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Anesth Analg 1999;89:191
© 1999 International Anesthesia Research Society

GENERAL ARTICLES

The Relaxant Effect of Propofol on Guinea Pig Tracheal Muscle Is Independent of Airway Epithelial Function and ß-Adrenoceptor Activity

Eiji Hashiba, MD, Tetsumi Sato, MD, Kazuyoshi Hirota, MD, Yoshio Hashimoto, MD, and Akitomo Matsuki, MD

Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki, Japan

Address correspondence and reprint requests to Eiji Hashiba, MD, Department of Anesthesiology, University of Hirosaki School of Medicine, 5 Zaifucho, Hirosaki, 036-8562, Japan.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Airway epithelium and vascular endothelium modulate the tension of the underlying smooth muscle by releasing relaxing factors such as prostanoids and nitric oxide (NO). We investigated whether the relaxant effect of propofol on airway smooth muscle is dependent on airway epithelial function. Tracheal spirals of female guinea pigs were mounted in water-jacketed organ baths filled with Krebs-bicarbonate buffer aerated with 95% O2 and 5% CO2 at 37°C. Changes in isometric tension of the specimens were measured with a force-displacement transducer and recorded with a polygraph. Propofol (10-4 to 10-3 M) inhibited carbachol (CCh)-, histamine (HA)-, or endothelin-1–induced contractions of the muscles in a dose-dependent manner. Neither mechanical removal of the epithelial layer, chemical inhibition of epithelial synthesis of prostanoids, nor NO affected the relaxant effect of propofol on CCh- or HA-induced tracheal contraction. Furthermore, the blockade of ß-adrenoceptors did not change the relaxant effect of propofol. These results indicate that the relaxant effect of propofol on the airway smooth muscle is independent of the epithelial function or ß-adrenoceptor activity. Propofol is an excellent anesthetic for patients with hyperreactive airways in which the epithelial layer is damaged.

Implications: Airway epithelium, as well as vascular endothelium, plays an important role in modulating the baseline tone and reactivity of underlying smooth muscle. We investigated, in vitro, whether the relaxant effect of propofol on airway smooth muscle is dependent on airway epithelial function. We suggest that propofol relaxes airway smooth muscle independently of the epithelial function.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Although its mechanism of smooth muscle relaxation is unknown, propofol has been associated with less bronchoconstriction during anesthetic induction (1) and has reversed bronchoconstriction associated with fentanyl (2). It has also proven useful for decreasing airway resistance in patients with reactive airway disease (3,4).

The epithelial cells of hyperreactive airways seem to be damaged significantly (5–7). The airway epithelial and vascular endothelial cells modulate the baseline tone and reactivity of the underlying smooth muscle by releasing epithelium-derived relaxing factors (EpDRFs), such as prostaglandins (PGs) (8,9) and nitric oxide (NO) (10,11). In addition, the removal of epithelium causes hyperreactivity of the muscle to a variety of spasmogenic stimuli (12). Furthermore, epithelium-dependent relaxations have been induced by ß-adrenoceptor agonists (13), arachidonic acid (14), and the calcium antagonist verapamil (15).

We have often used propofol in combination with ketamine for total IV anesthesia, and we previously demonstrated that the relaxant effect of ketamine on guinea pig airway smooth muscle is epithelium-independent (16). However, no information is available concerning the effect of propofol on the airway epithelium. We therefore investigated the role of the epithelium in propofol-induced airway smooth muscle relaxation using guinea pig tracheas in vitro. We also evaluated whether the effect of propofol, like that of ketamine, is attenuated by the blockade of ß-adorenoceptors.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After our institutional animal care and use committee approved the protocol, female guinea pigs weighing 250–400g were killed with an overdose of pentobarbital (75 mg/kg intraperitoneally). The tracheas were removed and cut spirally into two strips 15 mm long and 3 mm wide. The tracheal strips were mounted vertically in a 30-mL water-jacketed organ bath filled with Krebs-bicarbonate buffer aerated with a mixture of 95% O2 and 5% CO2 at 37°C. The composition of the Krebs-bicarbonate buffer was as follows (in mM): NaCl 124, KCl 5, MgSO4 1.3, CaCl2 2.5, NaHCO3 25, NaH2PO4 0.6, and glucose 10. The bottom end of the strip was fixed to an L-shaped hook, and the top end was tied to a stainless steel wire connected to a force-displacement transducer. Changes in isometric tension were recorded. Before each experiment, each strip was subjected to a load of 2 g for at least 2 h, with frequent changes of Krebs-bicarbonate buffer, until a stable baseline tension was obtained. Thereafter, each strip was exposed to 10-7 M carbamylcholine chloride (CCh) or 10-5 M histamine hydrochloride (HA) to test the responsiveness of the muscles. Any strip that developed <1 g of tension after exposure to CCh or HA was excluded from the study. Immediately after the peak tension developed, the strips were washed thoroughly with Krebs-bicarbonate buffer and were kept unstimulated until a stable baseline tension was obtained again. In all experiments, each drug was added into the organ bath in a quantity of <=300 µL. All drug concentrations indicated are expressed as the final concentration in the organ bath.

After the initial equilibration phase, 60 tracheal strips were studied to examine the effect of propofol on tracheal contraction induced by CCh and HA. Concentration-response (C-R) curves for CCh (10-9 to 10-5 M) and HA (10-8 to 10-3 M) were obtained in the absence or presence of propofol or 10% Intralipid® (Pharmacia AB, Stockholm, Sweden), a vehicle of propofol (10% soya bean oil, 2.2% glycerol, 1.2% egg phosphatide). Three concentrations of propofol (10-5, 10-4, or 10-3 M) and a concentration of 10% Intralipid®, the same concentration as in the 10-3 M propofol solution, were studied. The C-R curves for CCh and HA were fitted by nonlinear regression, and the concentration giving 50% of the maximal response (EC50) was determined.

Twelve tracheal strips were studied to examine the effect of propofol on tracheal contraction induced by 3 x 10-8 M endothelin-1 (ET-1). In preliminary experiments, this dose generated a force of >1.5 g, similar to the 70% effective concentration of 10-6 M CCh. Immediately after the contractile response reached its plateau, propofol (10-5 to 10-3 M) was added cumulatively to the bath. One strip was used to study the relaxation by propofol and the other from the same trachea was always used to determine the degree of spontaneous relaxation.

The epithelial layer was mechanically removed by gentle rubbing of the luminal surface of the tracheal strips with a cotton applicator. Forty-eight epithelium-denuded strips were studied to determine the contribution of the tracheal epithelium to the relaxant effect of propofol. After the initial equilibration phase, C-R curves for CCh and HA were obtained in the absence or presence of propofol in the same manner as previously described, and the EC50 values were determined. Histological evidence of denuding the epithelium was evaluated by microscopic examination of strips (hematoxylin-eosin staining) at the end of the experiment.

Twelve strips were studied to investigate the effect of blockade of synthesis of cyclooxygenase metabolites or NO on the relaxant effect of propofol for each group. After the initial equilibration phase, synthesis of cyclooxygenase metabolites or NO was blocked pharmacologically by incubating the strips in Krebs-bicarbonate buffer containing 10-5 M indomethacin (16) or 1.2 x10-4 M N{omega}-nitro-L-arginine methyl ester (L-NAME) (16) for 30 min, respectively. After the incubation, the C-R curves for CCh or HA were obtained in the presence or absence of 10-4 M propofol.

Twelve strips were studied to investigate the effect of ß-adrenoceptors on the relaxant effect of propofol, and ß-adrenoreceptors were blocked by incubating the strips in Krebs-bicarbonate buffer containing 10-5 M propranolol (16) for 30 min. After the incubation, the C-R curves for CCh were obtained in the absence or presence of 10-4 M propofol.

Propofol, applied in its commercially available form, 1% Diprivan® (10 mg/mL propofol, 10% soya bean oil, 2.25% glycerol, 1.2% purified phospholipid), was purchased from Zeneca (Osaka, Japan). Pentobarbital sodium (Nembutal®) was obtained from Abbott Laboratories (North Chicago, IL); CCh, HA, indomethacin, L-NAME, and propranolol were obtained from Sigma Chemical Co. (St. Louis, MO); and ET-1 was obtained from American Peptide Company, Inc. (Sunnyvale, CA). Other chemicals used for the Krebs-bicarbonate solution were purchased from Wako (Osaka, Japan). Twice-distilled and deionized water was always used to make buffer and stock solutions of the drugs except indomethacin. CCh and HA were dissolved as 10-1 M stock solution; ET-1, L-NAME, and propranolol were dissolved as 3 x 10-5 M, 1.2 x 10-1 M, and 10-1 M stock solutions, respectively. These stock solutions were diluted appropriately with buffer immediately before use. Indomethacin was dissolved in absolute ethanol as a 5 x 10-3 M stock solution and was diluted with buffer immediately before use.

The tension of strips contracted by spasmogens is expressed as a percentage of the maximal contraction, which was taken as 100%. All EC50 values are presented as mean ± SEM. Comparison of the mean values was performed by using one-factor analysis of variance and Fisher's protected least significant difference. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Propofol in 10-4 and 10-3 M concentrations significantly inhibited the tracheal contractions induced by CCh or HA (Figure 1). In the CCh group, propofol had a relaxant property in a dose-dependent manner because 10-3 M propofol was significantly more effective than 10-4 M propofol. The 10% Intralipid® did not affect contractions induced by CCh and HA (Figure 1). All EC50 values of the C-R curves are presented in Table 1. Propofol also relaxed the tracheal strips contracted by ET-1 in a dose-dependent manner (Figure 2).



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  		Figure 1. Effect of propofol on the concentration-response curves of carbachol (CCh; left) or histamine (HA; right). Tensions are expressed as percentages of the peak contractile response, which is taken as 100%. A vertical line indicates SEM. Propofol 10-4 M and 10-3 M significantly shifted the curves to the right. Intralipid® (Pharmacia AB, Stockholm, Sweden) did not affect the curves. In each curve, n = 6.

 

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  		Table 1. The 50% Effective Concentration Values for Carbachol or Histamine
 


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  		Figure 2. Effect of propofol on endothelin-1–induced tracheal contraction. White and black bars represent control and propofol, respectively. Propofol significantly relaxed the contractions induced by 3 x 10-8 M endothelin-1 in a dose-dependent manner. Tensions are expressed as percentages of the peak contractile response. Bars and vertical lines represent mean ± SEM (n = 6). *P < 0.01 versus the value before propofol administration and #P < 0.01 versus each control value.

 
Microscopic examination of the tracheal strips proved that removal of the epithelial layer was accomplished without producing any visible damage to the smooth muscle layer. Mechanical removal of the epithelial layer resulted in a significant decrease of the EC50 of C-R curves for HA but did not affect the C-R curves for CCh and did not change the maximal tension for CCh or HA (Table 2). Despite denuding the tracheal epithelial layer, propofol 10-4 and 10-3 M significantly inhibited the tracheal contractions induced by CCh or HA (Figure 3). In the CCh group, propofol also relaxed the denuded strips in a dose-dependent manner. The EC50 values of the denuded group are presented in Table 1.


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  		Table 2. The 50% Effective Concentration (EC50) Values and the Maximal Tension for Carbachol (CCh) or Histamine (HA)
 


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  		Figure 3. Effect of mechanical denudation of the epithelium on the concentration-response curves of carbachol (CCh; left) or histamine (HA; right) in the presence or absence of propofol. Propofol significantly shifted the curves for CCh or HA to the right, and epithelial denudation did not affect the inhibitory effect of propofol. A vertical line indicates SEM. In each curve, n = 6.

 
Indomethacin 10-5 M shifted the C-R curves for CCh to the right but did not affect the C-R curves for HA. Indomethacin 10-5 M also increased the maximal tension of the strips contracted by CCh and HA (Table 2). However, indomethacin 10-5 M did not affect the inhibitory effect of 10-4 M propofol on tracheal contractions induced by CCh or HA. The EC50 value for CCh or HA in the intact strips with 10-4 M propofol was 4.1 ± 0.36 x 10-7 M or 5.5 ± 0.28 x 10-6 M, respectively. The EC50 value for CCh or HA in indomethacin-treated strips with 10-4 M propofol was 3.7 ± 0.40 x 10-7 M or 4.7 ± 0.17 x 10-6 M, respectively. There was no significant difference between the two EC50 values for the same spasmogen, either CCh or HA.

L-NAME 1.2 x 10-4 M did not affect the C-R curves for CCh or HA but did increase the maximal tension of the strips contracted by CCh and HA (Table 2). However, L-NAME 1.2 x 10-4 M did not affect the inhibitory effect of 10-4 M propofol on tracheal contractions induced by CCh or HA. The EC50 value for CCh or HA in the intact strips with 10-4 M propofol was 4.1 ± 0.36 x 10-7 M or 5.5 ± 0.28 x 10-6 M, respectively. The EC50 value for CCh or HA in L-NAME-treated strips with 10-4 M propofol was 3.2 ± 0.24 x 10-7 M or 5.7 ± 0.17 x 10-6 M, respectively. There was no significant difference between the two EC50 values for the same spasmogen.

The blockade of ß-adrenoceptors by 10-5 M propranolol shifted the C-R curves for CCh to the right and increased the maximal tension of the strips contracted by CCh (Table 2). However, 10-5 M propranolol had no effect on the inhibitory effect of 10-4 M propofol on tracheal contractions induced by CCh. The EC50 value for CCh in the intact strips with 10-4 M propofol was 4.1 ± 0.36 x 10-7 M, and that for CCh in propranolol-treated strips with 10-4 M propofol was 3.8 ± 0.30 x 10-7 M. There was no significant difference between their EC50 values (Figure 4).



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  		Figure 4. Effect of 10-5 M propranolol on the concentration-response curves of carbachol (CCh) in the presence of 10-4 M propofol. A concentration of 10-5 M propranolol did not affect the inhibitory effect of 10-4 M propofol. {blacktriangleup} = intact strips, {triangleup} = 10-5 M propranolol-treated strips. A vertical line indicates SEM. In each curve, n = 6.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The main finding of this study is that the relaxant effect of propofol on the guinea pig tracheal muscle is independent of airway epithelial function, as substantiated by the fact that propofol inhibited the contraction induced by CCh or HA in tracheal strips with denuded epithelium. This was also proven by the application of indomethacin and L-NAME on tracheal strips with intact epithelium. In addition, we demonstrated that propofol did not seem to activate ß-adrenoceptors based on the observation that propranolol block of ß-adrenoceptors did not alter the relaxant effect of propofol.

The airway epithelial layer, as well as the vascular endothelial layer, plays an important role in modulating the baseline tone and reactivity of underlying smooth muscle because the layer is a barrier against irritant factors that metabolize spasmogens and release EpDRFs. In fact, the epithelial denudation resulted in a significant decrease of the EC50 values of C-R curves for HA but did not change the C-R curves for CCh, which indicates that the epithelial layer is not a mere diffusion barrier against irritant factors and that HA-induced contractions are decreased due to the epithelial relaxant function. Murlas (12) also demonstrated that removal of the epithelim increased the sensitivity of airway muscle to HA and suggested that HA-induced contractions probably occur, in part, through presynaptic HA stimulation of acetylcholine release. In addition, Murlas (14) suggested that the epithelium may be associated with PGE2 production, which is thought to depress the release of acetylcholine from intramural nerve terminals. Although the application of indomethacin and L-NAME did not shift the EC50 values for HA to the left in our study, the maximal contractions induced by CCh or HA were increased by blockade of the cyclooxygenase metabolites and NO. These results indicate that the effects of indomethacin or L-NAME on the tracheal strips were not similar to the epithelial denudation, but cyclooxygenase metabolites and NO did modify the contraction of tracheal strips, and epithelium may release other unknown EpDRFs. However, indomethacin and L-NAME did not affect the relaxant effect of 10-4 M propofol. These results indicate that the relaxant property of propofol is independent of the cyclooxygenase metabolites and NO.

Whether the relaxant effect of propofol is dependent on the endothelial cells in vascular smooth muscles is controversial. Park et al. (17) suggested that propofol stimulates the release of vasodilating cyclooxygenase metabolites from rat vascular rings with intact endothelium. Gagar et al. (18) reported that the relaxing property of propofol on bovine coronary artery rings, at least in part, depends on an endothelium-induced reaction and that one of the endothelium-derived relaxing factors might be NO. Petros et al. (19) also showed that propofol stimulates NO production in a concentration-dependent manner in cultured endothelial cells. However, Chang and Davis (20) showed that propofol produces concentration-dependent relaxation that is independent of endothelium function in a rat aortic ring preparation. From these results and our findings, some differences in the mechanisms of the relaxant effect of propofol on airway smooth muscle and on vascular smooth muscle would be expected with regard to the dependency of epithelium and endothelium function.

The epithelium-independent relaxant property of propofol is favorable for patients with airway hyperreactivity, as well as for those with normal responsiveness. Because there is significant damage to epithelial cells in the airway of patients with hyperreactive airway disease (5–7), the epithelial damage may be related to bronchial hyperresponsiveness (6,7). These results indicate that propofol is safe for patients with hyperreactive airways.

The possible sites of airway-relaxing action of propofol in an in vitro study would be: 1) the extracellular site, from which EpDRFs are released; 2) the receptor site with which spasmogens bind; and 3) the site beyond the level of receptor stimulation. We studied the possibility of the first and second sites. The airway epithelial layer as the extracellular site is independent of the relaxant effect of propofol, as proved by our investigation. As with the receptor site, the relaxant effect of propofol may not simply be due to antagonism at the specific receptor sites because propofol has a relaxant property against various spasmogens of CCh, HA, and ET-1, which stimulate different receptors in the airway smooth muscle cell systems. Pedersen et al. (21) also demonstrated that propofol relaxed guinea pig tracheal contraction induced not only by CCh and HA, but also by PGF2{alpha} and potassium ions. As with the receptor site, the relaxant effect of propofol may not simply be due to antagonism at the specific receptor sites, and thus propofol may inhibit some common pathways in the signal transduction mechanism of a variety of spasmogens.

The most likely action site of propofol is the site beyond the level of receptor stimulation. Yamakage and Hirshman (22) described propofol inhibiting L-type voltage-dependent Ca2+ channels in porcine tracheal smooth muscle cells. As with vascular smooth muscle, blockade of L-type voltage dependent Ca2+ channels (18,21,23) and reduction of inositol phosphates (23) are proposed as the essential mechanisms for the vasodilating effect of propofol. Tanabe et al. (24) also reported that the inhibitory effect of propofol might be exerted at a point between the ET-1 receptor and its GTP binding protein in rat aortic smooth muscle cells.

In conclusion, we demonstrated that the relaxant effect of propofol on the guinea pig trachea is independent of the epithelial function and ß-adrenoceptor activity. Propofol directly antagonizes the contraction of airway smooth muscle induced by spasmogens. Propofol is an excellent anesthetic for patients with hyperreactive airways in whom the epithelial layer is damaged.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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  14. Farmer SG, Hay DW, Raeburn D, et al. Relaxation of guinea-pig tracheal smooth muscle to arachidonate is converted to contraction following epithelium removal. Br J Pharmacol 1987;92:231–6.[Web of Science][Medline]
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  19. Petros AJ, Bogle RG, Pearson JD. Propofol stimulates nitric oxide release from cultured porcine aortic endothelial cells. Br J Pharmacol 1993;109:6–7.[Web of Science][Medline]
  20. Chang KSK, Davis RF. Propofol produces endothelium-independent vasodilation and may act as a Ca2+ channel blocker. Anesth Analg 1993;76:24–32.[Abstract/Free Full Text]
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Accepted for publication April 7, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press