Activation of histamine H3 receptors produces presynaptic inhibition of neurally evoked cat nictitating membrane responses in vivo

Summary

This study was undertaken in order to determine the potential role of prejunctional histamine H₃ receptors in an in vivo adrenergic model system. Frequency-dependent nictitating membrane responses were elicited by sympathetic nerve stimulation in anesthetized cats. Systemic administration of the selective histamine H₃ receptor agonist, (R)-α-methylhistamine (RαMeHA) produced a dose-related depression of amplitude of the evoked nictitating membrane responses with a threshold of about 10 μg/kg and maximal effect (50% depression at the lowest frequency; 0.5 Hz) seen at 100–300 gg/kg. Responses obtained with low frequency stimulation were more sensitive to depression by RaMeHA than were responses evoked with higher frequencies of stimulation. Larger doses of RaMeHA given to the same animals, failed to produce additional inhibition.

RαMeHA depressed the amplitude of nictitating membrane responses evoked by either pre- or postganglionic nerve stimulation to an equivalent degree. This depressant action of RαMeHA was antagonized by pretreatment with the specific histamine H₃ antagonist, thioperamide (3 mg/kg), but not by combined pretreatment with histamine H₁ and H₂ blockers chlorpheniramine (300 Ftg/kg) and cimetidine (5 mg/kg). Intravenous administration of adrenaline (1–30 wg/kg) also produced graded nictitating membrane responses that were not altered by subsequent administration of RαMeHA.

These results suggest that histamine H₃ receptors are involved in the modulation of neurally evoked noradrenaline release in the cat nictitating membrane by an inhibitory presynaptic action. The most likely site of drug action appears to be at the neuroeffector junction as no appreciable ganglionic effect of RαMeHA was observed in this in vivo model system.