Effect of propofol on vascular reactivity in thoracic aortas from rats with endotoxemia : Journal of the Chinese Medical Association

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Original Article

Effect of propofol on vascular reactivity in thoracic aortas from rats with endotoxemia

Tsao, Cheng-Minga; Chen, Shiu-Jenb; Tsou, Mei-Yunga; Wu, Chin-Chenc,*

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Journal of the Chinese Medical Association: June 2012 - Volume 75 - Issue 6 - p 262-268
doi: 10.1016/j.jcma.2012.04.009

    Abstract

    1. Introduction

    Septic shock has detrimental effects leading to circulatory failure and abnormal tissue perfusion. Altered tissue perfusion may be caused by vascular hyporeactivity to adrenergic agonists. It is believed that enhanced formation of nitric oxide (NO), principally because of activation of the calcium-independent, inducible isoform of NO synthase (iNOS), contributes to the hyporeactivity to endogenous and exogenous vasoconstrictor agents in septic shock and thus underlies hypotension.1 In addition, our previous studies have shown that K+ channels are involved in the mechanism of abnormal relaxation of arteries in rats during endotoxic shock induced by lipopolysaccharide (LPS).2–4

    Propofol (2,6-diisopropylphenol) is a short-acting intravenous anesthetic/hyponotic agent. It has been shown that propofol causes hypotension via myocardial depression,5,6 direct vascular relaxation,7,8 and/or a decrease in sympathetic activity.9 In isolated arteries, propofol decreased vascular tone and adrenoceptor agonist-induced vasoconstriction.10–12 There are three NOS isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and iNOS.13 The release of NO induced by eNOS in the vascular endothelium partially contributes to propofol-induced relaxation.11,12,14 By contrast, vasodilation in response to propofol has been attributed to a decrease in intracellular Ca2+ availability within vascular smooth muscle cells, reflecting inhibition of the Ca2+ influx through voltage- or receptor-gated Ca2+ channels.12,15,16

    Propofol is widely used not only in anesthesia but also in critical care units.17 Therefore, whether arterial sensitivity to vasoconstrictors and/or vasodilators can be modulated by propofol is an important issue in ill patients.In this study, we investigated the effect of propofol on norepinephrine (NE)-induced contractile responses in thoracic aortas isolated from Wistar rats treated with LPS. In addition, we assessed whether propofol can modulate the action of NE by studying endothelium-dependent and -independent relaxant responses.

    2. Methods

    Sixty male Wistar rats (250–300 g) were purchased from BioLASCO Taiwan (Taipei, Taiwan). The animals were maintained on a 12-hour light/dark cycle and were given free access to water and standard rat chow. Animal experiments were approved by our institutional and Committee on the Care and Use of Animals (National Defense Medical Center, Taipei, Taiwan, ROC) and all animals received humane care according to the criteria of the National Academy of Sciences.

    The rats were anesthetized by intraperitoneal injection of urethane (1.2 g/kg) and body temperature was maintained at approximately 36 °C with a heating pad. The trachea was cannulated to facilitate respiration. The right carotid artery was cannulated and connected to a pressure transducer (P23ID, Statham, Oxnard, CA, USA) for measurement of mean arterial blood pressure and heart rate, which were displayed on a polygraph recorder (MacLab/4e, ADInstruments, Castle Hill, Australia). The left jugular vein was cannulated for administration of endotoxin or vehicle. On completion of the surgical procedure, cardiovascular parameters were allowed to stabilize for 20 min. After recording baseline hemodynamic parameters, animals received Escherichia coli LPS (10 mg/kg intravenous infusion for 10 minutes) or normal saline (same volume as LPS) and were monitored for 6 hours. Bacterial LPS (E. coli serotype 0127:B8, L3127) was obtained from Sigma Chemical (St. Louis, MO, USA).

    At 6 hour after injection of saline or LPS, thoracic aortas were isolated from sham controls and rats treated with LPS under anesthesia. The thoracic aorta was cleaned of adhering periadventitial fat in ice-cold (4 °C) Krebs solution and was cut into rings of approximately 3 mm in length, with four aortic rings assessed from one rat.The Krebs solution (pH 7.4) consisted of (mM): NaCl 118, KCl 4.7, KH2PO4 1.2, MgSO4 1.2, NaHCO3 25, CaCl2 2.5 and glucose 11. To analyze endothelium-independent effects of the drug, the endothelium was removed from some by gently rubbing the intimal surface.2 For the remaining rings, care was taken not to touch the inner surface of the blood vessel. Aortic rings were mounted in 20-mL organ baths containingoxygenated (95% O2–5% CO2) Krebs solution kept at 37 °C. Two S-shaped stainless steel hooks were inserted through the lumen; the lower hook was fixed and the upper one was attached to anisometric force displacement transducer (Grass FT03 transducer, Grass Technologies, Quincy, MA, USA). The resting tension was set to 2 g (determined to be optimal in preliminary length–tension experiments) and preparations were allowed to equilibrate for at least 60 minutes. During this incubation period, each ring was washed three times with fresh Krebs solution. Endothelial integrity or denudation was confirmed in each ring by testing relaxation induced by acetylcholine (ACh, 1 μM) after precontraction with the alpha-adrenergic agonist NE (100 nM). Lack of a relaxation response to ACh was considered as evidence that the endothelium had been removed. After this procedure, the rings were washed and allowed to re-equilibrate to baseline tension for 45 minutes.

    In the first series of experiments, eight rats were used in each sham control groupand each group of rats treated with LPS.Cumulative NE concentration–response curves were calculated without propofol. After washing three times with fresh Krebs solution for 30 minutes, aortic rings were then incubated with or without propofol (10 μM) in fresh Krebs solution for 20 minutes, and cumulative NE concentration–response curves were calculated for all vessels with or without endothelium. It was noted that vascular reactivity was not altered by repetition of agonist stimulation, and that propofol did not modify the basal tension of rings from sham and LPS-treated rat aortas during the time course of incubation before agonist addition.

    In the second series of experiments, eight rats were also used in each sham control groupand each group of rats treated with LPS. To study the role of propofol in extracellular calcium influx and intracellular store release induced by NE, endothelium-intact aortic rings were incubated with or without propofol (10 μM) in fresh Krebs solution for 20 minutes and then the rings were contracted with NE (1 μM). When maximal contraction was attained, rings were washed three times with Ca2+-free Krebs solution and the protocol was repeated after a 45-minute equilibration period in Ca2+-free solution. The calcium-free solution was of the same composition as Krebs solution except that CaCl2 was omitted. The maximal NE-induced contraction of aortic rings in normal and Ca2+-free Krebs solution was termed S and F phase, respectively, as previously described.18 The fast initial phase (F phase) of NE-induced contraction depends on a common intracellular Ca2+ store, and the slow tonic phase (S phase) of NE-induced contraction mostly depends on the extracellular Ca2+ influx.19–21

    In the third series of experiments, eight rats were used in each sham control groupand each group of rats treated with LPS. Cumulative concentration–response curves for ACh (1 nM to 1 μM) and propofol (1 nM to 10 μM) were obtained for aortic rings precontracted with NE in endothelium-intact and -denuded preparations. The NE-induced contraction level in preparations obtained from the LPS-treated group was adjusted to the same level as that in the sham group. Therefore, 100 nM NE was used in the sham group and 1 μM NE in the LPS-treated group. The vasodilatory response to propofol was expressed as a percentage of the initial contraction induced by NE.

    In the fourth series of experiments, six rats were used in each sham control groupand each group of rats treated with LPS. To clarify the role of the NO–cGMP pathway and K+ channels in propofol-induced vasodilation, inhibitors of NO synthase (Nω-nitro-L-arginine methyl ester, L-NAME; 300 μM), soluble guanylate cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ; 1 μM), or K+ channels (tetraethylammonium, TEA; 1 mM) were used. Endothelium-intact aortic rings were incubated with each inhibitor for 20 minutes and then the vasodilatory response to propofol (10 μM) was measured for rings precontracted with NE.

    All drugs were obtained from Sigma (St. Louis, MO, USA). Propofol and ODQ were initially dissolved in dimethylsulfoxide (DMSO) and further diluted in distilled water. Control experiments indicated that DMSO had no direct effect in the final concentrations applied. All other stock solutions were prepared in distilled water. Drug concentrations are expressed as final molar concentrations in the organ bath.

    All results are expressed as mean ± SEM for n observations, where n is the number of rats from which blood vessels were obtained. Statistical analysis of the data was performed by generalized estimating equations to account for repeated measures per rat with post hoc analysis using the Bonferroni correction or Student's t test, as appropriate. A p value < 0.05 was considered statistically significant.

    3. Results

    Cumulative concentrations (1 nM to 3 μM) of NE induced vasoconstriction in a dose-dependent manner in aorta from sham rats, with maximum contraction achieved at 1 μM (Fig. 1A). ACh caused dose-dependent vasodilation in aortic rings precontracted with NE (Fig. 1B). In LPS-treated rats,however, NE-induced vasoconstriction and ACh-induced vasodilation were significantly attenuated (both p < 0.001, Fig. 1A,B).

    F1-5
    Fig. 1:
    Concentration–response curves for (A) norepinephrine (NE) and (B) acetylcholine (ACh) in sham and lipopolysaccharide (LPS)-treated rat aortic rings. Values are mean ± SEM for n = 8 animals per group. #p <0.001, LPS-treated versus sham group.

    Preincubation of aortic rings from sham rats with 10 μM propofol caused a significant decrease in NE-induced vasoconstriction compared to sham controls only at 10 nM NE (p < 0.001, Fig. 2A). However, propofol significantly decreased NE-induced vasoconstriction (10 nM–1 μM NE) in aortic rings from LPS-treated rats (p = 0.05, Fig. 2C). Thus, propofol effectively enhanced LPS-induced hyporeactivity to NE in intact aortic rings. In denuded aortic rings, preincubation with 10 μM propofol also caused a decrease in NE-induced vasoconstriction at the lower concentrations (1 and 10 nM) in sham rats (p < 0.001, Fig. 2B). In LPS-treated rats, preincubation with propofol significantly decreased vasoconstriction induced by 10 nM–1 μM NE in denuded aortic rings (p < 0.01, Fig. 2D).

    F2-5
    Fig. 2:
    Concentration–response curves for norepinephrine (NE) in (A,B) sham and (C,D) lipopolysaccharide (LPS)-treated rat aortic rings with (+E) and without endothelium (–E) in the presence and absence of propofol (10 μM). Values are mean ± SEM for n = 8 animals per group. #p < 0.001, †p < 0.01, *p < 0.05, pretreatment with versus without propofol.

    Comparison of aortas with and without endothelium revealed that endothelium removal increased the contractile response to NE (1–10 nM) in sham controls (p < 0.05) but not in LPS-treated (p = 0.3) rats. However, endothelium removal did not significantly affect NE-induced vasoconstriction in aortic rings pretreated with propofol (10 μM) in sham controls (p = 0.07) and LPS-treated rats (p = 0.46). Thus, propofol modulated endothelium-dependent vascular reactivity in aortas from sham controls, but not from LPS-treated rats.

    NE evoked an initial fast phase of contractionin endothelium-intact aortic rings from sham rats, and this was significantly attenuated in endothelium-intact rings from LPS-treated rats (p < 0.05, Fig. 3A). Preincubation of aortic rings with 10 μM propofol significantly decreased the initial responses to NE in sham controls (p = 0.01, Fig. 3A), but not in LPS-treated rats. However, the S phase of contraction to NE was not significantly attenuated in aortas from LPS-treated rats when compared to sham controls (p = 0.15, Fig. 3B). Preincubation of aortic rings with 10 μM propofol significantly decreased the slow tonic responses in both sham controls (p = 0.03) and LPS-treated rats (p = 0.01; Fig. 3B).

    F3-5
    Fig. 3:
    Effects of propofol on extracellular calcium influx and intracellular store release induced by norepinephrine (NE). The fast initial phase (F phase) of NE-induced aortic contraction in Ca2+-free solution depends on a common intracellular Ca2+ store and the slow tonic phase (S phase) of NE-induced contraction depends on Ca2+ influx in aortic rings from sham and lipopolysaccharide (LPS)-treated rats. Values are mean ± SEM for n = 8 animals per group.*p < 0.05, pretreatment with versus without propofol; #p < 0.05, LPS-treated versus sham group.

    Cumulative doses of propofol evoked a concentration-dependent relaxation in endothelium-intact and -denuded rings from sham (Fig. 4A) and LPS-treated rats (Fig. 4B). Endothelium removal significantly decreased the relaxation response to propofol in aortic rings from sham rats (p < 0.01) but not from LPS rats (p = 0.158). This suggests that the aortic relaxation response to propofol was endothelium-dependent in sham rats, but endothelium-independent in LPS rats. In the presence of either L-NAME or ODQ, the propofol-induced vasodilation in aortas from sham controls and LPS-treated rats was reduced (p < 0.05, Fig. 5), suggesting that propofol-induced relaxation was, at least in part, via the NO–cGMP pathway. However, propofol-induced vasodilation in aortas from sham and LPS-treated rats was not significantly affected by the presence of TEA (Fig. 5).

    F4-5
    Fig. 4:
    Concentration–response curves for propofol in sham and lipopolysaccharide (LPS)-treated rat aortic rings with (+E) or without (–E) endothelium. Rings were precontracted using norepinephrine (NE). Relaxation is expressed as the percentage response to the initial contraction induced by NE. Values are mean ± SEM for n = 8 animals per group. †p < 0.01, with versus without endothelium.
    F5-5
    Fig. 5:
    Effects of Nω-nitro-l-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and tetraethylammonium (TEA) on propofol-induced relaxation in aortic rings from sham and lipopolysaccharide (LPS)-treated rats. For rings precontracted with norepinephrine (NE), relaxation induced by propofol (10 μM) was examined in the presence and absence of L-NAME (300 μM), ODQ (1 μM), or TEA (1 mM).Relaxation is expressed as the percentage response to the initial contraction induced by NE. Values are mean ± SEM for n = 6 animals per group. *p < 0.05, pretreatment with versus without inhibitors.

    4. Discussion

    This study provides a number of interesting observations. First, propofol modulated vascular reactivity in aortas from LPS-treated rats. Propofol decreased the magnitude of NE-induced vasoconstriction in these vessels compared with those from sham controls. Similar findings were reported by Grissom and colleagues with respect to halothane (an inhalation anesthetic agent) in phenylephrine-contracted aortic strips from LPS-treated rats,22 suggesting that the contractile response of the aorta during LPS-induced septic shock is more sensitive to the effects of anesthetic agents compared to normal aorta. Second, our study shows that preincubation with propofol can decrease vascular reactivity in LPS-treated rats during NE contraction, largely via blockade of the extracellular calcium influx, but apparently not via blockade of intracellular calcium release. In addition, propofol-induced relaxation partly involved the NO–cGMP pathway, but not K+ channel activation, in aortas isolated from both sham controls and LPS-treated rats.

    Several changes in vascular responses causing abnormal reactivity have been demonstrated in LPS-treated rats, and may help to explain the difference in propofol effects between LPS-treated and sham rats. These changes include lower responsiveness to receptor agonists, which may result from overproduction of vasodilators under pathophysiological conditions.1,23,24 Previous studies have demonstrated that the vascular hyporeactivity seen in endotoxic shock reflects anoverexpression of iNOS and abnormal activation of K+ channels, in particular the large-conductance Ca2+-activated K+ (BKCa)-channel, ATP-sensitive K+ (KATP)-channel, and Na+-K+ pump.24–26 In the present study, preincubation with propofol reduced the sensitivity of NE-induced vasoconstriction in aorta more effectively for LPS-treated rats than for sham controls. This effect was not significantly altered by the endothelium. These findings suggest that the modulatory effect of propofol against NE-induced vasoconstriction in LPS-treated rats may mainly involve an effect on smooth muscle.

    The vascular contraction induced by NE reflects intracellular calcium elevation, mainly due to calcium release from the sarcolemma reticulum (SR) and increased extracellular calcium influx.20 Bolton19 and Van Breemen and co-workers21 independently suggested that NE elicits Ca2+ release from the SR to cause contraction (F phase), then opens receptor-operated Ca2+ channels, leading to Ca2+ influx and sustained contraction (S phase).20 It has been shown that propofol can decrease Ca2+ influx in smooth muscle through either voltage-gated Ca2+ channels or/and receptor-mediated channels, depending on which is predominantly present.15,16 In the present study, preincubation of aorta with propofol suppressed both the initial and the sustained contraction to NE. However, propofol only suppressed the slow and sustained, but not the fast initial, contractions in aorta from LPS-treated rats. Thus, the effect of propofol may predominantly involve inhibition of the extracellular Ca2+ influx in LPS-treated rats, while it reduces both intracellular Ca2+ release and extracellular Ca2+ influx in sham controls. It has been observed that the intracellular Ca2+ concentration can be decreased by NO when mice aortic segments were contracted with phenylephrine.27 Therefore, propofol may modulate Ca2+ movement in rat aortic rings through NO.

    In the current study, propofol induced endothelium-dependent vasodilation in aortic rings from sham rats, which may have partly involved the NO–cGMP pathway. Similar results have been observed in pulmonary and coronary artery rings, showing that propofol-induced relaxation partly depends on the endothelium.28,29 In addition, some reports have proposed that propofol-induced relaxation reflects stimulation of NO release from endothelial cells,13,29,30 and that propofol-induced hyperpolarization reflects activation of K+ channels.31,32 By contrast, other reports suggest that propofol relaxes arteries in an endothelium-independent manner.11,15,16 In this study, we found that propofol induced comparable relaxation in aortas from LPS-treated rats with and without endothelium, and this vasodilation was significantly attenuated byinhibitors of NO synthase and of soluble guanylate cyclase. By contrast, the vasodilation was not significantly suppressed by non-specific K+ channel blockers. It has been shown that NO induces vascular relaxation via cGMP in vascular smooth muscle and is an important mediator of vascular tone during sepsis, as iNOS is upregulated during the late stage.33 Thus, we speculate that propofol-induced vasodilation in aortic rings from LPS-treated ratscould be modulated by smooth muscle-derived NO (via iNOS) and cGMP.

    These vascular effects of propofol occur at a clinically relevant concentration (10 μM), as the typical peak serum concentration of propofol during anesthesia ranges from 2 to 10 μg/mL (approx. 10–60 μM) in humans.34 However, the free drug concentration is markedly reduced by approximately 97% by protein binding.35 Therefore, direct extrapolation of our results to a clinical situation requires some caution.

    In conclusion, our results confirm that propofol differentially modulates vascular contractile responses to agonists in arterial tissues from LPS-treated and control rats. Suppression of NE-induced vascular contraction by propofol in the aorta was greaterin endotoxemia than in the normal condition, associated with a defect in extracellular Ca2+ influx and an increase in response to NO–cGMP in aortas from endotoxemic rats. These findings may further explain, at least in part, why there is a higher incidence of hypotension in critically ill patients when propofol is used to induce anesthesia.

    Acknowledgments

    This work was supported by grants from the National Science Council, Taiwan, ROC (grant number NSC 94-2320-B-345-002) and Taipei Veterans General Hospital, Taiwan, ROC (grant numbers 95DHA0100255 and 94DHA0100109).

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    Keywords:

    calcium influx; nitric oxide; propofol; sepsis; vascular smooth muscle

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