Agents and Actions

, Volume 9, Issue 5–6, pp 428–434 | Cite as

Gastric and cardiovascular effects of histamine in the dog

  • B. I. Hirschowitz
  • J. Rentz
  • E. Molina
  • A. L. Waldo
Histamine and Kinins

Abstract

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 μg base/kg.h and 4(Me)histamine, (4(Me)H), 1.4 to 210 μg 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 μg/kg.h) than for cardiac chronotropism (25 to 27 μg/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 μg 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 μg/kg.h in 45-min steps) or as a 100 μg/kg bolus during the infusion of 4(Me)H 50 μg/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 μg/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.

Keywords

Systolic Blood Pressure Histamine Cimetidine Gastric Acid Secretion Acid Output 

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References

  1. [1]
    J.W. Black, W.A.M. Duncan, C.J. Durant, C.R. Ganellin andE.M. Parsons,Definition and Antagonism of Histamine H 2 -Receptors, Nature236, 385–390 (1972).PubMedGoogle Scholar
  2. [2]
    B.I. Hirschowitz,H-2 Histamine Receptors, in:Annual Review of Pharmacology and Toxicology, vol. 19 (Annual Reviews Inc., Palo Alto, CA, 1979), pp. 203–244.Google Scholar
  3. [3]
    B.I. Hirschowitz,Apparent Kinetics of Histamine Dose-Reponsive Gastric Water and Electrolyte Secretion in the dog, Gastroenterology54, 514–522 (1968).PubMedGoogle Scholar
  4. [4]
    G.J. Durant, J.C. Emmett, C.R. Ganellin, A.M. Roe andR.A. Slater,Potential Histamine H-2 Receptor Antagonists. 3. Methylhistamines, J. Med. Chem.19, 923–928 (1976).PubMedGoogle Scholar
  5. [5]
    R.W., Brimblecombe, W.A.M. Duncan, G.J. Durant, J.C. Emmett, C.R. Ganellin andM.E. Parsons,Cimetidine. Non-thiourea H-2 Receptor Antagonist, J. Int. Med. Res.3, 86–91 (1975).Google Scholar
  6. [6]
    D.A.A. Owen,Histamine Receptors in the Cardiovascular System, Gen. Pharmacol.8, 141–156 (1977).PubMedGoogle Scholar
  7. [7]
    B.I. Hirschowitz, R. Gibson andG. Hutchison,Stimulation of Acid and Pepsin Secretion in the Fistula Dog by 4(5)Methylhistamine, a Specific H-2 Agonist. Am. J. Dig. Dis.19, 307–314 (1974).PubMedGoogle Scholar
  8. [8]
    G.O. Barbezat, F.S.B. Bowey, E.R. Kaplan andR. Hickman,Effect of Histamine H 1 - and H 2 -Receptor Blockade on Canine Gastric Acid Secretion, Am. J. Dig. Dis.23, 222–224 (1978).PubMedGoogle Scholar
  9. [9]
    B.L. Tepperman, L.L. Tague andE.D. Jacobson.Inhibition of Canine Gastric Acid Secretion by an H-1 Receptor Antagonist to Histamine, Am. J. Dig. Dis.23, 801–808 (1978).PubMedGoogle Scholar
  10. [10]
    W.W. Douglas,Autacoids, in: The Pharmacological Basis of Therapeutics, 5th ed. (Eds. L.S. Goodman and A. Gilman; McMillan Publishing Co., N.Y., 1975, pp. 589–629.Google Scholar
  11. [11]
    M. Impicciatore, G. Bertaccini, F. Mossini, D. Hansen andM.I. Grossman,N-Methyl,5-methyl Histamine Evokes a Higher Maximal Rate of Gastric Acid Secretion than Histamine, Proc. Soc. Biol. Med.156, 296–298 (1977).Google Scholar
  12. [12]
    R.W. Brimblecombe, D.A.A. Owen andM.E. Parsons,The Cardiovascular Effects of Histamine in Laboratory Animals, Agents and Actions4, 191–192 (1974).PubMedGoogle Scholar
  13. [13]
    D.A.A. Owen,The Effects of Histamine and Some Histamine-like Agonists on Blood Pressure in the Cat, Br. J. Pharmacol.55, 173–179 (1975).PubMedGoogle Scholar
  14. [14]
    M.F. Lokhandwala,Pharmacological Analysis of the Tachycardia Produced by Histamine and Specific H 1 and H 2 -Receptor Antagonists in Anesthetized Dogs, Eur. J. Pharmacol.51, 351–359 (1978).PubMedGoogle Scholar
  15. [15]
    D. Reinhardt, J. Wagner andJ.H. Schumann,Differentiation of H 1 - and H 2 -Receptors Mediating Positive Chrono- and Inotropic Responses to Histamine on Atrial Preparations of the Guinea Pig, Agents and Actions4, 217–221 (1974).PubMedGoogle Scholar
  16. [16]
    G.R. Hageman, F. Urthaler, J.H. Isobe andT.N. James,Chronotropic and Dromotropic Effects of Histamine on the Canine Heart, Chest75, 597–604 (1979).PubMedGoogle Scholar
  17. [17]
    M.J. Hughes andI.A. Coret,On Specificity of Histamine Receptors in the Heart, Am. J. Physiol.223, 1257–1262 (1972).PubMedGoogle Scholar
  18. [18]
    J.R. Powell andM.J. Brody,Identification and Specific Blockade of Two Receptors for Histamine in the Cardiovascular System, J. Pharmacol. Exp. Therap.196, 1–14 (1976).Google Scholar
  19. [19]
    R. Levi andJ.O. Kuye,Pharmacological Characterization of Cardiac Histamine Receptors: Sensitivity to H-1 Receptor Antagonists, Eur. J. Pharmacol.27, 330–338 (1974).PubMedGoogle Scholar
  20. [20]
    A. Tucker, E.K. Weir, J.T. Reeves andR.F. Grove,Histamine H 1 - and H 2 -Receptors in Pulmonary and Systemic Vasculature of the Dog, Am. J. Physiol.29, 1008–1013 (1975).Google Scholar
  21. [21]
    R. Levi, G. Allan andJ.H. Zavecz,Cardiac Histamine Receptors, Fed. Proc.35, 1942–1947 (1976).PubMedGoogle Scholar
  22. [22]
    B.I. Hirschowitz andA.L. Waldo,An H-1 Type Histamine Action which Causes Cardiac Deceleration in the Intact Dog, Clin. Res.25, 46A (1977) (abstract).Google Scholar
  23. [23]
    M. Thermann, W. Lorenz, A. Schmal, F. Schingale, P. Dormann andH. Hamelmann.Influence of H 1 - and H 2 -Receptor Antagonists on the Circulatory System and on the Endogenous Plasma Histamine Concentrations in Dogs, Agents and Actions7, 97–101 (1977).PubMedGoogle Scholar
  24. [24]
    N. Chand andP. Eyre,Classification and Biological Distribution of Histamine Receptor Sub-types, Agents and Actions5, 277–295 (1975).PubMedGoogle Scholar
  25. [25]
    J.R. Woods, Jr., C.R. Brinkman, III, A. Dandavino, K. Murayama andN.S. Assali,Action of Histamine and H 1 and H 2 Blockers on the Cardiopulmonary Circulation, Am. J. Physiol.232, H73-H78 (1977).PubMedGoogle Scholar
  26. [26]
    D.W. Powell andB.I. Hirschowitz,Sodium Pentobarbital Depression of Histamine- or Insulin Stimulated Gastric Secretion, Am. J. Physiol.212, 1001–1006 (1967).PubMedGoogle Scholar
  27. [27]
    S.B. Flynn andD.A.A. Owen,Histamine Receptors in Peripheral Vascular Beds in the Cat, Br. J. Pharmacol.55, 181–188 (1975).PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag 1979

Authors and Affiliations

  • B. I. Hirschowitz
    • 1
    • 2
  • J. Rentz
    • 1
    • 2
  • E. Molina
    • 1
    • 2
  • A. L. Waldo
    • 1
    • 2
  1. 1.Division of GastroenterologyUniversity of Alabama in BirminghamBirminghamUSA
  2. 2.Veterans Administration HospitalBirminghamUSA

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