Anesth Analg 2004;99:97-102
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000118107.62304.25
ANESTHETIC PHARMACOLOGY
Bupivacaine Inhibits Thromboxane A2-Induced Vasoconstriction in Rat Thoracic Aorta
Klaus Hahnenkamp, MD*,
Joke Nollet, MD
,
Danja Strümper, MD*,
Tobias Halene*,
Pia Rathman*,
Eike Mortier, MD PhD,
Hugo Van Aken, MD PhD*,
Joerg Knapp, MD PhD
,
Marcel E. Durieux, MD PhD*, and
Christian W. Hoenemann, MD
*Department of Anesthesiology and Intensive Care, University Hospital, Münster, Germany, the
Department of Anesthesiology, University Hospital, Gent, Belgium, the
Institute of Pharmacology and Toxicology, Westfälische-Wilhelms-Universität, Münster, Germany, and the
Department of Anesthesiology, Marienhospital, Vechta, Germany
Address correspondence to Marcel E. Durieux, MD, PhD, Department of Anesthesiology, University of Virginia, PO Box 800710, Charlottesville, VA 22908–0710. Address email to durieux{at}virginia.edu
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Abstract
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Plasma levels of thromboxane A2 (TXA2), an inflammatory mediator inducing platelet aggregation, bronchoconstriction, and vasoconstriction, are increased in the perioperative period. A major role in the pathogenesis of perioperative thromboembolic and ischemic syndromes is attributed to this prostanoid. Local anesthetics (LA) inhibit signaling of TXA2 receptors expressed in cell models. Therefore, we hypothesized that LA may inhibit vasoconstriction induced by the TXA2 analog U46619 in rat thoracic aorta. Rings (3-mm length) of the rat thoracic aorta were mounted in organ baths and isometric contractile force was measured. Rings, with or without endothelium, were incubated for 60 min in bupivacaine (10–6 or 10–5 M) or Krebs-Henseleit solution (control group) and subsequently exposed to cumulative concentrations of U46619 (10–10 to 10–6 M). The reversibility of the TXA2-induced vasoconstriction by bupivacaine was also studied. Pretreatment of rings with bupivacaine concentration-dependently diminished TXA2-induced contraction in rat aortic rings. We found no significant differences in relaxing effect of bupivacaine between rings with and without endothelium. Contraction in rings established with U46619 could not be reversed by cumulative concentrations of bupivacaine. Bupivacaine inhibited carbachol-induced vascular relaxation. This study provides experimental evidence that bupivacaine is an endothelium-independent inhibitor of TXA2-induced vasoconstriction of rat thoracic aorta.
IMPLICATIONS: Bupivacaine inhibits thromboxane A2-induced vasoconstriction in rat thoracic aorta rings in an endothelium-independent manner.
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Introduction
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The eicosanoid thromboxane A2 (TXA2) is released mainly from activated platelets and vascular smooth muscle cells, where its synthesis from the membrane phospholipid-derived fatty acid arachidonic acid is catalyzed by the enzymes cyclooxygenase and TXA2 synthase (1). TXA2 is one of the most potent vasoconstricting (2), bronchoconstricting (3), and platelet-stimulating (2) agents known. Therefore, it is considered to be of importance in the development of thrombotic and ischemic syndromes (1). Plasma concentrations of TXA2 and its stable metabolite, thromboxane B2, are increased after orthopedic (4), cardiac (5), thoracic, abdominal (6), vascular (7), and obstetric surgery (8). Even immediately after skin incision, increased concentrations of TXA2 and its metabolite are found (9).
Regional anesthesia protects against postoperative ischemic and thrombotic events (10), and some of these beneficial actions appear to result from the blood levels of local anesthetics (LA) attained during epidural anesthesia, rather than from neuronal blockade per se (11). Interference with TXA2 signaling might explain part of these effects of LA. If so, one would expect LA to interfere with TXA2-mediated vasoconstriction and/or platelet aggregation, as these are the main mechanisms underlying thrombotic and ischemic events. In previous studies from our laboratory, we demonstrated that LA interfere with the signaling of TXA2 receptors expressed in animal (12) and human cell models, as well as with TXA2-mediated early platelet aggregation (13). In contrast, the effects of LA on TXA2-mediated vascular constriction have not been investigated in detail. We therefore studied the actions of bupivacaine, the LA used most commonly for postoperative epidural analgesia, on TXA2-induced vascular smooth muscle contraction. In addition, we investigated whether any effect of bupivacaine is dependent on the presence of functional endothelium and if the compound is able to reverse preexisting constriction.
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Methods
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The protocol was approved by the local Animal Care and Use Committee. Preparation of vessels was undertaken as described elsewhere (14). Briefly, 15 male Wistar rats (300–350 g) were killed by cervical dislocation and exsanguination. The descending thoracic aorta was removed and transferred immediately into chilled Krebs-Henseleit solution (KHS, containing in mmol/L: NaCl 118.3, KCl 4.7, CaCl2 · 2, MgSO4 · 7, KH2PO4 1.2, NaHCO3 25, glucose 11.1, ethylenedinitrilotetraacetic acid [EDTA] 0.026). The aortas were cleaned from adherent connective tissue and fat using a microscope, and cut into rings of an approximate length of 3 ± 0.5 mm. The number of rings studied was 79. In 37 rings the endothelium was removed by gently rinsing them 2 times with Triton X-100 (1%), followed by several rinses with KHS. Each data point was obtained from at least 6 different rings from 6 different rats, and each ring was used to obtain concentration-response data for U46619 in the presence of only one of the test compounds (KHS as control, bupivacaine 10–6 or 10–5 M). The effects of the compounds were studied at the same time on separate rings obtained from the same rat.
The rings were suspended on 2 wire hooks in organ chambers filled with 10 mL KHS (37°C, pH 7.40) aerated with a gas mixture of 95% oxygen and 5% CO2. The upper hook was connected to a force transducer (Tim 1020; Föhr, Engelsbach, Germany) and changes in isometric force were recorded and printed (We-Ka-graph WK-480 R; Föhr). During the first 60–90 min rings were precontracted to a tension of 15 mN and allowed to equilibrate. The rings were then contracted twice with 75 mM KCl for 20 min. Subsequently, the KCl was rinsed and the rings were allowed to equilibrate again.
To determine the presence of functional endothelium, the rings were contracted with norepinephrine (NE, 10–7 M) for 10 min, followed by the application of carbachol (CB, 10–6 M), an endothelium-dependent relaxing factor, for another 10 min. The presence of an undamaged endothelium was confirmed by a relaxation of at least 70% in response to CB. Rings not treated with Triton X-100 were expected to have normally functional endothelium. If such rings showed <70% of relaxation of the maximal NE-effect, they were considered to have a partially damaged endothelium and discarded. Conversely, rings treated with Triton X-100 1% were supposed to be free of endothelium and show no or minor relaxation to CB. If such rings responded to CB with relaxation they were excluded from further experiments. After this test for endothelial function, rings were rinsed several times and allowed to equilibrate for 30 min before experimentation.
U46619 (9,11-dideoxy-9
,11-epoxymethanoprosta-glandin F2) was obtained from Calbiochem Chemicals (Bad Soden, Germany), bupivacaine was obtained from AstraZeneca (Sodertalje, Sweden); NE and CB and all other chemicals used were obtained from Sigma (Diesenhofen, Germany). U46619 was obtained as a solution in methylacetate (10 mg/mL) and subsequently diluted to different concentrations with KHS. Bupivacaine was diluted in KHS just before use. NE and CB were diluted in freshly prepared L-(+) ascorbinic acid 0.1% and protected from light. The concentrations of the drugs are expressed as final concentrations in the bath solution unless stated otherwise.
Results are expressed as mean ± SEM. Differences between treatment groups were analyzed using Student’s t-test for paired and unpaired observations or analysis of variance followed by Tukey’s test, as appropriate. A P value <0.05 was considered significant. Concentration-response curves were fit to the following logistic function, derived from the Hill equation:
where ymax and ymin are the maximum and minimum response obtained, n is the Hill coefficient and x50 is the half-maximal effect concentration (EC50 for agonist).
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Results
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We first determined the concentration-response relationship for the TXA2 analog U46619 in our model. Cumulative concentrations of U46619 (10–10 M, 3 x 10–10 M, 10–9 M, 3 x 10–9 M, 10–8 M, 3 x 10–8 M, 10–7 M, 3 x 10–7M, 10–6 M) were added to rings with (n = 13) and without (n = 15) endothelium. The response to each concentration of U46619 was monitored until it produced a maximal, stable tension before the next concentration was added. U46619 contracted rat aortic rings in a concentration-dependent manner (Fig. 1). The smallest concentration used (10–10 M), similar to baseline concentrations as determined in vivo (15), did not alter the resting-tension of 15 mN. At concentrations larger than 10–6 M no further increase in contractile force was obtained. Calculated EC50 of U46619 for the induced force of contraction was 9.4 x 10–9 ± 8.3 x 10–10 M and 1.1 x 10–8 ± 3.9 x 10–9 M in rings with and without endothelium, respectively. These values were not significantly different (P = 0.7). Our results are comparable to data in the same model as reported by Dorn and Becker (16). The maximal force of contraction, obtained with 10–6 M U46619, was 66.02 ± 1.03 mN and 66.34 ± 4.68 mN in rings with and without endothelium, respectively.
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Figure 1. Cumulative concentration-response curve for U46619-induced contractions in rings with (A) or without (B) endothelium. EC50s are: 9.4 x 10–9 M (± 8.3 x 10–10 M) and 1.1 x 10–8 M (± 3.9 x 10–9 M), respectively, in rings with (A) or without (B) endothelium. The corresponding maximal contraction forces in response to U46619 (10–6 M) are 66.02 (± 1.03) mN and 66.34 (± 4.68) mN, respectively.
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We next determined the effect of bupivacaine on aortic rings in the absence of agonists. We exposed rings (5 with and 4 without endothelium) to cumulative concentrations of bupivacaine (10–8 – 10–5 M). No increase in tension above the basal level of 15 mN was observed in the concentration-range from 10–8 to 10–6 M bupivacaine. Some rings (3 of 5 with and 2 of 4 without endothelium) showed a slight contraction to bupivacaine 10–5 M (mean increase from 15 mN to 17.8 ± 1.2 mN, P = 0.02, and to 18.3 ± 1.0 mN, P = 0.04 respectively) and all responded to bupivacaine 10–4 M (mean increase from 15 mN to 24 ± 3.5 mN, P = 0.02, and 22.3 ± 2.5 mN, P = 0.04) (Fig. 2). For subsequent determination of the effect of bupivacaine on U46619-induced contraction, bupivacaine concentrations of 10–6 and 10–5 M were used, as these concentrations are of clinical relevance (17) and had no (10–6 M) or only minor (10–5 M) direct effect on the rings.
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Figure 2. Direct effect of bupivacaine on aortic rings with or without endothelium. No increase in tension above the basal level of 15 mN was observed in the concentration range from 10–8 to 10–6 M bupivacaine in rings with (endo+) or rings without (endo-) endothelium. Rings showed a slight concentration dependent and endothelium-independent contraction to bupivacaine 10–5 M and to bupivacaine 10–4 M.
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We then studied the effects of pretreatment with bupivacaine on U46619-induced contraction. Concentration- contraction curves to U46619 were cumulatively obtained in rings from 10 rats in the absence or presence of bupivacaine. We tested 2 concentrations of bupivacaine (10–5 M and 10–6 M, dissolved in KHS) and used equal amounts of normal KHS as control. To assess whether the endothelium mediates any bupivacaine-induced inhibitory effect on the TXA2-induced contraction, results in rings with and without endothelium were compared. One-hour pretreatment of the rat aortic rings with bupivacaine significantly inhibited U46619-induced contraction in a concentration-dependent manner. This occurred in rings with (Fig. 3A) and in those without endothelium (Fig. 3B). In rings with endothelium EC50-values for U46619-induced contraction were 1.8 x 10–8 ± 1.8 x 10–9 M and 1.7 x 10–8 ± 2.6 x 10–9 M in the presence of 10–6 or 10–5 M bupivacaine, respectively. Corresponding EC50 obtained in endothelium-free rings were 1.4 x 10–8 ± 1.9 x 10–9 M and 1.2 x 10–8 ± 1.6 x 10–9 M, respectively. None of these values were significantly different from those obtained under control conditions. Maximal contractile force obtained using U46619 (10–6 M) in rings with endothelium was 66.0 ± 1.0 mN. In endothelium-denuded rings, U46619 10–6 M induced a contraction of 66.3 ± 4.7 mN. In the presence of 10–6 M bupivacaine the maximal contractile force was not affected either in rings with (61.0 ± 1.1 mN, P = 0.24) or without (61.2 ± 1.7 mN, P = 0.21) endothelium. Pretreatment with 10–5 M bupivacaine decreased responses to 55.1 ± 1.8 mN (P < 0.01) in rings with endothelium and to 51.1 ± 1.3 mN (P < 0.01) in denuded rings, respectively. The effect of bupivacaine was concentration-dependent (P = 0.01). There was no statistical difference in the inhibitory effect of bupivacaine between rings with or without endothelium.
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Figure 3. Effects of pretreatment with bupivacaine on U46619-induced contraction. One-hour pretreatment of the rat aortic rings with bupivacaine significantly inhibited U46619-induced contraction in a concentration-dependent manner. This occurred in rings with (A) and in those without (B) endothelium. There was no statistically significant difference in rings with or without endothelium in EC50-values for U46619-induced contraction in the presence of 10–6 or 10–5 M bupivacaine. In the presence of 10–6 M bupivacaine the maximal contractile force was not affected either in rings with (61.0 ± 1.1 mN, P = 0.24) or without endothelium (61.2 ± 1.7 mN, P = 0.21). Pretreatment with 10–5 M bupivacaine decreased responses to 55.1 ± 1.8 mN (P < 0.01) in rings with endothelium and to 51.1 ± 1.3 mN (P < 0.01) in denuded rings, respectively. The effect of bupivacaine was concentration-dependent (P = 0.01). There was no statistical difference in the inhibitory effect of bupivacaine between rings with or without endothelium. Maximal contractile force obtained using U46619 (10–6 M) in rings with endothelium was significantly decreased in a concentration dependent manner. In endothelium-denuded rings only bupivacaine 10–5 M decreased the maximal contractile force (from 66.3 mN to 51.1 mN).
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As we demonstrated that bupivacaine diminishes U46619-induced contraction, we wished to investigate if the LA would also be able to reverse contraction induced by the TXA2 analog. We therefore contracted 2 groups of rings (3 rings with and 4 without endothelium) with U46619 (10–8 M). After 10 min, U46619-induced contraction reached a plateau. Rings were subsequently exposed to cumulative concentrations of bupivacaine (10–8 to 10–4 M). No concentration of bupivacaine was able to decrease the tonic contraction induced by U46619 (Fig. 4).
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Figure 4. Example trace of the effect of bupivacaine on a ring precontracted with U46619 with endothelium. Cumulative concentrations of bupivacaine (10–8 to 10–4 M) after precontraction with U46619 (10–8 M) were not able to decrease the tonic contraction induced by U46619.
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As the effect of bupivacaine on U46619-induced contraction was not affected by the presence or absence of endothelium, we also studied the effect of the LA on endothelium-dependent relaxation. To do this, we used the standard approach of precontracting aortic rings (n = 6) using NE (10–7 M), and subsequently relaxing them using CB (10–6 M). The effects of 15 min pretreatment with bupivacaine (10–5 M) on both NE-induced contraction and CB-induced relaxation were investigated separately. Bupivacaine (10–5 M) significantly reduced NE-induced force by 26% (43.3 ± 1.6 mN and 32.0 ± 2.7 mN with and without bupivacaine 10–5 M respectively, P = 0.002, Fig. 5A). Bupivacaine (10–5 M) also significantly inhibited endothelium-dependent relaxation by CB (72% ± 3% relaxation of the maximal NE-response in control rings versus 56% ± 8% in the bupivacaine-group, P = 0.04, Fig. 5B).
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Figure 5. Effect of bupivacaine 10–5 M (BUP) pretreatment on noradrenaline (NE) induced contraction and endothelium-dependent relaxation. A, BUP 10–5 M inhibits vasoconstriction induced by noradrenaline (NE, 10–7 M). *P < 0.01 compared with NE control. B, relaxation of the maximal NE response induced by carbachol (CB, 10–6 M) is reduced after incubation in BUP 10–5 M. *P < 0.05 compared with control (BT = basal tension).
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Discussion
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In the present study, we demonstrate that bupivacaine inhibits U46619-induced contraction of aortic vascular rings. The effect is concentration-dependent and does not require endothelium for its effect. The LA is unable to reverse previously established contraction by U46619. In addition, we demonstrate that bupivacaine interferes with NE-induced contraction as well as CB-induced relaxation. These effects occur at concentrations of agonist and LA that are routinely attained in the perioperative period when patients receive epidural anesthesia.
Other authors (18–20) previously reported various effects of LA on vascular contractile state. Although a dual action on vascular smooth muscle has been described (vasoconstriction at smaller concentrations, vasodilation at larger concentrations) (18), in our study bupivacaine modestly constricted aortic rings at the largest concentration tested. However, similar to the previous report (18), we found little direct effect of bupivacaine in concentrations that are of clinical relevance after systemic or epidural administration of the drug. In contrast, we observed pronounced effects on U46619-, NE-, and CB-mediated signaling. Similar to our findings, Johns (19) described inhibition of endothelium-dependent vasodilation by LA at a concentration of 1 x 10–4 M.
At first glance, these various effects on different receptor systems may appear bewildering. However, data from our group demonstrating that LA selectively inhibit functioning of Gq proteins help to explain this variety of actions. TXA2 receptors signal largely through Gq (13). The primary adrenergic receptor responsible for constriction of vascular smooth muscle is the 1 subtype, and the m3 muscarinic receptor is primarily responsible for endothelium-dependent vasodilation in response to CB (21). Both these receptors couple to Gq proteins. Hence, inhibition by bupivacaine of Gq protein function in vascular rings can parsimoniously explain the effects on all three signaling systems. The noncompetitive effects of bupivacaine, as well as the lack of endothelium dependence, are compatible with this hypothesis.
The findings from the present study are largely in agreement with our previous reports on LA interactions with TXA2 signaling. Hönemann et al. (12) demonstrated that bupivacaine, in concentrations that are commonly observed after epidural administration, inhibits signaling of TXA2 receptors expressed in Xenopus laevis oocytes, as well as endogenous TXA2 receptors in the human cell line K562. Furthermore, LA were shown to inhibit platelet aggregation induced by U46619 (13), although much larger concentrations than used in the present study were required. Signaling pathways, and interference of LA with these pathways, are likely to be considerably more complex in more physiological models than in simplified in vitro studies, which may explain differences in concentration-response relationships and rank order of potency. For example, when we studied the effect of lidocaine, bupivacaine, or ropivacaine on U46619-induced pulmonary vasoconstriction using a rat isolated lung model, ropivacaine, but none of the other LA, was able to attenuate significantly U46619-induced increases in pulmonary vascular pressures (22). Importantly, in our previous study (22) ropivacaine did not attenuate pulmonary vasoconstriction induced by angiotensin II, which is in agreement with our findings that angiotensin signaling is not inhibited by LA in vitro (23), and with our observation that angiotensin receptors (in Xenopus oocytes) couple primarily to G11 and G14 rather than to Gq (24). However, phenylephrine-induced pulmonary vasoconstriction was also not affected by LA, which is different from our current findings using NE. The difference in models allows for a number of potential explanations for this discrepancy, of which the type of vasculature studied (pulmonary versus aortic) may be of primary importance.
Of relevance is our finding that, whereas bupivacaine attenuated a subsequently induced contraction by U46619, it was not able to reverse preexisting contraction. This suggests that TXA2 receptor signaling induces downstream events that remain active even if receptor signaling is inhibited by the LA. One potential mechanism would be protein phosphorylation by protein kinase C, which is activated by Gq-coupled receptor signaling. Interestingly, we observed the same effect in our previous study on the pulmonary vasculature: whereas ropivacaine attenuated a subsequent U46619-induced increase in pulmonary artery pressures, it was not able to reverse a preestablished contraction (22).
Our current study used an in vitro model, and results should therefore not be extrapolated to the clinical setting. Nonetheless, our findings suggest some areas where investigation of the clinical actions of LA might be of relevance. For example, the TXA2 receptor is one of the most important constricting receptors in the internal mammary artery and radial artery, used frequently as grafts in coronary artery bypass grafting (25). Although several vasodilators, such as nitroglycerin and calcium antagonists, are used clinically to prevent graft spasm, their effects on TXA2-related contractions (via receptor-operated calcium channels) in grafts is limited (25). He and Yang (25) demonstrated in vitro that the specific TXA2 receptor antagonist GR32191B completely blocks TXA2-mediated contraction in human radial artery. Our current findings suggest that it might be of interest to investigate if bupivacaine reduces the risk of perioperative spasm of these grafts. Also of relevance is our finding that the vasodilator effect of bupivacaine was not abolished in the absence of endothelium. Therefore, bupivacaine might possibly be useful in the treatment of spasm arising from endothelium dysfunction, as caused by surgical procedures or atherosclerosis. The finding that preestablished contraction was not reversible by bupivacaine suggests that in clinical investigations the compound should be applied before the spasm-inciting event.
In conclusion, our results show that clinically relevant concentrations of bupivacaine are able to inhibit, but not reverse, TXA2-induced contractions in rat aortic rings in an endothelium-independent manner.
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Footnotes
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The contributions of Dr. Nollet and Dr. Hahnenkamp to this article should be considered equal.
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References
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- Fitzgerald DJ, Doran J, Jackson E, FitzGerald GA. Coronary vascular occlusion mediated via thromboxane A2-prostaglandin endoperoxide receptor activation in vivo. J Clin Invest 1986; 77: 496–502.
- Yamamoto Y, Kamiya K, Terao S. Modeling of human thromboxane A2 receptor and analysis of the receptor-ligand interaction. J Med Chem 1993; 36: 820–5.[ISI][Medline]
- Kurosawa M. Role of thromboxane A2 synthetase inhibitors in the treatment of patients with bronchial asthma. Clin Ther 1995; 17: 2–11.[ISI][Medline]
- Vesterqvist O, Schott U, Berseus O, et al. In vivo production of thromboxane and prostacyclin in patients following total hip arthroplasty. Scand J Clin Lab Invest 1988; 48: 233–9.[ISI][Medline]
- Teoh KH, Fremes SE, Weisel RD, et al. Cardiac release of prostacyclin and thromboxane A2 during coronary revascularization. J Thorac Cardiovasc Surg 1987; 93: 120–6.[Abstract]
- Schilling MK, Gassmann N, Sigurdsson GH, et al. Role of thromboxane and leukotriene B4 in patients with acute respiratory distress syndrome after oesophagectomy. Br J Anaesth 1998; 80: 36–40.[Abstract/Free Full Text]
- Barry MC, Kelly CJ, Stokes K, et al. Glyceryl trinitrate prevents neutrophil activation but not thromboxane release following ischaemia-reperfusion injury. Br J Surg 1996; 83: 1095–100.[ISI][Medline]
- Ylikorkala O, Makila UM. Prostacyclin and thromboxane in gynecology and obstetrics. Am J Obstet Gynecol 1985; 152: 318–29.[ISI][Medline]
- von Houwelingen AC, Thorngren M, Hornstra G, Born GV. Release of thromboxane A2 and beta-thromboglobulin during in-vivo plug formation following standardized skin incisions: effect of a moderate fish intake. Thromb Haemost 1992; 67: 713–7.[ISI][Medline]
- Rodgers A, Walker N, Schug S, et al. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ 2000; 321: 1493.[Abstract/Free Full Text]
- Hahnenkamp K, Theilmeier G, Van Aken HK, Hoenemann CW. The effects of local anesthetics on perioperative coagulation, inflammation, and microcirculation. Anesth Analg 2002; 94: 1441–7.[Free Full Text]
- Honemann CW, Arledge JA, Podranski T, et al. Volatile and local anesthetics interfere with thromboxane A2 receptors recombinantly expressed in Xenopus oocytes. Adv Exp Med Biol 1999; 469: 277–83.[ISI][Medline]
- Lo B, Honemann CW, Kohrs R, et al. Local anesthetic actions on thromboxane-induced platelet aggregation. Anesth Analg 2001; 93: 1240–5.[Abstract/Free Full Text]
- Knapp J, Boknik P, Linck B, et al. The effect of the protein phosphatases inhibitor cantharidin on beta-adrenoceptor-mediated vasorelaxation. Br J Pharmacol 1997; 120: 421–8.[ISI][Medline]
- Hirsh PD, Hillis LD, Campbell WB, et al. Release of prostaglandins and thromboxane into the coronary circulation in patients with ischemic heart disease. N Engl J Med 1981; 304: 685–91.[Abstract]
- Dorn GW, Becker MW. Thromboxane A2 stimulated signal transduction in vascular smooth muscle. J Pharmacol Exp Ther 1993; 265: 447–56.[Abstract/Free Full Text]
- Rygnestad T, Zahlsen K, Bergslien O, Dale O. Focus on mobilisation after lower abdominal surgery: a double-blind randomised comparison of epidural bupivacaine with morphine vs. lidocaine with morphine for postoperative analgesia. Acta Anaesthesiol Scand 1999; 43: 380–7.[ISI][Medline]
- Ishiyama T, Dohi S, Iida H, Watanabe Y. The effects of topical and intravenous ropivacaine on canine pial microcirculation. Anesth Analg 1997; 85: 75–81.[Abstract]
- Johns RA. Local anesthetics inhibit endothelium-dependent vasodilation. Anesthesiology 1989; 70: 805–11.[ISI][Medline]
- Turan NN, Tuncay DA, Celebi H. Effects of lidocaine on rabbit isolated thoracic aorta. Pharmacol Res 2000; 42: 453–8.[ISI][Medline]
- Struemper D, Durieux ME, Roekarts P. Endothelial and microvascular function. Semin Cardiothorac Vasc Anesth 2003; 7: 225–38.[Abstract/Free Full Text]
- Fischer LG, Honemann CW, Patrie JT, et al. Ropivacaine attenuates pulmonary vasoconstriction induced by thromboxane A2 analogue in the isolated perfused rat lung. Reg Anesth Pain Med 2000; 25: 187–94.[ISI][Medline]
- Nietgen GW, Chan CK, Durieux ME. Inhibition of lysophosphatidate signaling by lidocaine and bupivacaine. Anesthesiology 1997; 86: 1112–9.[ISI][Medline]
- Hollmann MW, Wieczorek KS, Berger A, Durieux ME. Local anesthetic inhibition of G protein-coupled receptor signaling by interference with Galpha(q) protein function. Mol Pharmacol 2001; 59: 294–301.[Abstract/Free Full Text]
- He GW, Yang CQ. Inhibition of vasoconstriction by the thromboxane A2 antagonist GR32191B in the human radial artery. Br J Clin Pharmacol 1999; 48: 207–15.[ISI][Medline]
Accepted for publication January 7, 2004.
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Abstract
Introduction
