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CARDIOVASCULAR ANESTHESIA

The Effect of Propofol on Angiotensin II-Induced Ca²⁺ Mobilization in Aortic Smooth Muscle Cells from Normotensive and Hypertensive Rats

Emmanuel Samain, MD, PhD^*, Hélène Bouillier, Jean Marty, MD^*, Michel Safar, MD, PhD, and Georges Dagher, PhD

*Department of Anesthesiology, Beaujon Hospital, University Xavier Bichat, Clichy; and INSERM U337, Paris, France

Address correspondence and reprint requests to Emmanuel Samain, MD, PhD, Department of Anesthesiology, Beaujon Hospital, University Xavier Bichat, 100 Blvd. General Leclerc, 92110 Clichy, France.

	Abstract

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We studied the effect of propofol (5.6–560 µmol/L; 1–100 µg/mL) on the mechanisms involved in Ca²⁺ mobilization elicited by angiotensin II (AngII) in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. We studied the variations in intracellular Ca²⁺ ([Ca²⁺]_i) concentrations in cultured aortic vascular smooth muscle cells (VSMCs) isolated from 6-wk-old WKY and SHR rats loaded with the Ca²⁺-sensitive fluorescent dye, Fura-2, using fluorescent imaging microscopy. In the absence of external Ca²⁺, AngII (1 µmol/L) induced a transient [Ca²⁺]_i mobilization from internal stores that was larger in SHR than in WKY rats. Ca²⁺ influx was assessed after external Ca²⁺ (1 mmol/L) reintroduction. Propofol (1–100 µg/mL) added 5 min before the experiments did not alter AngII-induced Ca²⁺ release from internal stores in either strain. By contrast, Ca²⁺ influx elicited by AngII was significantly decreased by propofol. This effect occurred at a smaller concentration of propofol in the SHR than in the WKY rats. When Ca²⁺ stores were depleted by exposure of cells to thapsigargin, an inhibitor of the sarcoendoplasmic reticulum Ca²⁺-ATPase, reintroduction of Ca²⁺ to the medium induced a capacitative Ca²⁺ influx of similar magnitude than that elicited by AngII. This influx was also significantly decreased by propofol at 100 µg/mL (

WKY: 27 ± 3% of control values, n = 107;

SHR: 16 ± 3%, n = 47; P < 0.001). In conclusion, propofol decreased AngII-induced Ca²⁺ influx through voltage-independent channels, without altering Ca²⁺ release from internal stores in aortic VSMCs. The hypertensive rats were found to be more sensitive to the effect of propofol than the normotensive rats. This suggests that the response of VSMCs to AngII may be altered by propofol.

Implications: In rat aortic vascular smooth muscle cells, propofol reduced angiotensin II-elicited Ca²⁺ entry through capacitative Ca²⁺ channels without altering Ca²⁺ release from intracellular stores. Spontaneously hypertensive rats were more sensitive to these effects of propofol than normotensive rats. The response of vascular smooth muscle cells to angiotensin II may be altered by propofol.

	Introduction

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Propofol (2,6-diisopropylphenol) causes a decrease in arterial blood pressure that is partly due to a decrease in systemic vascular resistance (1,2). A direct relaxant action of propofol on vascular smooth muscle cells (VSMCs) may be one of the mechanisms of propofol-induced vasodilation (3–5). Recently, several studies have attempted to identify the cellular mechanisms implicated in the action of propofol and, in particular, how the effects of vasoactive substances are modulated. In this regard, transduction of signal through intracellular Ca²⁺ ([Ca²⁺]_i) mobilization is particularly important because VSMC tension is closely related to Ca²⁺ variations elicited by vasoactive agents (6–9). Imura et al. (10) suggested that propofol decreased norephinephrine-induced [Ca²⁺]_i release from storage sites in VSMCs from mesenteric arteries. In cultured A10 VSMCs, derived from embryonic rat aorta, propofol moderately decreased inositol 1,4,5-triphosphate (1,4,5-IP3) production induced by endothelin-1 or arginine vasopressin, but not by sodium fluoride, an activator of guanosine triphosphate-binding proteins (11,12). Furthermore, propofol was reported to inhibit Ca²⁺ influx through L-type channels elicited by either endothelin-1 (11,12) or norepinephrine (10). However, little is known about the effects of propofol on angiotensin II (AngII). This peptide is a potent vasoconstrictor that is important in the short-term control of blood pressure, particularly in the hypovolemic state that may be encountered in the perioperative period. The hemodynamic effects of AngII are mediated through binding to angiotensin subtype 1 (AT₁) receptors, leading to Ca²⁺ release from internal stores and to Ca²⁺ influx from extracellular spaces (7–9).

Structural and functional abnormalities of the arterial wall have been reported in some experimental models of genetic hypertension and have been associated with an increase in Ca²⁺ mobilization in VSMCs in response to several agonists, especially AngII (13–19). These abnormalities may be linked to the lability of blood pressure observed during general anesthesia in individuals with preexisting hypertension (20). The present study was undertaken to examine the effect of propofol on [Ca²⁺]_i mobilization induced by AngII in VSMCs of spontaneously hypertensive (SHR) rats and a normotensive strain.

	Methods

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Cell Culture
The study was approved by our institutional animal investigation committee and was conducted after recommendations established by the Guide for the Care and Use of Laboratory Animals. Cultured VSMCs from thoracic aorta of 6-wk-old male SHRs with a mean arterial pressure (± SEM) of 136 ± 5 mm Hg (n = 25) and Wistar Kyoto (WKY) rats (98 ± 4 mm Hg, n = 30) were obtained by enzymatic digestion as previously described (21). In brief, aortas were incubated for 10 min in a dissecting solution containing Dulbecco’s modified Eagle’s medium (DMEM; Eurobio, Les Ulis, France), supplemented with glutamine (2 mmol/L), 0.1% bovine serum albumin, penicillin (100 units/mL), streptomycin (100 µg/mL), and collagenase (295 units/mL). The adventitia was stripped off mechanically, and the endothelial layer was gently scraped off. The medial layer of the aorta was then incubated for 20 min, at 37°C in dissecting solution in which CaCl₂ content has been reduced to 0.8 mmol/L, and to which elastase (90 units/mL) and pronase (0.33 mg/mL) had been added. Cells were then detached by gently pipetting the tissue through a large-hole Pasteur pipette. The undigested tissue was incubated in fresh dissecting medium for another 20 min, and the procedure was then repeated twice. At the end of the digestion procedure, CaCl₂ was added progressively by steps of 0.25 mmol/L to reach a final concentration of 1.6 mmol/L. To obtain secondary cultures, isolated cells were seeded at 1.5 to 2 x 105 cells/mL into 25 cm² flasks in DMEM supplemented with 10% fetal calf serum (Eurobio), 2 mmol/L of L-glutamine, 25 mmol/L of N-(2-hydroxyethyl) piperazine-N'-(2-ethanesulfonic) acid (HEPES), pH 7.4, 100 units/mL of penicillin, and 100 µg/mL streptomycin, and incubated at 37°C and 5% CO₂ in a humidified incubator. The medium was changed every 48 h. At confluence, secondary cultures were obtained by serial passage after the cells were harvested with 0.5 g/L trypsin and 0.2 g/L EDTA (Sigma, St. Louis, MO) and reseeded in fresh DMEM containing 10% fetal calf serum.

Cell Ca²⁺ Measurements
[Ca²⁺]_i variations were assessed in single cells by using fluorescence imaging as described previously (18). In brief, cells seeded on glass coverslips were loaded with the acetoxymethyl ester form of the Ca²⁺-sensitive fluorescent dye, Fura-2 (5 µmol/L, 30 min at 37°C; Molecular Probe, Junction City, OR). The coverslips were mounted on the stage of a Nikon Diaphot microscope (Nikon, Japan) fitted with a cooled integrating CCD imaging system (Newcastle Photometric System, Newcastle-upon-Tyne, UK). Cells were illuminated alternately at 350 and 380 nm, and the intensity of emitted light from single cells over a 500-ms period at wavelength greater than 520 nm was measured. The ratio of the light intensities at the two wavelengths, plotted against time, was used to reflect qualitative changes in [Ca²⁺]_i (22). Because calibration procedures are prone to error and rest on a number of assumptions, no attempt was made to calibrate the ratio values (9,23,24). Therefore, qualitative changes in [Ca²⁺]_i are represented by changes in the ratio of the emitted fluorescence at 350 nm/380 nm. Cells were superfused with Na⁺-HEPES solution at 37°C at a flow rate of 1 mL/min.

Cell Ca²⁺ variations induced by AngII were studied in single cells. As previously described, AngII induced a receptor desensitization that precluded repetitive stimulation of the same cell by AngII (25).

Because propofol is insoluble in water, we used the available form of propofol using a soya bean emulsion as solvent (Zeneca Pharma, Cergy, France). Propofol, in concentrations of 1–100 µg/mL (5.6–560 µmol/L), was added to the perfusion medium 5 min before the experiment and maintained throughout each study. We also tested the solvent itself (10 g/L soya bean oil, 22 g/L glycerol, and 12 g/L egg phosphatide; Intralipide®, Pharmacia & Upjohn SA, Saint Quentin-en-Yvelines, France) at a concentration of 10 µL/mL, corresponding to the highest concentration of propofol studied.

Fluids and Drugs
The composition of the Na⁺-HEPES solution (mmol/L) was 140 NaCl, 4.5 KCl, 0.8 MgCl₂, 0.8 KH₂PO₄, 1.0 CaCl₂, 5.6 glucose, and 10 HEPES. Ca²⁺-free Na⁺-HEPES solution was made without CaCl₂ and with the addition of 1 mmol/L EGTA. N-methyl-glucamine (NMG)-HEPES solution was made by replacing the NaCl with NMG (Sigma). AngII, thapsigargin (a potent inhibitor of the sarcoendoplamsic reticulum Ca²⁺ ATPase), obtained from Sigma, CI-996 from Parke-Davis Pharmaceutical Research, CGP-48933 from Ciba-Geigy, and nifedipine from Bayer were dissolved in Na⁺-HEPES solution before use.

Statistical Analysis
Results are presented as the means ± SEM. The values of variables of Ca²⁺ mobilization measured in treated cells are expressed as percentages of the values obtained in the control (untreated) cells. Student’s t-test for unpaired data was used to compare mean values obtained in control cells to values obtained in treated cells, and to compare mean values obtained in WKY rats to those in SHR rats using Statview 4.5 software (Abacus Concepts, Inc., Berkeley, CA). A comparison of the values obtained in cells from passages 3 to 9 for each strain was performed by using analysis of variance (ANOVA), with multiple testing according to the Bonferroni method, using SuperAnova software (Abacus Concepts). P < 0.05 was considered significant.

	Results

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Effect of AngII on Cell Ca²⁺
AngII addition caused a transient increase in [Ca²⁺]_i, characterized by the amplitude and area under the Ca²⁺ variation over time (total Ca²⁺ released) (Fig. 1A). AngII-induced Ca²⁺ release from internal stores was assessed in Ca²⁺-free Na⁺-HEPES medium (Fig. 1B). The maximum effect was obtained at concentrations above 0.5 µmol/L (Fig. 2) (15,18). Therefore, the effect of AngII was assessed at 1 µmol/L in both strains. AT₁ antagonists CGP-48 933 (100 nM) and CI-996 (100 nM) inhibited the response to AngII in both strains (>95% inhibition, P < 0.0001 for each).

View larger version (11K): [in this window] [in a new window]   Figure 1. The effect of angiotensin II (AngII; 1 µmol/L) on intracellular Ca2+: (A) in the presence of external Ca2+ (Ca0++) and (B) in the absence of external Ca2+. Ratios of the emission fluorescence (>520 nm) measured at excitation wavelengths of 350 and 380 nm are shown on the ordinate. The abscissa shows the time course of the experiments in seconds. Intracellular Ca2+ mobilizations were characterized by the amplitude (peak-basal values) of intracellular Ca2+ released; and the area under the Ca2+ variation (amount of intracellular Ca2+ mobilized). The first rate of increase in Ca2+ elicited by reintroduction of external Ca2+ to the medium (B) was measured to represent Ca2+ influx.

View larger version (16K): [in this window] [in a new window]   Figure 2. Effect of different concentrations of angiotensin II on the amplitude of intracellular Ca2+ increase in vascular smooth muscle cells from spontaneously hypertensive rats (•) and Wistar Kyoto rats (). Results are expressed as means ± SEM of 16–25 cells per concentration of angiotensin II.

View larger version (31K): [in this window] [in a new window]   Figure 3. The effect of solvent (10 µL/mL) and propofol (1–100 µg/mL) in vascular smooth muscle cells from Wistar Kyoto rats (WKY; left) and spontaneously hypertensive rats (SHR; right) on the amplitude of intracellular Ca2+ released () and total Ca2+ release () elicited by the addition of angiotensin II. Results are expressed as the percentage of control values obtained in control, untreated cells.

View larger version (14K): [in this window] [in a new window]   Figure 4. The effect of solvent (10 µL/mL) and propofol (1–100 µg/mL) in vascular smooth muscle cells from Wistar Kyoto rats (WKY; left) and spontaneously hypertensive rats (SHR; right) on the intracellular Ca2+ influx elicited by addition of angiotensin II. Results are expressed as the percentage of control values obtained in control, untreated cells. *P < 0.05 propofol versus control cells. P < 0.05 SHR versus WKY rats.

	Discussion

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The present study demonstrates that propofol can alter the response of VSMCs to AngII. Propofol was found to reduce Ca²⁺ influx through voltage-independent Ca²⁺ channels elicited by AngII, but to be without effect on AngII-induced Ca²⁺ mobilization from internal stores in VSMCs from both SHR and WKY rats.

In aortic VSMCs, binding of AngII to AT₁ receptors causes a transient increase in [Ca²⁺]_i due to the release of Ca²⁺ from intracellular stores, and a Ca²⁺ influx across the membrane via Ca²⁺ channels (7–9,26). AngII activates phospholipase C that hydrolyzes phophatidylinositol 4,5-biphosphate, thereby releasing 1,4,5-IP3 to the cytosol. The latter moiety binds to its receptor releasing Ca²⁺ from storage pools. Our results show that the pathway from AT₁ binding to Ca²⁺ mobilization is not altered by propofol. Previous studies have assessed the effect of propofol on VSMC tension (4,10,27). Propofol reduces the phasic increase in force in rabbit mesenteric arteries caused by norepinephrine (10). This was attributed to a decrease in Ca²⁺ release from internal stores. Heterogeneities in Ca²⁺ transport mechanisms elicited by G protein-coupled receptors between species and between vascular beds may account for this difference.

The depletion of Ca²⁺ from intracellular stores through agonist-induced release is replenished by Ca²⁺ influx from the extracellular space (7,26). The major finding of this study is that propofol inhibits this influx in both WKY and SHR rats. In aortic VSMCs, the major Ca²⁺ entry mechanism induced by AngII is voltage-independent [this study and (8,28)]. This is in contrast to other vascular beds, such as the mesenteric bed, where voltage-dependent Ca²⁺ channels have been reported (29). Propofol has been reported to act as a voltage-dependent Ca²⁺ channel blocker in several experimental models (10–12). Previous studies in mesenteric VSMCs and A10 lines have shown that the voltage-dependent Ca²⁺ channels characteristic of these vascular beds—and elicited by norepinephrine, endothelin-1, or arginine vasopressin—are inhibited by propofol (10–12,30). In VSMCs, capacitative Ca²⁺ influx is known to be elicited by either 1,4,5-IP3 or an increase in cell Ca²⁺. Studies using agents such as thapsigargin that inhibit the Ca²⁺-ATPase have demonstrated that Ca²⁺ store depletion provides a full and sufficient signal for the activation of capacitative Ca²⁺ entry (26,31,32). Our results show that propofol also inhibits thapsigargin-induced Ca²⁺ influx. However, the nature of the signal linking pool depletion to the opening of the capacitative Ca²⁺ influx remains controversial. Direct protein–protein interaction between the 1,4,5-IP3 receptor and the capacitative Ca²⁺ entry channel, or a diffusible messenger released or formed with Ca²⁺ mobilization, would stimulate Ca²⁺ influx (26,32). Our results suggest that propofol does not affect the signaling pathway linking AT₁ receptor activation to 1,4,5-IP3 formation, but its mechanism of action on Ca²⁺ channels remains to be determined.

The rise in intracellular-free Ca²⁺ is the principal mechanism initiating contraction in VSMCs. Two major types of excitation-contraction coupling have been described in VSMCs: electromechanical coupling, in which action potential and/or depolarization cause an increase in [Ca²⁺]_i, and pharmacomechanical coupling, that occurs without necessary changes of the membrane potential (33). The relative contribution of Ca²⁺ release from internal stores and Ca²⁺ influx responsible for activation of the contractile apparatus during pharmacological coupling remains controversial (34,35). Voltage-independent Ca²⁺ channels are believed to not only play an important role in replenishing depleted intracellular stores, but also act as a source of activator Ca²⁺ for the regulation of smooth muscle tone (36). In this regard, the opening of ligand-gated channels was suggested be responsible for sustaining the contraction of several types of smooth muscle cells (33,37).

In the SHR strain, the effect of propofol on Ca²⁺ influx was observed at a propofol concentration of 3 µg/mL (16.9 µmol/L). This corresponds to a concentration seen during propofol anesthesia (38,39). However, conclusions concerning the free concentration of this drug in the plasma or interstitial space should be made cautiously, because several factors may affect the microkinetics of propofol (9,11,12).

The difference between the hypertensive and normotensive strains may be linked to the structural and functional abnormalities of the arterial wall, and to the alteration in Ca²⁺ handling observed in VSMCs from SHR rats (14,16,19). [Ca²⁺]_i and Ca²⁺ storage pools in cultured aortic VSMCs from SHRs were found to be increased under nonstimulated conditions. The response to various agonists, including AngII, is also enhanced in the SHR rat [this study and (15)]. Furthermore, AngII signaling pathways of the normotensive and hypertensive strains have been shown to differ in several respects, suggesting a signaling pattern characteristic of the hypertensive phenotype (9,13,18,40). In this regard, we observed an increase in the amplitude of [Ca²⁺]_i variation induced by AngII, suggesting an increase in Ca²⁺ mobilization from internal stores in the SHR rat, compared with WKY rats, in accordance with previous studies (13,15). However, the area under the curve was not different between the two strains, suggesting an enhanced recovery of Ca²⁺ to internal stores or extrusion to the external medium (41,42). Alternatively, the difference in the effect of propofol may be related to a difference in the cell membrane permeability to propofol. Further experiments are required to elucidate this point.

In conclusion, the present results establish that propofol brings about a dose-dependent decrease in Ca²⁺ influx through capacitative Ca²⁺ channels elicited by AngII without altering Ca²⁺ mobilization from internal stores in cultured rat aortic VSMCs. The same effect is also observed in the SHR rats at a lower concentration. These results may prove useful in understanding the alteration in vascular reactivity observed during propofol anesthesia, particularly in hypertensive individuals.

	Acknowledgments

 
We wish to thank Mr. Owen Parkes for reviewing the manuscript.

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