title: Involvement of NK1 and NK2 receptors in pulmonary responses elicited by non-adrenergic, non-cholinergic vagal stimulation in guinea-pigs.
abstract: Previous studies from our laboratory using exogenously administered neurokinin (NK) agonists have shown that both NK1- and NK2-receptor subtypes are involved in plasma extravasation in the guinea-pig airways. In the present study, we have extended these observations using antidromic vagal stimulation to stimulate sensory c-fibres as a means of eliciting the release of endogenous tachykinins in propranolol- and atropine-treated guinea-pigs. Antidromic vagal stimulation (5 ms, 30 s) induced frequency-dependent (1-10 Hz) bronchoconstriction that was completely abolished by co-administration of the NK1-selective antagonist CP-99,994 ((2s-methoxy-benzyl)-(2-phenyl-piperidin-3s-yl)-amine), and the NK2-selective antagonist SR-48,968 ((S)-N-methyl-N-[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl) butyl]benzamide), each at a dose sufficient to block NK1 and NK2 receptors, respectively (each at 0.3 mg kg-1, i.v.). In contrast, SR-48,968 when given alone only partially blocked the vagal stimulation-induced bronchospasm, whereas CP-99,994 had no effect. Significant increases (2-3-fold) in plasma extravasation of [125I]fibrinogen in the trachea, main bronchi, distal airways and oesophagus following vagal stimulation (5 Hz, 5 min, 10 V, 5 ms) were observed. Pretreatment with the neutral endopeptidase inhibitor, thiorphan (1 mg kg-1, i.v.), and the angiotensin-converting enzyme inhibitor, enalapril (1 mg kg-1, i.v.), potentiated both vagal stimulation-induced bronchoconstriction and plasma leakage in all tissues examined. This potentiation was due to reduced metabolism of endogenously released tachykinins since enhanced plasma overflow of immunoreactive substance P was observed following vagal stimulation in thiorphan- and enalapril-treated guinea-pigs. CP-99,994 substantially blocked plasma leakage in all parts of the airways and in the oesophagus. In comparison, SR-48,968 had no significant effect in the trachea and the oesophagus but partially inhibited plasma leakage in the main bronchi and distal airways. Co-administration of both CP-99,994 and SR-48,968 abolished the residual plasma leakage in these two regions. These results support the hypothesis that both NK1 and NK2 receptors are involved in tachykinin-induced pulmonary responses in the airways.
authors.affiliation: Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Savoie
authors.forename: C
authors.initials: C
authors.lastname: Tousignant
authors.forename: I W
authors.initials: IW
authors.lastname: Rodger
authors.forename: C C
authors.initials: CC
authors.lastname: Chan
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001980:Bronchi / Q000378:metabolism; D016084:Bronchoconstriction; D002199:Capillary Permeability; D004656:Enalapril / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D018041:Receptors, Neurokinin-2 / Q000502:physiology*; D013373:Substance P / Q000378:metabolism; D015244:Thiorphan / Q000494:pharmacology; D014132:Trachea / Q000378:metabolism; D014630:Vagus Nerve / Q000502:physiology*
chemical_list: D001549:Benzamides; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; D004656:Enalapril; C073839:SR 48968; D015244:Thiorphan