Pharmacologic evaluation of neurokinin-2 receptor antagonists in the guinea pig respiratory tract

Background Propofol is the anesthetic of choice for patients with reactive airway disease and is thought to reduce intubation- or irritant-induced bronchoconstriction by decreasing the cholinergic component of vagal nerve activation. However, additional neurotransmitters including neurokinins play a role in irritant-induced bronchoconstriction. We questioned the mechanistic assumption that propofol's clinically recognized protective effect against irritant-induced bronchoconstriction during intubation was due to attenuation of airway cholinergic reflexes. Methods Muscle force was continuously recorded from isolated Guinea pig tracheal rings in organ baths. Rings were subjected to exogenous contractile agonists (acetylcholine, histamine, endothelin-1, substance P, acetyl-substance P and neurokinin A) or to electrical field stimulation (EFS) to differentiate cholinergic or non-adrenergic, non-cholinergic nerve mediated contraction with or without cumulatively increasing concentrations of propofol, thiopental, etomidate or ketamine. Results Propofol did not attenuate the cholinergic component of EFS-induced contraction at clinically relevant concentrations. In contrast, propofol relaxed non-adrenergic, non-cholinergic mediated EFS contraction at concentrations within the clinical range ((20-100 μM) n = 9, P < 0.05) and propofol was more potent against an exogenous selective neurokinin 2 receptor versus neurokinin 1 receptor agonist contraction (n = 6, p < 0.001). Conclusions Propofol, at clinically relevant concentrations, relaxes airway smooth muscle contracted by nonadrenergic, noncholinergic-mediated EFS and exogenous neurokinins but not contractions elicited by the cholinergic component of EFS. These findings suggest that the mechanism of propofol's protective effects against irritant-induced bronchoconstriction involves attenuation of tachykinins released from nonadrenergic, noncholinergic nerves acting at neurokinin 2 receptors on airway smooth muscle.

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Pharmacologic evaluation of neurokinin-2 receptor antagonists in the guinea pig respiratory tract

Cited by 2 publications

References 32 publications

Antagonist profile of ibodutant at the tachykinin NK2 receptor in guinea pig isolated bronchi

Antagonist profile of ibodutant at the tachykinin NK2 receptor in guinea pig isolated bronchi

Propofol Preferentially Relaxes Neurokinin Receptor-2-induced Airway Smooth Muscle Contraction in Guinea Pig Trachea

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