.d.) pg/kg. Two hours after i.v. and 8 hours after i.d. administration, ADR-932 (1 and 50 ug/kg respectively) was still able to inhibit significantly B-Jr. Antiemetic activity of ADR-932 was studied in dogs; the compound, given orally 60 min before cisplatin or i.v. 30 min before and 120 min after inhibited emesis with ED,,s of 8.1 (i-v.) and 29.1 (p.0.) cisplatin, w/kg Oral and i-v. activity of ADR-932 on gastric emptying was also studied in rats receiving a semi-solid meal containing 20 ion exchange resin beads. ADR-932 from 0.1 to 10 mgjkg, like After both oral and i.v routes, zacopride 1 mg/kg, increased gastric emptying from 150 to 300%. These results indicate that ADR-932 is a new, potent and long lasting 5-HT, antagonist in rats and dogs.
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