Volume 126, Issue 1, Page 264

British Journal of Pharmacology

January 1999, Volume 126, Issue 1, Pages 264 - 268

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Original Article

In vivo demonstration of H₃-histaminergic inhibition of cardiac sympathetic stimulation by R--methyl-histamine and its prodrug BP 2.94 in the dog
Catherine Mazenot¹, Christophe Ribuot¹, Andrée Durand¹, Yves Joulin², Pierre Demenge¹ & Diane Godin-Ribuot^1,3
¹PCEBM, UFR de Pharmacie, Université Grenoble I, Domaine de la Merci, 38706 La Tronche     ²Laboratoire Bioprojet, 9 rue Rameau, 75002 Paris, France

³Author for correspondence at: Laboratoire de Pharmacologie Cardiovasculaire Expérimentale-Biomolécules, UFR de Pharmacie, Domaine de la Merci, 38706 La Tronche, France

Keywords

H₃-receptors;   R- alpha -methyl-histamine;   BP 2.94;   catecholamines;   cardiac sympathetic nerves;   dog

Abstract

1   The aim of this study was to investigate whether histamine H₃-receptor agonists could inhibit the effects of cardiac sympathetic nerve stimulation in the dog.
2   Catecholamine release by the heart and the associated variation of haemodynamic parameters were measured after electrical stimulation of the right cardiac sympathetic nerves (1 - 4 Hz, 10 V, 10 ms) in the anaesthetized dog treated with R- alpha -methyl-histamine (R-HA) and its prodrug BP 2.94 (BP).
3   Cardiac sympathetic stimulation induced a noradrenaline release into the coronary sinus along with a tachycardia and an increase in left ventricular pressure and contractility without changes in mean arterial pressure. Intravenous administration of H₃-receptor agonists significantly decreased noradrenaline release by the heart (R-HA at 2 µmol kg^-1 h^-1: +77±25 vs +405±82; BP 2.94 at 1 mg kg^-1: +12±11 vs +330±100 pg ml^-1 in control conditions, P0.05), and increases in heart rate (R-HA at 2 µmol kg^-1 h^-1: +26±8 vs +65±10 and BP 2.94 at 1 mg kg^-1: +30±8 vs 75±6 beats min^-1, in control conditions P0.05), left ventricular pressure, and contractility. Treatment with SC 359 (1 mg kg^-1) a selective H₃-antagonist, reversed the effects of H₃-receptor agonists. Treatment with R-HA at 2 µmol kg^-1 h^-1 and BP 2.94 at 1 mg kg^-1 tended to decrease, while that with SC 359 significantly increased basal heart rate (from 111±3 to 130±5 beats min^-1, P0.001).
4   Functional H₃-receptors are present on sympathetic nerve endings in the dog heart. Their stimulation by R- alpha -methyl-histamine or BP 2.94 can inhibit noradrenaline release by the heart and its associated haemodynamic effects.

Received 24 July 1998; Revised 23 September 1998; Accepted 29 September 1998