Gastric and cardiovascular effects of histamine in the dog

The H-2 receptor stimulation of gastric acid secretion and of heart rate by histamine, a mixed H-1–H-2 agonist, given in 45-min successive step doses 2–150 g base/kg.h and 4(Me)histamine, (4(Me)H), 1.4 to 210 g base/kg.h, a specific H-2 agonist, in five conscious gastric fistula dogs showed no difference between the agonists in ED₅₀s or in maximal responses. The ED₅₀ for acid was lower (15–16 g/kg.h) than for cardiac chronotropism (25 to 27 g/kg.h). Both effects were competitively antagonized by the H-2 antagonist cimetidine, 0.5 to 1 mg/kg.h. Background infusions of diphenhydramine, 2 mg/kg.h, raised the maximum heart rate increase caused by histamine from +108 to +149 beats/min (p<0.05) but not that of 4(Me)H; acid outputs were not augmented. Diphenhydramine 2 mg/kg.h alone caused no significant change in heart rate or blood pressure. Histamine reduced systolic blood pressure (SBP) by 48 mmHg and with diphenhydramine background by 61 mmHg (p<0.05). 4(Me)H at a top dose of 210 g base/kg.h reduced SBP by 81 mmHg (p<0.05). To test whether the effects of added diphenhydramine could be interpreted as an H-1 receptor effect of histamine, the H-1 agonist 2-pyridylethylamine (PEA) was given alone (2–150 g/kg.h in 45-min steps) or as a 100 g/kg bolus during the infusion of 4(Me)H 50 g/kg.h. There was no effect of PEA on gastric acid, heart rate or blood pressure. Even though diphenhydramine augments the effect of histamine on heart rate and blood pressure, the lack of PEA effect would indicate that there is not a direct H-1 receptor mediated effect on gastric acid, heart rate or systolic blood pressure in the conscious dog. This contrasts with published data obtained in anesthetized animals. After a single dose of 4(Me)H, 50 g/kg.h had been infused i.v. for 45 min, acid output had reached 70% of the maximum seen at 90 min, heart rate had increased by 65% of its maximum response but SBP had not yet changed. Cimetidine blocked 4(Me)H-induced hypotension completely but blocked the heart rate increase only partially and competitively. We conclude that in the intact animal there is evidence for a direct H-2 mediated stimulation of heart rate in the conscious dog with kinetics similar to the H-2 stimulation of gastric acid secretion.Supported by Research Grant No. AM09260 from the National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health and by the Medical Research Service of the Veterans Administration.