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Anesth Analg 2007;104:112-118
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000251200.14449.4a

ANESTHETIC PHARMACOLOGY

Propofol Increases Pulmonary Vascular Resistance During {alpha}-Adrenoreceptor Activation in Normal and Monocrotaline-Induced Pulmonary Hypertensive Rats

Mitsutaka Edanaga, MD*, Masayasu Nakayama, MD*, Noriaki Kanaya, MD{dagger}, Noritsugu Tohse, MD, PhD*, and Akiyoshi Namiki, MD, PhD*

From the Departments of *Anesthesiology and {dagger}Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.

Address correspondence and reprint requests to Mitsutaka Edanaga, MD, S1, W16, Chuo-ku, Sapporo, Hokkaido, 0608543, Japan. Address e-mail to edanaka{at}sapmed.ac.jp.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: Using isolated perfused lungs of normal or monocrotaline (MCT: 50 mg/kg)-induced pulmonary hypertensive rats, we tested the hypothesis that the pulmonary vascular effects of propofol depend on activation of the {alpha}-adrenoreceptor.

METHODS: Changes in pulmonary perfusion pressure induced by propofol (10–5 to 10–4 M) were measured with or without phenylephrine (10–6 M) pretreatment. Before phenylephrine administration, we assessed the effects of inhibitors of nitric oxide synthase (N{omega}-nitro-l-arginine methylester: 10–4 M), cyclooxygenase (indomethacin: 10–5 M), and protein kinase C inhibitor, bisindolylmaleimide I (10–6 M) or calphostin C (10–6 M).

RESULTS: Changes in pulmonary perfusion pressure by phenylephrine after pretreatment of nitric oxide synthase inhibitor and indomethacin in normal rats were significant (5 ± 3 and 7 ± 2 mm Hg), whereas that after pretreatment of bisindolylmaleimide I were small in MCT-rats (2 ± 1 mm Hg). Propofol caused pulmonary vasoconstriction after phenylephrine pretreatment both in normal and MCT-treated rats. In normal rats, the propofol-induced increase in pulmonary perfusion pressure after indomethacin pretreatment was slightly smaller than that in the non-pretreated lungs (P < 0.05). In MCT-treated rats, the propofol-induced increases in pulmonary perfusion pressure after both protein kinase C inhibitors were smaller than that in the non-pretreated lungs (P < 0.05).

CONCLUSIONS: Propofol may increase pulmonary vascular resistance during {alpha}-adrenoreceptor activation.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although the IV anesthetic propofol is generally recognized as a vasodilator in systemic circulation (1), there are conflicting reports concerning the pulmonary vascular effects of propofol (2–4).

Propofol is often used in patients whose pulmonary vasomotor tone is acutely increased because of sympathetic adrenoreceptor activation (e.g., cardiovascular surgery or postoperative sedation). However, little is known about the influence of vasomotor tone on the effect of propofol on pulmonary circulation.

To investigate this, using an in situ isolated perfused rat lung model, we tested the hypothesis that the effects of propofol on pulmonary vascular resistance depend on {alpha}-adrenoreceptor activation. We assessed the effects of propofol in a normal rat model as well as in a monocrotaline (MCT)-induced pulmonary hypertension (PH) rat model that caused a progressive increase in pulmonary vascular resistance.

It has been reported that {alpha}-adrenoreceptor-induced vasoconstriction is mediated by activation of protein kinase C (PKC) (5) and modulated nitric oxide (NO) (6) and prostacyclin (7). Thus, we investigated the roles of the NO pathway, cyclooxygenase pathway, and PKC signal pathway on the effect of propofol on pulmonary vascular resistance.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Isolated Ventilated Perfused Rat Lung Preparation
All experimental procedures and protocols were approved by Sapporo Medical University Animal Care and Use Committee. Male Sprague Dawley rats (6 wk old), weighting 150–200 g, were subcutaneously given a vehicle (control group) or MCT (60 mg/kg; Sigma Chemical) (PH group) (8). At 21 days after injection, each rat was anesthetized with 50 mg/kg IP injection of pentobarbital sodium, and the trachea was cannulated with a polyethylene tube. The lungs were ventilated with a gas mixture of 21% O2, 5% CO2 and 74% N2 using a respirator (model SN-480–7, Sinano Factory, Tokyo, Japan) at 60 breaths/min and at an inspiratory pressure of 9 cm H2O. In the preliminary experiments, we confirmed that the perfusate Po2 was from 100 to 150 mm Hg, and that the perfusate Pco2 was from 35 to 40 mm Hg. The lungs and the heart were exposed by median sternotomy. After heparinization (300 U), an incision was made in the right ventricle and a polyethylene tube (2.33 mm diameter) was inserted into the main pulmonary artery. A suture (0.35–0.40 mm diameter) was placed around the pulmonary artery and the aorta to secure the tube and prevent systemic blood flow. A polyethylene tube (2.33 mm diameter) was inserted into the left atrium and secured with suture (0.5–0.599 mm diameter) around the ventricles. The pulmonary circulation was first perfused in a nonrecirculating manner with bovine serum albumin (Wako Pure Chemical Industries, Osaka, Japan) dissolved in physiological salt solution until the effluent was clear. Then, the lungs were perfused at constant flow of 7 mL/min with a recirculated volume of 50 mL using a Perista Pump (Atto CO, Tokyo, Japan). The physiological salt solution contained 110 mM NaCl, 4 mM KCl, 1 mM MgSO4, 1 mM KH2PO4, 24 mM NaHCO3, 7 mM glucose, 1.8 mM CaCl2, and 0.026 mM EDTA. Perfusate temperature was maintained at 37°C, and pH was kept between 7.35 and 7.45 by addition of HCl or NaOH as needed. Pulmonary artery pressure (PAP) and left atrium pressure (LAP) were monitored continuously using pressure transducers placed at the level of the right atrium and connected to a Pressure Monitor 4 (Living Systems Instrumentation, Burling, VT). All data were recorded on a computer (Machintosh).

Pulmonary perfusion pressure was calculated by PAP minus LAP. The LAP was maintained at 0 mm Hg by adjusting the height of the reservoir. Because pump flow was held constant, changes in pulmonary perfusion pressure reflected changes in pulmonary vascular resistance. The lungs were allowed 15 min to equilibrate before the experiments were begun. The various drugs used were injected in a bolus and added to the reservoir to the calculated circulating concentration. Changes in pulmonary perfusion pressure with each drug administration were compared after the response to each preceding concentration had reached a steady state.

Propofol inj, Maruishi® (B. Braun, Melsungen, Germany) and 10% Intralipid® (Fresenius Kabi AB, Uppsala, Sweden) were used as vehicle for propofol. The formulations of 10 mg/mL of propofol are in a 10% fat emulsion consisting of long-chain triglycerides and medium-chain triglycerides.

In the preliminary study, we confirmed that isolated perfused lungs of control and PH rats without any interventions showed stable pulmonary perfusion pressure over the time of the longest experiments. Moreover, we confirmed that increases in pulmonary perfusion pressure by phenylephrine and propofol did not change over the same time period.

In other rats (normal rat: n = 1, MCT rat: n = 1), to confirm pathological changes induced by MCT, the isolated lungs were fixed in 10% neutral buffered formalin and embedded in paraffin. Each section was stained with hematoxylin and eosin.

Experimental Protocols
Protocol 1: Effects of Propofol on Pulmonary Perfusion Pressure at Baseline and During {alpha}-Adrenoreceptor Activation
At baseline conditions, changes in pulmonary perfusion pressure were assessed during cumulative administration of propofol (10–5, 3 x 10–5, and 10–4 M) in the control group (n = 6) and PH group (n = 5). Using different rats (control group: n = 8, PH group: n = 8), the same protocol was repeated after 10–6 M of phenylephrine administration.

Protocol 2: Effects of NO Synthase Inhibition or Cyclooxygenase Pathway Inhibition on Propofol-Induced Pulmonary Vasoconstriction During {alpha}-Adrenoreceptor Activation
To assess the contribution of the NO pathway or cyclooxygenase pathway to the propofol-induced change in pulmonary perfusion pressure, similar experiments were performed during NO synthase inhibitor or cyclooxygenase inhibitor. Phenylephrine was administrated after pretreated with N{omega}-nitro-l-arginine methylester (L-NAME: 10–4 M) or indomethacin (10–5 M). Propofol (10–5 to 10–4 M) was administrated cumulatively to the perfusion solution in the control group (L-NAME: n = 5, indomethacin: n = 6) and PH group (L-NAME: n = 6, indomethacin: n = 7).

Protocol 3: Effects of PKC Pathway Inhibition on Propofol-Induced Pulmonary Vasoconstriction During {alpha}-Adrenoreceptor Activation
To assess the contribution of myofilament Ca2+ sensitivity of the pulmonary vascular smooth muscle, similar experiments were performed during pretreatment with bisindolylmaleimide I (10–6 M), a highly selective PKC inhibitor (9), or calphostin C (10–6 M), a specific inhibitor of PKC that inhibits both phorbol ester binding and phosphotransferase activity of PKC (5). Phenylephrine was administrated after bisindolylmaleimide I or calphstine C treatment. Propofol was administrated cumulatively to the perfusion solution in the control group (bisindolylmaleimide I: n = 6, calphostin C: n = 5) and PH group (bisindolylmaleimide I: n = 7, calphostin C: n = 5).

Statistical Analysis and Data Presentation
All values are expressed as means ± sd. Unpaired Student’s t-test was used to assess the effects of phenylephrine on pulmonary perfusion pressure after pretreatment with inhibitors. One-way analysis of variance with Bonferroni-Dunn post hoc test was used to assess the effects of propofol on pulmonary perfusion pressure within each group. Two-way analysis of variance was used to assess the effects of propofol on pulmonary perfusion pressure between groups. Differences were considered statistically significant at a value of P < 0.05.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Morphological changes in the pulmonary artery in both groups are shown in Figure 1. Compared with that of the normal rat lung, bodies and nuclei of smooth muscle cells appeared to be swollen, and thickening of media was observed in MCT-treated rat lung, PH group, as described previously (8).


Figure 123
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  		Figure 1. Microphotographs of sections stained with hematoxylin and eosin in pulmonary arteries of lungs isolated from a normal rat (n = 1) (A) and from a monocrotaline (MCT)-treated rat (n = 1) (B). The arrow shows the pulmonary artery in both groups. Endothelial cells were located along the inner surface. And smooth muscle cells were located in the medial layer.

 

Protocol 1: Effects of Propofol on Pulmonary Perfusion Pressure at Baseline and During {alpha}-Adrenoreceptor Activation
The baseline pulmonary perfusion pressure in the PH group was more than that in the control group (Table 1). Phenylephrine caused pulmonary vasoconstriction in both groups (Table 2). Propofol had no effect on the baseline pulmonary perfusion pressure in both the control group and the PH group (Fig. 2A). After phenylephrine pretreatment, propofol caused pulmonary vasoconstriction in both groups (Figs. 2B and 3). Pulmonary perfusion pressure did not change significantly after administration of a vehicle control (Intralipid).


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  		Table 1. Baseline Pulmonary Perfusion Pressure Before Pretreatment with Inhibitors and Propofol

 

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  		Table 2. The Phenylephrine-Induced Increases in Pulmonary Perfusion Pressure After Pretreatment with Inhibitors and Before Propofol Administration

 

Figure 223
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  		Figure 2. Effects of propofol on pulmonary perfusion pressure at baseline (A) and during {alpha}-adrenoreceptor activation by phenylephrine (B). PH = pulmonary hypertension, PE = phenylephrine, PAP = pulmonary artery pressure, LAP = left atrium pressure. Pulmonary perfusion pressure = PAP – LAP. Values are expressed as mean ± sd; *P < 0.05 versus control group; {dagger}P < 0.05 versus after PE. The number of each group is as follows: (A) control group: n = 6, PH group: n = 5, (B) control group: n = 8, PH group: n = 8.

 


Figure 323
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  		Figure 3. Increases in pulmonary perfusion pressure induced by propofol. PH = pulmonary hypertension, PE = phenylephrine, PAP = pulmonary artery pressure, LAP = left atrium pressure. Pulmonary perfusion pressure = PAP – LAP. Values are expressed as mean ± sd; *P < 0.05 versus control group; {dagger}P < 0.05 versus after PE. The number of each group is as follows: control group: n = 8, PH group: n = 8. Graph 3 shows the degree of increase of absolute PAP – LAP values in Graph 2.

 
Protocol 2: Effects of NO Synthase Inhibition or Cyclooxygenase Pathway Inhibition on Propofol-Induced Pulmonary Vasoconstriction During {alpha}-Adrenoreceptor Activation
Neither L-NAME nor indomethacin had an effect on baseline pulmonary perfusion pressure either in the control or the PH group. The phenylephrine-induced increase in pulmonary perfusion pressure after L-NAME or indomethacin pretreatment in the control group was slightly more than that in the nontreated lungs (Table 2). In the PH group, a propofol-induced increase in pulmonary perfusion pressure after L-NAME pretreatment was more than that in the non-pretreated lungs (Fig. 4B). In contrast, the propofol-induced increase in pulmonary perfusion pressure after indomethacin pretreatment in the control group (Fig. 5A), but not in the PH group (Fig. 5B), was slightly less than in the nontreated lungs.


Figure 423
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  		Figure 4. Effects of N{omega}-nitro-l-arginine methyleste (L-NAME) on propofol-induced pulmonary vasoconstriction in the control group (A) and PH group (B). PH = pulmonary hypertension, PE = phenylephrine, PAP = pulmonary artery pressure, LAP = left atrium pressure. Pulmonary perfusion pressure = PAP – LAP. Values are expressed as mean ± sd; *P < 0.05 versus no treatment; {dagger}P < 0.05 versus after PE. (A) No treatment: n = 8, L-NAME: n = 5; (B) no treatment: n = 8, L-NAME: n = 6.

 

Figure 523
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  		Figure 5. Effects of indomethacin on propofol-induced pulmonary vasoconstriction in the control group (A) and PH group (B). PH = pulmonary hypertension, PE = phenylephrine, PAP = pulmonary artery pressure, LAP = left atrium pressure. Pulmonary perfusion pressure = PAP – LAP. Values are expressed as mean ± sd; *P < 0.05 versus no treatment; {dagger}P < 0.05 versus after PE. (A) No treatment: n = 8, indomethacin: n = 6; (B) no treatment: n = 8, indomethacin: n = 7.

 

Protocol 3: Effects of PKC Pathway Inhibition on Propofol-Induced Pulmonary Vasoconstriction During {alpha}-Adrenoreceptor Activation
The phenylephrine-induced increase in pulmonary perfusion pressure after bisindolylmaleimide I pretreatment in the PH group, or after calphostin C pretreatment in the control group (Table 2), was less than in the non-pretreated lungs. The propofol-induced increases in pulmonary perfusion pressure after both PKC inhibitors in the PH group (Fig. 6B), but not in the control group (Fig. 6A), were less than in the non-pretreated lungs.


Figure 623
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  		Figure 6. Effects of protein kinase C (PKC) inhibition on propofol-induced pulmonary vasoconstriction in the control group (A) and PH group (B). PH = pulmonary hypertension, PE = phenylephrine, PAP = pulmonary artery pressure, LAP = left atrium pressure. Pulmonary perfusion pressure = PAP – LAP. Values are expressed as mean ± sd; *P < 0.05 versus no treatment; {dagger}P < 0.05 versus after PE. (A) No treatment: n = 8, bisindolylmaleimede I: n = 6, calphostin C: n = 5; (B) no treatment: n = 8, bisindolylmaleimede I: n = 7, calphostin C: n = 5.

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study demonstrated that 1) propofol had no effect on baseline pulmonary perfusion pressure but caused pulmonary vasoconstriction during {alpha}-adrenoreceptor activation by phenylephrine in both normal and MCT-treated pulmonary hypertensive rats and that 2) propofol-induced pulmonary vasoconstriction may be partially mediated by cyclooxygenase pathway inhibition in normal rats and PKC activation in MCT-treated rats.

We found that propofol had no effect on baseline pulmonary perfusion pressure in normal rat lungs. Nakayama and Murray, and Toullec et al. (10,11) found no pulmonary vasodilating effects of general anesthetics and concluded that normal pulmonary circulation has little vasomotor tone. Therefore, because pulmonary circulation is close to being maximally vasodilated at baseline, a propofol-induced vasodilator effect would not be expected.

MCT administration resulted in a significant increase in pulmonary perfusion pressure, indicating an increase in pulmonary vascular resistance. However, propofol again had no effect on baseline pulmonary perfusion pressure in MCT-treated rat lungs. MCT-induced PH is pathologically associated with vascular remodeling such as medial hypertrophy and increase in connective tissue (8). Therefore, it was not surprising that propofol did not exert a pulmonary vasodilator influence on MCT-induced hypertensive pulmonary circulation in the current study.

In contrast, propofol caused pulmonary vasoconstriction after phenylephrine pretreatment. This finding is consistent with the results of a study by Kondo et al. (12) using chronically instrumented dogs, demonstrating that propofol had a vasoconstrictive effect on pulmonary circulation after phenylephrine- or U46619-induced preconstruction. These results suggest that propofol may have a pulmonary vasoconstrictive effect during {alpha}-adrenoreceptor activation by phenylephrine (10–6 M).

To investigate the mechanism responsible for this effect of propofol, we tested the hypothesis that propofol attenuates the modulating influence of endogenous pulmonary vasodilator products during {alpha}-adrenoreceptor-mediated vasoconstriction. The phenylephrine-induced increase in pulmonary perfusion pressure after L-NAME pretreatment was more than that in the nontreated lungs, suggesting that the NO pathway may modulate the vasoconstrictor responses to phenylephrine. The effect of propofol on the NO pathway is controversial (13,14). Park et al. (13) showed that propofol induced vasodilation in an endothelium-dependent manner in rat distal coronary arteries. In contrast, Chang and Davis (14) showed that the vasodilation induced by propofol was endothelium-independent and may be due to blockade of influx of CA. In our study, L-NAME did not inhibit the propofol-induced increase in pulmonary perfusion pressure. Therefore, the NO pathway is an unlikely contributor to the mechanism of propofol-induced pulmonary vasoconstriction.

We next tested the hypothesis that pulmonary vasoconstriction induced by propofol is caused by inhibition of cyclooxygenase pathway-mediated vasodilation. Activation of {alpha}-adrenoreceptors stimulates phospholipase C and phospholipase A2, resulting in an increase in the release of arachidonic acid (7), which is metabolized by cyclooxygenase to prostacyclin, thromboxane A2, and other prostaglandins. Among these products, prostacyclin is the major cyclooxygenase metabolite in vascular tissue (15). We confirmed this by the observation that the phenylephrine-induced increase in pulmonary perfusion pressure after indomethacin pretreatment in the control group was more than that in the nontreated lungs. In contrast to L-NAME, the propofol-induced increase in pulmonary perfusion pressure after indomethacin pretreatment was slightly smaller than that in nontreated rat lungs. The results suggest that the pulmonary vasoconstrictive effect of propofol may be partially mediated by cyclooxygenase pathway inhibition. In canine pulmonary arterial rings, Ogawa et al. (2) found that propofol enhanced phenylephrine-induced pulmonary vasoconstriction by inhibiting the production of prostacyclin by cyclooxygenase. The mechanism by which propofol inhibits the cyclooxygenase pathway might be its properties of antioxidant action or its action as a free-radical scavenger (16). Because cyclooxygenase is an enzyme that adds oxygen to arachidonic acid, an antioxidant or free-radical scavenger could inhibit cyclooxygenase activity (17).

The MCT-induced PH model is characterized by a number of abnormalities in pulmonary structure, including endothelial injury, extension of smooth muscle into normally nonmusclarized arteries, and thickening of the pulmonary trunk (8). The phenylephrine-induced increase in pulmonary perfusion pressure after L-NAME pretreatment in the PH group was significantly more than that in the control group, suggesting that the NO-signal pathway might have been augmented in MCT-treated rats. This observation agrees with results of studies showing NO activity in MCT-induced hypertensive lung (18). However, neither indomethacin nor L-NAME had an effect on the propofol-induced increase in pulmonary perfusion pressure in MCT-treated rats. Therefore, we hypothesized that mechanisms other than the action of these modulators contributed to the response to propofol in MCT-treated rats.

{alpha}-Adrenoreceptor-mediated constriction in vascular smooth muscle results from increases in intracellular Ca2+ concentration and myofilament Ca2+ sensitivity of vascular smooth muscle cells (19). An increase in myofilament Ca2+ sensitivity via the PKC pathway has been suggested to play a role in vascular smooth muscle contraction. According to our results, propofol-induced increases in pulmonary perfusion pressure after both PKC inhibitor pretreatment were smaller than that in the nontreated lungs, suggesting that the pulmonary vasoconstrictive effect to propofol may be partially caused by PKC activation. There are conflicting results concerning the effects of propofol on myofilament Ca2+ sensitivity (20–22). Propofol was reported to decrease myofilament Ca2+ sensitivity in rat ventricular myocytes at a supraclinical concentration (20). In contrast, Nakae et al. (21) reported that propofol at a clinically relevant concentration increased myofilament Ca2+ sensitivity in isolated guinea pig hearts. Similarly, Tanaka et al. (22) demonstrated that, in canine pulmonary artery smooth muscle, propofol increases Ca2+ sensitivity through PKC activation. According to our results, propofol is likely to activate the PKC pathway resulting in vasoconstriction in the perfused rat lung model.

Despite propofol’s propensity to increase myofilament Ca2+ sensitivity, PKC inhibition had no effect on the propofol-induced increase in pulmonary perfusion pressure in the control group. Even if the PKC pathway is blocked by the PKC inhibitors, the cyclooxygenase pathway would exist in the normal rat. Therefore, it is suggested that the propofol-induced increase in pulmonary perfusion pressure may be due to cyclooxygenase pathway inhibition by propofol, and that PKC activation may have a relatively minor effect on the vasoconstrictive effect of propofol during {alpha}-adrenoreceptor activation in normal rats.

In the current study, propofol increased pulmonary vascular resistance during {alpha}-adrenoreceptor activation. Therefore, in patients whose pulmonary vascular resistance is acutely increased by sympathetic activation, administration of propofol could increase right ventricular afterload inducing right ventricular heart failure.

Although a solvent for propofol increases pulmonary vascular resistance (23), Intralipid had no effect on pulmonary perfusion pressure in the present study. We used commercially available 1% propofol inj. Maruishi, which is formulated in medium-chain triglyceride and long-chain triglyceride, Lipofundin®. Because Lipofundin is not currently available in Japan, Intralipid—a long-chain triglyceride fat emulsion (24)—was used to assess the effect of the vehicle for propofol. Because the elimination of medium-chain triglyceride- and long-chain triglyceride-enriched fat emulusions is reported to be faster than that of long-chain triglyceride emulsion, vehicle had little effect on pulmonary circulation in the present study.

In the present study, it was difficult to randomize the experimental groups because we lost many rats during MCT-induced PH. Moreover, some rats died because of the loss of vascular integrity with concomitant pulmonary edema during the protocol.

In the present study, we tested the effect of propofol on pulmonary circulation using pharmacological approaches. Thus, in further studies, we are planning to measure NO and prostacyclin production directly. Moreover, to confirm the effect of propofol on myofilamental Ca2+ sensitivity, it is necessary to measure the changes in intracellular Ca2+ concentration.

In summary, these data suggest that propofol may increase pulmonary vascular resistance during {alpha}-adrenoreceptor activation by phenylephrine (10–6 M). This pulmonary vasoconstrictive effect of propofol may be partially mediated by cyclooxygenase pathway inhibition in normal rats and by PKC activation in MCT-treated rats.


   Footnotes
 
Accepted for publication October 12, 2006.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Yamanoue T, Brum JM, Estafanous FG. Vasodilation and mechanism of action of propofol in porcine coronary artery. Anesthesiology 1994;81:443–51.[ISI][Medline]
  2. Ogawa K, Tanaka S, Murray PA. Propofol potentiates phenylephrine-induced contraction via cyclooxygenase inhibition in pulmonary artery smooth muscle. Anesthesiology 2001;94:833–9.[ISI][Medline]
  3. Claeys MA, Gepts E, Camu F. Haemodynamic changes during anaesthesia induced and maintained with propofol. Br J Anaesth 1988;60:3–9.[Abstract/Free Full Text]
  4. Rich GF, Roos CM, Anderson SM, et al. Direct effects of intravenous anesthetics on pulmonary vascular resistance in the isolated rat lung. Anesth Analg 1994;78:961–6.[Abstract/Free Full Text]
  5. Kaye AD, Nossaman BD, Ibrahim IN, et al. Influence of protein kinase C inhibitors on vasoconstrictor responses in the pulmonary vascular bed of cat and rat. Am J Physiol 1995;268:L532–8.
  6. Boer C, van der Linden PJ, Scheffer GJ, et al. RhoA/Rho kinase and nitric oxide modulate the agonist-induced pulmonary artery diameter response time. Am J Physiol Heart Circ Physiol 2002;282:H990–8.[Abstract/Free Full Text]
  7. LaBelle EF, Polyak E. Norepinephrine stimulates arachidonic acid release from vascular smooth muscle via activation of cPLA2. Am J Physiol 1998;274:C1129–37.
  8. Nakazawa H, Hori M, Murata T, et al. Contribution of chloride channel activation to the elevated muscular tone of the pulmonary artery in monocrotaline-induced pulmonary hypertensive rats. Jpn J Pharmacol 2001;86:310–15.[Medline]
  9. Lennon PF, Murray PA. Pulmonary vascular effects of isoflurane anesthesia after left lung autotransplantation in chronically instrumented dogs. Anesthesiology 1996;85:592–9.[ISI][Medline]
  10. Nakayama M, Murray PA. Propofol selectively attenuates endothelium-dependent pulmonary vasodilation in chronically instrumented dogs. Anesthesiology 1999;91:760–71.[ISI][Medline]
  11. Toullec D, Pianetti P, Coste H, et al. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J Biol Chem 1991;266:15771–81.[Abstract/Free Full Text]
  12. Kondo U, Kim SO, Nakayama M, Murray PA. Pulmonary vascular effects of propofol at baseline, during elevated vasomotor tone, and in response to sympathetic {alpha}- and ß-adrenoreceptor activation. Anesthesiology 2001;94:815–23.[ISI][Medline]
  13. Park KW, Dai HB, Lowenstein E, Sellke FW. Propofol-associated dilation of rat distal coronary arteries is mediated by multiple substances, including endothelium-derived nitric oxide. Anesth Analg 1995;81:1191–6.[Abstract]
  14. Chang KS, 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]
  15. Smith WL. The eicosanoids and their biochemical mechanisms of action. Biochem J 1989;259:315–24.[ISI][Medline]
  16. Bao YP, Williamson G, Tew D, et al. Antioxidant effects of propofol in human hepatic microsomes: concentration effects and clinical relevance. Br J Anaesth 1998;81:584–9.[Abstract/Free Full Text]
  17. Agradi E, Petroni A, Socini A, Galli C. In vitro effects of synthetic antioxidants and vitamin E on arachidonic acid metabolism and thromboxane formation in human platelets and on platelet aggregation. Prostaglandins 1981;22:255–66.[ISI][Medline]
  18. Tyler RC, Muramatsu M, Abman SH, et al. Variable expression of endothelial NO synthase in three forms of rat pulmonary hypertension. Am J Physiol 1999;276:L297–L303.
  19. Damron DS, Kanaya N, Homma Y, et al. Role of PKC, tyrosine kinases, and Rho kinase in {alpha}-adrenoreceptor-mediated PASM contraction. Am J Physiol Lung Cell Mol Physiol 2002;283:L1051–64.[Abstract/Free Full Text]
  20. Kanaya N, Murray PA, Damron DS. Propofol and ketamine only inhibit intracellular Ca2+ transients and contraction in rat ventricular myocytes at supraclinical concentrations. Anesthesiology 1998;88:781–91.[ISI][Medline]
  21. Nakae Y, Fujita S, Namiki A. Propofol inhibits Ca(2+) transients but not contraction in intact beating guinea pig hearts. Anesth Analg 2000;90:1286–92.[Abstract/Free Full Text]
  22. Tanaka S, Kanaya N, Homma Y, et al. Propofol increases pulmonary artery smooth muscle myofilament calcium sensitivity: role of protein kinase C. Anesthesiology 2002;97:1557–66.[ISI][Medline]
  23. Ilkiw R, Maruyama K, Rabinovitch M. Intralipid effect on normal and hypoxic remodeled rat pulmonary vasculature. Am J Physiol 1988;255:H1499–508.
  24. Theilen HJ, Adam S, Albrecht MD, Ragaller M. Propofol in a medium- and long-chain triglyceride emulsion: pharmacological characteristics and potential beneficial effects. Anesth Analg 2002;95:923–9.[Abstract/Free Full Text]




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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