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 the clinically recognized protective effect of propofol 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 nonadrenergic, noncholinergic 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 nonadrenergic, noncholinergic-mediated EFS contraction at concentrations within the clinical range (20-100 mum, 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 protective effects of propofol against irritant-induced bronchoconstriction involves attenuation of tachykinins released from nonadrenergic, noncholinergic nerves acting at neurokinin-2 receptors on airway smooth muscle.

Figure 1

Guinea pig tracheal ring muscle force generated in response to cholinergic electrical field-stimulated (EFS) contraction expressed as percent change from baseline contraction and response to the addition of intravenous anesthetics to the organ bath. A) propofol 0.5-100 μM (n = 8), B) thiopental 0.5-200 μM (n = 8), C) Ketamine 0.5-50 μM (n = 8), D) etomidate 0.008-16 μM (n = 8), (*p < 0.05, **p < 0.01, ***p < 0.001). Mean ± SEM. No intravenous anesthetic relaxed cholinergic EFS-induced contraction at clinically relevant concentrations.

Figure 2

Guinea pig tracheal ring muscle force generated in response to non-adrenergic, non-cholinergic (NANC) electrical field-stimulated (EFS) contraction expressed as percent change from baseline contraction and response to the addition of intravenous anesthetics to the organ bath. A) propofol 5-100 μM (n = 9), B) thiopental 5-200 μM (n = 8), C) Ketamine 0.5-50 μM (n = 11), D) etomidate 0.008-16 μM (n = 10), (*p < 0.05, **p < 0.01, ***p < 0.001). Mean ± SEM. Only propofol relaxed NANC EFS-induced contraction at clinically relevant concentrations.

Figure 3

Guinea pig tracheal ring muscle force generated in response to exogenous acetylcholine induced-contraction expressed as percent change from baseline peak contraction and response to the addition of intravenous anesthetics to the organ bath. A) propofol 0.5-100 μM (n = 10), B) thiopental 0.5-200 μM (n = 11), C) Ketamine 0.5-50 μM (n = 5), D) etomidate 0.008-16 μM (n = 5), (*p < 0.05, ***p < 0.001.) Mean ± SEM. Only thiopental relaxed exogenous acetylcholine-induced contraction at concentrations routinely reached clinically.

Figure 4

Guinea pig tracheal ring muscle force generated in response to exogenous substance P-induced-contraction expressed as percent change from peak contraction and response to the addition of intravenous anesthetics to the organ bath. A) propofol 0.5-100 μM (n = 12), B) thiopental 0.5-200 μM (n = 11), C) Ketamine 0.5-50 μM (n = 10), D) etomidate 0.008-16 μM (n = 10), (*p < 0.05, **p < 0.01, ***p < 0.001). Mean ± SEM. Only propofol relaxed exogenous substance-P-induced contraction at concentrations reached clinically.

Figure 5

Guinea pig tracheal ring muscle force generated in response to substance P expressed as percent change from peak contraction and response to intravenous anesthetics. A) propofol 0.5-100 μM (n = 4), and thiopental 10-200 μM (n = 4) versus substance-P time control after C-fiber neurotransmitter depletion by capsaicin analogue n-vanillylnonanamide, and B) propofol 10-100 μM (n = 4), and thiopental 10-200 μM (n = 4) versus substance-P time control after mast cell neurotransmitter depletion by compound 48/80. Only propofol causes significant relaxation of substance-P induced contraction after mast cell and NANC nerve neurotransmitter depletion suggesting a role for propofol induced relaxation of substance-P induced contraction at the airway smooth muscle itself.

Figure 6

Guinea pig tracheal ring muscle force generated by selective neurokinin-1 and neurokinin-2 receptor agonists acetyl-substance-P and neurokinin A, respectively. Data expressed as percent change from peak contraction and response to propofol 20-100 μM (n = 10) versus acetyl-substance-P and neurokinin A. Mean ± SEM. While propofol relaxed both neurokinin 1 and 2 receptor mediated contractions, only neurokinin 2 mediated contraction was relaxed at clinically relevant concentrations. Relaxation of neurokinin 2 specific agonist neurokinin A suggests propofol's protective effect against reflex induced bronchoconstriction is at least in part mediated by the neurokinin 2 receptor mediated NANC contraction.

Figure 7

Guinea pig tracheal ring muscle force generated by addition of exogenous histamine or endothelin-1. Data expressed as percent change from peak contraction and response to intravenous anesthetics. A) propofol 0.5-100 μM (n = 10), and thiopental 0.5-200 μM (n = 10) versus histamine-induced contraction time control, B) propofol 0.5-100 μM (n = 10), and thiopental 0.5-200 μM (n = 10) versus endothelin-1-induced contraction time control. (*p < 0.05, ** p < 0.01, *** p <0.001). Mean ± SEM. Neither propofol nor thiopental relaxed either histamine or endothelin-1-induced contractions at clinically relevant doses.