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Species variations in cardiac effects of histamine

University of British Columbia

The cardiac effects of histamine and its analogs were studied in tissues isolated from kittens, guinea-pigs and rats. Rate changes were recorded in right atria, while inotropic responses were recorded from electrically paced (1Hz) left atria, right ventricle strips and right papillary muscles. In the kitten isolated right atrium, both histamine and 4-methylhistamine, a specific histamine H₁-receptor agonist, caused dose-dependent changes in rate. These responses were not affected by a histamine H₁-receptor antagonist (promethazine). Both cimetidine (a histamine H₂-receptor antagonist) and propranolol (a β-adrenoceptor antagonist) caused significant reductions in the chronotropic responses produced by histamine and 4-methylhistamine. In the electrically paced preparations from kitten hearts, the inotropic responses of both histamine and 4-methylhistamine were observed at only high doses of agonist. The inotropic responses to these agonists were not affected by either promethazine or cimetidine. Propranolol caused marked inhibition of the inotropic response produced by histamine and 4-methylhistamine in the kitten left atrium, right ventricle strip and right papillary muscle. Based on these results, it was concluded that the cardiac effects of histamine in the kitten were predominantly due to an indirect β-adrenoceptor stimulation. In addition, it was demonstrated that part of the chronotropic effect of histamine and 4-methylhistamine was due to histamine H₂-receptor stimulation. The use of 2 - (2-pyridyl) ethylamine (PEA) in the study of cardiac histamine H₁-receptors was next investigated using guinea-pig right atria, left atria and right ventricle strips. The chronotropic response produced by PEA was not due to interaction with either histamine H₁-or H₂ receptors, as indicated by experiments with the specific histamine receptor antagonists. In atria depleted of endogenous catecholamines (using reserpine-pretreated guinea-pigs), the chronotropic response of PEA was abolished. In guinea-pig left atria and right ventricle strips, inotropic responses of low doses of PEA were antagonised by promethazine. However, at higher doses of PEA, promethazine was unable to antagonise the increases in force of contraction in both the tissues used. The inotropic response due to high doses of PEA were reduced by propranolol or following reserpine pretreatment. The absence of histamine H₁-receptors in the guinea-pig right atrium was confirmed. The results obtained also indicate that PEA has a dual action, by causing an initial direct histamine H₁-receptor stimulation at low doses, while at higher doses causing an indirect β-adrenoceptor stimulation. Finally, the effect of histamine in isolated rat atria (right and left) was studied. Large doses of histamine produced changes in rate and force that were unaffected by promethazine or cimetidine. Following pretreatment of rats with reserpine (or by using propranolol in untreated tissues) the inotropic response due to histamine was abolished. At the same time, a negative chronotropic response (reversed by addition of atropine) revealed a cholinergic component in addition to an indirect adrenergic component in the cardiac effects of histamine in the rat. In summary, the cardiac effects of histamine and its analogs show tremendous species variability. The results indicate that some responses were due to direct histamine H₁-or H₂ receptor stimulation. In addition, it was also demonstrated that the cardiac responses of histamine were not always due to such receptor interactions.

Text

2010-03-19

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http://hdl.handle.net/2429/22146

Pharmaceutical Sciences

University of British Columbia

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