Involvement of NK1 and NK2 Receptors in Pulmonary Responses Elicited by Non-adrenergic, Non-cholinergic Vagal Stimulation in Guinea-pigs

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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 immuno-reactive 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.