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

Abstract

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.

Effects of Ginger and Its Constituents on Airway Smooth Muscle Relaxation and Calcium Regulation

“…Male guinea pigs were anesthetized, and their tracheas were removed. Epithelial-denuded tracheal rings were prepared as previously described (19). The rings were suspended in jacketed organ baths, bubbled with a gas mixture of 95% oxygen and 5% carbon dioxide, and refreshed every 15 minutes for 1 hour during equilibration of the tracheal rings at 1 g resting tension.…”

Neuropeptide Signaling Activates Dendritic Cell-Mediated Type 1 Immune Responses through Neurokinin-2 Receptor

“…Recent articles indicated that SP regulates the function of various leukocytes, such as vascular endothelial growth factor secretion from mast cells (19), cytotoxicity of NK cells (20), cytokine production by monocytes and T cells (21,22), induction of chemokine or chemokine receptor of macrophages (23,24), and Ag presentation of dendritic cells (DCs) (25). In contrast, NKA is known to control various vital responses, such as airway contraction, vasodilatation, and vascular permeability, in humans (15,16,26). However, the function of NKA in the immune system is less-well defined compared with the role of SP.…”

Issues Regarding Propofol Concentrations within the Clinical Range

“…Recently, Gleason et al 1 have demonstrated that propofol at concentrations of 2 ϫ 10 Ϫ5 to 2 ϫ 10 Ϫ4 M relaxes guinea pig tracheal rings in organ baths in response to noradrenergic noncholinergic-mediated electrical field stimulation; these researchers have adopted the concentrations of propofol within this clinical range. The plasma concentration of propofol during the induction of anesthesia in humans has been reported as up to 3 ϫ 10 Ϫ5 M, and burst suppression doses of propofol for cerebral protection are up to 6 ϫ 10 Ϫ5 M. [2][3][4] Effective concentrations of propofol (2 ϫ 10 Ϫ5 to 2 ϫ 10 Ϫ4 M) in the study by Gleason et al are probably much higher than those with clinical relevance if considering plasma-free concentrations calculated from both above clinical plasma concentrations of propofol and the substantial binding of this compound to plasma proteins (97-98%).…”

“…Kinoshita and Matsuda for their interest in our study. 1 In that work, we did not seek to determine whether propofol protects against irritant-induced bronchoconstriction in the clinical situation established by previous clinical studies 2,3 and clinical experience. In contrast, we sought to identify signaling pathways of irritant-induced bronchoconstriction against which propofol might be effective.…”

“…1 This focus was selected because previous clinical studies 4 -6 suggested that propofol's protective airway effects were via blockade of cholinergic mechanisms.…”