Histamine H3-receptors inhibit neurogenic microvascular leakage in airways

We studied the role of histamine H3-receptors on neurogenic microvascular leakage in guinea pig airways by measuring extravasation of Evans blue dye. In guinea pig airways the major component of the neurogenic leakage is nonadrenergic noncholinergic (NANC) mediated, due to release of tachykinins. Anesthetized guinea pigs were pretreated with propranolol and atropine to block the beta-adrenergic and cholinergic responses and with mepyramine and cimetidine to block histamine H1- and H2-receptors, respectively. Vagal stimulation significantly increased leakage of dye in trachea (Tr), main bronchi (MB), and central (cIPA) and peripheral intrapulmonary airways (pIPA). The selective H3-receptor agonist (R)-alpha-methylhistamine (alpha-MeHA, 0.3-3 mg/kg iv) did not alter basal leakage but inhibited NANC-mediated leakage in a dose-dependent manner with a maximal inhibition of 56.9 (Tr, P less than 0.01), 66.7 (MB, P less than 0.01), 67.5 (cIPA, P less than 0.01), and 58.2% (pIPA, P less than 0.05) at 1 mg/kg. Pretreatment with phentolamine (2.5 mg/kg iv) had no effect on the inhibitory response produced by alpha-MeHA, but the H3-receptor antagonist thioperamide (5 mg/kg ip) blocked its effect. Exogenous substance P (1 microgram/kg iv) caused comparable plasma leakage to NANC-mediated response but was not inhibited by alpha-MeHA. We conclude that H3-agonists inhibit neurogenic leakage by prejunctional inhibition of neuropeptide release from airway sensory nerves.