DRUG-INDUCED RELEASE AND PHARMACODYNAMIC EFFECTS OF HISTAMINE IN THE GUINEA-PIG HEART

¹ Department of Pharmacology, University of Graz, Graz, Austria

The purpose of this study was to find how histamine potentiates the stimulant effects of theophylline in the heart. In isolated perfused guinea-pig hearts, rate, amplitude of isotonic contractions and phosphorylase activity (percent phosphorylase a) were measured. The histamine content in the coronary perfusion fluid was bioassayed on the guinea-pig ileum. Histamine produced dose-dependent rises of rate, contractility and percent phosphorylase a which could not be blocked by DCI, by pronethalol or by the theophylline antagonist, imidazole. Similar effects of theophylline were significantly potentiated by histamine. This potentiation was always associated with a liberation of histamine from the heart. After histamine, previously ineffective doses of the histamine liberator, 48/80, also stimulated the heart and raised the histamine content in the perfusate. After 48/80 the potentiation of the theophylline effects and the release of histamine from the heart by theophylline were abolished. The results show that a fraction of the injected histamine is stored by the heart, probably in non-mast-cell sites. It can be released by theophylline and by 48/80 in amounts sufficient to stimulate the heart. The potentiation of theophylline can thus be explained by a releasing effect of this drug on histamine stored after a previous injection. The mode of action of histamine is discussed on the basis of the available evidence. It is postulated that histamine combines with a special cardiac receptor which gives rise to the formation of adenosine-3',5'-phosphate.

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