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Anesth Analg 2005;101:315-321
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000173210.12435.67

CARDIOVASCULAR ANESTHESIA

The Inhibitory Effects of Sevoflurane on Angiotensin II- Induced, p44/42 Mitogen-Activated Protein Kinase-Mediated Contraction of Rat Aortic Smooth Muscle

Jingui Yu, MD*, Kazuhiro Mizumoto, MD*, Yasuyuki Tokinaga, MD*, Koji Ogawa, MD{dagger}, and Yoshio Hatano, MD*

*Department of Anesthesiology and {dagger}Surgical Operating Center, Wakayama Medical University, Wakayama City, Japan

Address correspondence and reprint requests to Yoshio Hatano, MD, Department of Anesthesiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, 641-0012, Japan. Address e-mail to yhatano{at}wakayama-med.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Sevoflurane dilates blood vessels and reduces arterial blood pressure in a dose-dependent manner. Angiotensin II (Ang II) is one of the primary regulators of vascular tension and arterial blood pressure, and the p44/42 mitogen-activated protein kinases (p44/42 MAPK) are involved in Ang II-mediated vascular smooth muscle contraction. We designed this study to examine the effects of sevoflurane on Ang II-induced, p44/42 MAPK-mediated contraction of rat aortic smooth muscle. The effects of the p44/42 MAPK kinase (MEK1/2) inhibitor, PD 098059 (10–5 molar [M], 5 x 10–5 M and 10–4 M), and sevoflurane (1.7%, 3.4%, and 5.1%) on Ang II-induced contraction and p44/42 MAPK phosphorylation were tested in rat aortic smooth muscle, using isometric force measurement and Western blot analysis, respectively. Ang II induced both a transient contractile response and phosphorylation of p44/42 MAPK, which were significantly attenuated by PD 098059 (P < 0.05–0.01). Sevoflurane inhibited Ang II-induced contractile response in a dose-dependent manner (P < 0.05 and 0.01 in response to 3.4% and 5.1% sevoflurane, respectively). Sevoflurane also dose-dependently depressed Ang II-elicited p44/42 MAPK phosphorylation (P < 0.01 in response to 3.4% and 5.1% sevoflurane). These results suggest that the inhibitory effect of sevoflurane on Ang II-induced vasoconstriction is, at least in part, caused by the inhibition of the p44/42 MAPK-mediated signaling pathway.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Angiotensin II (Ang II) plays an important role in regulating vascular contraction and arterial blood pressure. Both Ca2+-dependent and Ca2+-independent signaling pathways are involved in Ang II-induced vascular smooth muscle contraction (1). Many protein kinases, such as protein kinase C (2), and Rho-kinase (3), contribute to Ang II-induced, Ca2+-independent vascular smooth muscle contraction. Increasingly, investigators have shown that anesthetic agents can inhibit Ang II-induced vascular contraction by altering intracellular Ca2+ concentrations (4,5), and/or by affecting the activation of protein kinases, such as protein kinase C (6).

It has been demonstrated that p44/42 mitogen-activated protein kinases (p44/42 MAPK) are also involved in mediating the vascular smooth muscle contraction effect of Ang II (7,8) as well as other vasoconstrictors, such as norepinephrine (9), endothelin-1 (10) and serotonin (11), in addition to their effects on regulating cell growth, division, and proliferation. Ang II activates p44/42 MAPK, which phosphorylates caldesmon to attenuate its inhibition of actomyosin ATPase activity, and consequently enhances smooth muscle contraction (12–14) (Fig. 1). However, it has not yet been determined whether volatile anesthetics relax vascular smooth muscle via the p44/42 MAPK-mediated contraction mechanism. The present study was designed to examine the effects of sevoflurane, one of the most popular clinically used anesthetics, on Ang II-induced, p44/42 MAPK-mediated contraction of rat aortic smooth muscle by isometric tension measurement and detection of p44/42 MAPK phosphorylation.



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  		Figure 1. Schematic of Ang II-activated p44/42 MAPK signaling pathway for smooth muscle contraction. Ang II binds to the AT1 receptor and activates G protein-coupled tyrosine kinases, such as pp60c-src, which phosphorylates p120 rasGAP and attenuates its activation. The increase in active p120 rasGTP successively phosphorylates and activates raf, MEK1/2 and p44/42 MAPK. The activated p44/42MAPK leads to phosphorylation of caldesmon, which alleviates the inhibition on actomyosin ATPase activity, and consequently promotes smooth muscle contraction. PD 098059 specifically inhibits MEK1/2 activation. Ang II: angiotensin II; AT1 receptor: angiotensin type 1 receptor; p120 rasGAP: p120 ras GTPase-activating protein; GEFs: guanine nucleotide exchange factors; raf: p44/42 MAPK kinase kinase; MEK1/2: p44/42 MAPK kinase; p44/42 MAPK: p44/42 mitogen-activated protein kinases; ERK 1/2: extracellular signal-regulated kinase 1/2.

 


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With permission from the Wakayama Medical University Animal Care and Use Committee, Male Wistar rats (300–400 g) were anesthetized with halothane and euthanized by exsanguination from the common carotid artery. The descending thoracic aorta was removed and cleared of excess fat and connective tissue. The aorta was then cut into rings 3–4 mm in length. Eight rings were typically harvested from 1 rat. The endothelium was removed by gentle rubbing of the internal surface with a stainless steel needle. Rings were mounted vertically between 2 stainless steel hooks in 10 mL-organ baths. The lower hook was fixed to the bottom of the organ bath, and the upper hook was attached to force-displacement transducers (Amplifier Case 7903, Nihondenki-sanei CO, Tokyo, Japan). The organ baths contained Krebs bicarbonate solution (KBS [mM]: NaCl 118.2, KCl 4.6, CaCl2 2.5, KH2PO4 1.2, MgSO4 1.2, NaHCO3 24.8 and dextrose 10.0). The KBS was constantly aerated with 95%O2–5%CO2 to maintain the pH within the range of 7.35–7.45, and the temperature was maintained at 36.5–37.5°C. Changes in isometric force were amplified and displayed on chart recorders (Recti-Horiz-8K, Nihondenki-sanei CO, Tokyo, Japan). The resting tone was set to 3.0 g, which was found in preliminary investigations to be optimal to induce maximal constriction under our experimental condition (6,15,16). Before the start of experiments, the aortic rings were allowed to equilibrate for 60 min, during which time the bathing fluid was replaced every 20 min.

After equilibration, the preparations were incubated with 30 mM KCl to determine the integrity of smooth muscle cells, and to assess their overall contractile responsiveness. Removal of the endothelium was confirmed in phenylephrine-precontracted (3 x 10–7 M) rings by the abolition of relaxation to 10–5 M acetylcholine. Only rings that developed at least 2.0 g contractile active force in response to 30 mM KCl and did not relax to acetylcholine were selected for further experimentation.

Sevoflurane was introduced into the gas mixture using an agent-specific vaporizer (Penlon limited Abingdon, Oxon, UK). The concentration of the resulting gas mixture was monitored and adjusted using a calibrated Atom 303 anesthetic monitor (Atom, Tokyo, Japan). The concentrations of the anesthetics in KBS currently used were measured by gas chromatography (Shimadzu Seisakusho, Kyoto, Japan) and were determined to be 0.17 ± 0.05 mM, 0.35 ± 0.02 mM and 0.50 ± 0.03 mM corresponding to gas mixture concentrations of 1.7% (1 human MAC), 3.4% (2 MAC) and 5.1% (3 MAC), respectively (n = 8–12).

Ang II (10–7 M) was used to induce ring contraction, based upon previous investigations (6,16). Ten rings from 10 different rats were used to determine the time course of Ang II-induced contractile response (n = 10). Four rings from each of 8 different rats were randomly incubated with the specific MEK1/2 inhibitor, PD 098059 (11,17,18), at concentrations of 0, 10–5 M, 5 x 10–5 M or 10–4 M, respectively, for 15 min and were then treated with Ang II, to examine the involvement of p44/42 MAPK in Ang II-induced contraction. To test the effects of sevoflurane on Ang II-induced contraction, 4 rings from each of the different rats were randomly exposed to 0, 1.7%, 3,4%, or 5.1% sevoflurane, respectively, for 15 min prior to Ang II challenge. Each ring was challenged by only one concentration of PD 098059 or sevoflurane, and a total of 32 rings from 8 different rats were used in each of the above 2 protocols (n = 8).

Descending thoracic aortas (about 3.5 cm in length) were excised from the rats, were carefully cleared of all extraneous structures, and were opened longitudinally. The endothelium was removed by gently rubbing with a stainless steel needle. One strip was obtained from each animal. The prepared aortic strips were bathed in 95%O2-5%CO2 KBS and were equilibrated for 60 min before exposure to the agents.

To examine the time course of Ang II-induced phosphorylation of p44/42 MAPK, 7 aortic strips from 7 different rats were randomly exposed to Ang II (10–7 M) for 0, 2, 4, 6, 8, 10, or 12 min, and were then rapidly frozen with dry ice. Each of the strips was subjected to only one of the exposure times, and 28 aortic strips from 28 different rats were used in this protocol (n = 4 per time point). The time-course findings demonstrated that phosphorylation of both p44 MAPK and p42 MAPK reached the maximal level 4 min after the application of Ang II. To further confirm the effect of Ang II on the phosphorylation of p44/42MAPK, 20 aortic strips from 20 different rats were randomly pre-incubated with PD 098059 at concentrations of 0, 10–5 M, 5 x 10–5 M, or 10–4 M, respectively, for 15 min, and were then quickly frozen 4 min after application of Ang II. Each strip was treated only once with a single concentration of PD 098059. One additional strip, without Ang II or PD 098059 treatment, served as a basal control. The dose-dependency of the effect of sevoflurane on Ang II-stimulated phosphorylation of p44/42 MAPK was examined by randomly pre-exposing 20 aortic strips from 20 different animals to sevoflurane at concentrations of 0, 1.7%, 3.4%, or 5.1% for 15 min, respectively, and then freezing the tissues 4 min after treatment with Ang II. Each strip was treated once with only one concentration of sevoflurane. One additional strip, without Ang II or sevoflurane treatment served as a basal control (n = 4 for each concentration of PD 098059 and sevoflurane).

Frozen aortas were cut into small pieces, and were homogenized in ice-cold lysis buffer (50 mM HEPES, pH 7.5, 1% Triton X-100, 50 mM NaCl, 50 mM sodium fluoride, 5 mM EDTA, 10 mM sodium pyrophosphate, 1 mM phenylmethanesulfonyl fluoride, 1 mM Na3VO4, 10 µg/mL leupeptin and 20 µg/mL aprotinin) (19). Tissue homogenates were centrifuged at 15,000 g for 15 min at 4°C. The supernatant was collected and the protein concentration was determined using the bicinchoninic acid method (20). Samples of the protein extracts were prepared by mixing them with an equal volume of 2 x SDS sample buffer. The diluted samples were then boiled for 3 min, and stored at –80°C for use at a later date.

In each experiment, aliquots for each sample (equivalent total protein content, 25–30µg) were used. Proteins were separated using 10% sodium-dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and were then electroblotted onto nitrocellulose membranes. The electroblotted membranes were incubated in blocking buffer (containing 20 mM Tris, pH 7.5, 150 mM NaCl, 3% bovine serum albumin and 0.02% sodium azide) overnight at 4°C, and were then incubated with the p44/42 MAPK antibody (1:2000) and phospho-p44/42 MAPK (Thr202/Tyr204) antibody (1:2000) for 4 h, respectively, followed by incubation with horseradish peroxidase-conjugated antibody (1:2000) for 1.5 h. The densities of the immunoreactive p44/42 MAPK bands and phosphorylated p44/42 MAPK bands were detected using the enhanced chemiluminescence (ECL) system (Amersham Pharmacia Biotech, Piscataway, NJ, USA) and were assessed with image analysis software (NIH Image 1.62, Bethesda, MD, USA).

Ang II (human) and PD 098059 were purchased from Sigma-Aldrich Fine Chemicals (St. Louis, MO). Sevoflurane was obtained from Dainabot Company Limited (Osaka, Japan). Anti-p44/42 MAPK and anti-phospho-p44/42 MAPK (Thr202/Tyr204) antibodies were provided by Cell Signaling Technology Inc. (Beverly, MA). The secondary antibody labeled with horseradish peroxidase was supplied by Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). All other reagents for the tension measurement and Western blot analysis were of analytical grade.

The results are presented as mean ± sd. The sample size (n values) represents the number of aortic rings (for tension measurement) or of aortic strips (for Western blot analysis), which is equivalent to the number of rats used in each protocol. Two-factorial analysis of variance was used to compare the effects of the different concentrations of PD 098059 and sevoflurane on Ang II-induced contraction, and densities of the p44/42 MAPK and phosphorylated p44/42 MAPK bands, using the StatView software program (Version 5.0, SAS Institute Inc. Cary, NC). P values < 0.05 were considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Ang II (10–7 M) induced a rapid and phasic contractile response, followed by a gradual decline to the tonic contraction, slightly above the baseline level in endothelium-denuded rat aortic rings. The Ang II-induced contraction reached a maximal level of 71.6 ± 4.8% (n = 10) of the 30 mM KCl-induced contraction and occurred 3.8 ± 0.6 min after application of Ang II (Fig. 2A).



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  		Figure 2. Time course of Ang II-induced contraction (A) and p44/42 MAPK phosphorylation (B) of rat aortic smooth muscle. The Ang II-induced contractile response and p44/42 MAPK phosphorylation were measured using an isometric force transducer and Western blot analysis, respectively. For tension measurements, n = 10 (10 rings from 10 different rats). For phosphorylation detection, n = 4 (4 strips from 4 different rats for each exposure times). * P < 0.05 and ** P < 0.01 compared to the values obtained in the absence of Ang II (0 min). Ang II: angiotensin II; p44/42 MAPK: p44/42 mitogen-activated protein kinases; p-p44/42 MAPK: phosphorylated p44/42 mitogen-activated protein kinases.

 

The densities of the p44 MAPK and p42 MAPK bands did not change in accordance with Ang II response. However, similar to Ang II contractile response, the densities of the phosphorylated p44 MAPK and p42 MAPK bands increased transiently, with the maximal level 4 min after application of Ang II (P < 0.01, n = 4). p42 MAPK was phosphorylated to a greater degree than p44 MAPK (Fig. 2B).

PD 098059 dose-dependently and significantly inhibited Ang II (10–7 M)-induced contraction, with reductions of 14.8 ± 3.5% (P < 0.05), 45.6 ± 9.4% (P < 0.01) and 43.7 ± 9.3% (P < 0.01) in response to 10–5 M, 5 x 10–5 M and 10–4 M of PD 098059, respectively (n = 8, Fig. 3A).



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  		Figure 3. The effects of PD 098059 on Ang II-induced contraction (A) and p44/42MAPK phosphorylation (B) of rat aortic smooth muscle. For tension measurements, n = 8 (8 rings from 8 different rats for each exposure concentration). * P < 0.05 and ** P < 0,01 compared to controls (in the absence of PD 098059). For phosphorylation detection, n = 4 (4 strips from 4 different rats for each exposure concentration). ** P < 0.01 compared to values obtained in the presence of Ang II, but in the absence of PD 098059. Ang II: angiotensin II; p44/42 MAPK: p44/42 mitogen-activated protein kinases; p-p44/42 MAPK: phosphorylated p44/42 mitogen-activated protein kinases; PD 098059: p44/42 mitogen-activated protein kinase inhibitor.

 

Treatment with PD 098059 alone did not elicit any changes in the densities of the p44 MAPK and p42 MAPK bands. However, the densities of Ang II (10–7 M)-induced, phosphorylated p44 MAPK and phosphorylated p42 MAPK bands were significantly attenuated by PD 098059, with reductions of 48.4 ± 10.5% (P < 0.01), 74.2 ± 8.9% (P < 0.01) and 72.6 ± 11.7% (P < 0.01) for phosphorylated p44 MAPK, and 52.6 ± 12.1% (P < 0.01), 72.8 ± 10.3% (P < 0.01) and 71.7 ± 10.7% (P < 0.01) for phosphorylated p42 MAPK in the presence of 10–5 M, 5 x 10–5 M and 10–4 M of PD 098059, respectively (n = 4, Fig. 3B).

Sevoflurane dose-dependently inhibited Ang II (10–7 M)-induced contraction of rat aortic smooth muscle, with decreases of 14.2 ± 7.2% (P > 0.05), 26.7 ± 8.9% (P < 0.05) and 38.5 ± 12.8% (P < 0.01) (n = 8) in response to 1.7%, 3.4% and 5.1% sevoflurane, respectively (Fig. 4A).



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  		Figure 4. The effects of sevoflurane on Ang II-induced contraction (A) and p44/42 MAPK phosphorylation (B) of rat aortic smooth muscle. For tension measurements, n = 8 (8 rings from 8 different rats for each exposure concentration). * P < 0.05 and ** P < 0.01 compared with controls (in the absence of sevoflurane). For phosphorylation detection, n = 4 (4 strips from 4 different rats for each exposure concentration). ** P < 0.01 compared with values obtained in the presence of Ang II, but in the absence of sevoflurane, Ang II: angiotensin II; p44/42 MAPK: p44/42 mitogen-activated protein kinases; p-p44/42 MAPK: phosphorylated p44/42 mitogen-activated protein kinases.

 

The presence of sevoflurane did not alter the densities of the p44 MAPK and p42 MAPK bands. However, the densities of Ang II (10–7 M)-stimulated, phosphorylated p44 MAPK and phosphorylated p42 MAPK bands were attenuated in a concentration-dependent manner by sevoflurane, with reductions of 7.5 ± 5.3 (P > 0.05), 49.1 ± 19.4 (P < 0.01) and 56.2 ± 16.9 (P < 0.01) for phosphorylated p44 MAPK band and 17.8 ± 14.2% (P > 0.05), 50.1 ± 17.8% (P < 0.01) and 65.9 ± 12.2% (P < 0.01) (n = 4) for phosphorylated p42 MAPK band in response to 1.7%, 3.4% and 5.1% sevoflurane, respectively (Fig. 4B).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The main findings of the present study are that Ang II-induced contraction and p44/42 MAPK phosphorylation of rat aortic smooth muscle were both significantly inhibited by the specific MEK1/2 inhibitor, PD 098059 (11,17,18). Furthermore, sevoflurane dose-dependently inhibited both Ang II-induced contraction and p44/42 MAPK phosphorylation of rat aortic smooth muscle.

In the current study, Ang II induced both phasic contraction (Fig. 2A) and transient p44/42 MAPK phosphorylation (Fig. 2B) of rat aortic smooth muscle with the same time course, consistent with previous investigations (21,22). Both Ang II-induced p44/42 MAPK phosphorylation and contraction were significantly inhibited by the MEK1/2 inhibitor, PD 098059, with a much greater degree of inhibition of p44/42 MAPK phosphorylation (Fig. 3B) than that of the contractile response (Fig. 3A). These results confirmed that the p44/42 MAPK signaling pathway is one of, but not the sole, mechanisms of Ang II-mediated vascular contraction (1–3). The importance of p44/42 MAPK in Ang II-induced tyrosine kinase-ras-raf-MEK1/2-p44/42MAPK-caldesmon cascade is well supported by many investigators (7,8,10,23,24).

The role of the renin-angiotensin system, especially its key component, Ang II, in the regulation of vascular tension and arterial blood pressure has been well established. The wide usage of angiotensin converting enzyme inhibitors, such as captopril, for the management of hypertension reflects the importance of Ang II in the pathophysiological alterations of the vasculature in hypertension (25,26). The introduction of anesthesia may cause severe hypotension in those patients treated with angiotensin converting enzyme inhibitors (27,28). The inhibitory effect of anesthetics on Ang II-induced vascular contraction (6,29) enhances angiotensin converting enzyme inhibitor-produced vasodilation.

The inhibitory effects of volatile anesthetic on Ang II-induced vascular contraction have been confirmed in vivo. Nyhan et al. (29) demonstrated that halothane significantly attenuated the exogenous Ang II-induced increase of systemic arterial blood pressure and abolished the increase in pulmonary vascular pressure/flow (P/Q) in conditioned dogs, using a chronically instrumented model. These investigators demonstrated that halothane inhibits both Ang II-mediated systemic and pulmonary vasoconstriction. However, there have been few in vivo or in vitro investigations about the effect of sevoflurane on Ang II-mediated vascular contraction. In a previous study (6), we demonstrated that sevoflurane dose-dependently inhibited Ang II-induced, Ca2+-dependent protein kinase C-mediated contraction of rat aortic smooth muscle, without significant attenuation of intracellular Ca2+ concentrations.

The present investigation supports the hypothesis that another mechanism by which sevoflurane can attenuate Ang II-induced vascular contraction involves p44/42 MAPK. Although the inhibition of Ang II-induced contraction and p44/42 MAPK phosphorylation were both dose-dependent, the degree of inhibition between the vascular contraction and p44/42 MAPK phosphorylation was not proportional. For example, the 3.4% sevoflurane-mediated inhibition of Ang II-induced p44/42 MAPK phosphorylation (49.1% and 50.1%, respectively) was generally equivalent to that of 10–5 M PD 098059 (48.4% and 52.6%, respectively), whereas the 3.4% sevoflurane-mediated inhibition of Ang II-induced contraction (26.7%) was larger than that of 10–5 M PD 098059 (14.8%). The greater degree of inhibition of tension compared with p44/42 MAPK phosphorylation by sevoflurane than by PD 098059 may suggest that sevoflurane inhibits Ang II-induced vascular contraction, through mechanisms in addition to p44/42 MAPK, which is supported by our previous investigation (6).

The present study demonstrated that sevoflurane is able to dose-dependently inhibit Ang II-induced, p44/42 MAPK-mediated contraction of rat aortic smooth muscle. But the degree to which the inhibition of p44/42 MAPK contributes to the relaxing effect of sevoflurane on Ang II-induced contraction is not available for this study. Further, whether this inhibition is caused by direct inhibition of p44/42 MAPK activation or by suppression of its up-stream effector(s) or by both of them is needed to determine in the future investigation. In conclusion, sevoflurane inhibits Ang II-induced, p44/42 MAPK-mediated contraction of rat aortic smooth muscle.


   Footnotes
 
This research was supported in part by grant-in-aid No. 13470327 and No. 13671607 for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan, Tokyo, Japan.

Accepted for publication March 14, 2005.


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 

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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