In vivo demonstration of H3-histaminergic inhibition of cardiac sympathetic stimulation by R-alpha-methyl-histamine and its prodrug BP 2.94 in the dog.
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 micromol 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, P < or = 0.05), and increases in heart rate (R-HA at 2 micromol 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 P < or = 0.05), 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 micromol 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), P < or = 0.001). 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.
PCEBM, UFR de Pharmacie, Université Grenoble I, La Tronche, France.
C
C
Mazenot
C
C
Ribuot
A
A
Durand
Y
Y
Joulin
P
P
Demenge
D
D
Godin-Ribuot
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006321:Heart / Q000187:drug effects* / Q000294:innervation; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D017442:Histamine Agonists / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007097:Imines / Q000494:pharmacology*; D008761:Methylhistamines / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D018100:Receptors, Histamine H3 / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects
D002395:Catecholamines; D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D007097:Imines; D008761:Methylhistamines; D010636:Phenols; D011355:Prodrugs; D018100:Receptors, Histamine H3; C106714:BP 2-94; C115705:ciproxifan; C069357:alpha-methylhistamine