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The effects of bupivacaine, ropivacaine and mepivacaine on the contractility of rat myometrium
International Journal of Obstetric Anesthesia (2004) 13, 95–98 Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ijoa.2003.10.007
ORIGINAL ARTICLE
The effects of bupivacaine, ropivacaine and mepivacaine on the contractility of rat myometrium G. Arici, B. Karsli, N. Kayacan, M. Akar* Akdeniz University Faculty of Medicine, Departments of Anesthesiology and Reanimation, and Department of Obstetric and Gynecology, Antalya, Turkey SUMMARY. Local anesthetic agents are commonly used for obstetric anesthesia and analgesia. We determined the effects of bupivacaine, ropivacaine and mepivacaine on the contractility of isolated pregnant rat uterine muscle strips. Uterine specimens were obtained from 18- to 21-day pregnant Wistar rats ðn ¼ 28Þ. Myometrial strips were obtained from the uterine horns after removing the fetuses and non-uterine tissue, incubated in organ baths and contractions stimulated with oxytocin. When contractions became regular, strips were exposed to increasing concentrations of the study drugs. Mepivacaine ðn ¼ 8Þ, ropivacaine ðn ¼ 10Þ and bupivacaine ðn ¼ 10Þ were used at cumulative doses from 108 to 104 mol/L. Two of the local anesthetics, bupivacaine most, ropivacaine least, caused a dose-dependent inhibition of uterine contractility. In contrast, mepivacaine significantly increased uterine contractility. Bupivacaine, ropivacaine and mepivacaine were found to have no effect on frequency of uterine contractions. These results demonstrate that bupivacaine and ropivacaine may inhibit myometrium contractility. Ó 2004 Elsevier Ltd. All rights reserved. Keywords: Bupivacaine; Ropivacaine; Mepivacaine; Uterine contractility; Rat
INTRODUCTION
METHODS
Regional anesthesia and analgesia have come into widespread use in obstetrics, and local anesthetics are often used for managing labor pain. Any effect they might have on the spontaneous contractility of the pregnant uterus is therefore potentially undesirable, since increased or decreased uterine contraction can be a significant limiting factor in the success of labor. Previous studies have suggested that some local anesthetics may alter the spontaneous contractility of uterine muscle.1–3 Bupivacaine is the most commonly used local anesthetic in obstetric procedures. In vivo clinical studies suggested that bupivacaine had no effect on uterine contractility, but its effects in vitro are not well documented.4 We have compared the effects of bupivacaine on contractions of isolated rat pregnant uterine muscle strips with those of mepivacaine and ropivacaine.
The study procedures were approved by the Faculty Animal Care and Use Committee. Pregnant Wistar rats at 18–21 days gestation were cared for in accordance with the guidelines of the Animal Care Center. A total of 30 rats were killed for the study, but two were excluded because full thickness myometrial strips were not obtained. Animals were sacrificed by cervical subluxation. The uterine horns were rapidly excised, carefully cleaned of surrounding connective tissue and opened longitudinally along the mesometrial border. Fetuses were removed and non-uterine tissues were dissected away and discarded. Full-thickness longitudinal myometrial muscle strip (approximately 3 10 mm) were obtained from each animal, mounted vertically and incubated in a 10-mL organ bath containing modified Krebs solution (composition in mmol/L: NaCl 154, KCl 5.6, CaCl2 1.9, MgCl2 0.95, NaHCO3 5.95, glucose 2.78) and aerated continuously at 37°C with 5% carbon dioxide in oxygen. Each myometrial strip was allowed to equilibrate at 1 g tension for 20 min, after which the preparation was challenged twice by administration of a maximally effective concentration of oxytocin (1 mU/ mL). Uterine strips were then allowed to equilibrate for
––––––––––––––––––––––––––––––––––––––––––––––––––––––––– Accepted October 2003 Correspondence to: Dr. Bilge Karsli, Akdeniz University Faculty of Medicine, Departments of Anesthesiology and Reanimation, Antalya, Turkey. Tel.: +90-242-2274343; fax: +90-242-2278836; E-mail: [email protected] 95
96 International Journal of Obstetric Anesthesia a further 60 min and, when the contractions became regular, they were exposed to cumulative concentrations of mepivacaine (Mepihexal, Hexal; n ¼ 8), ropivacaine (Naropin, Astra; n ¼ 10) or bupivacaine (Marcaine, Astra; n ¼ 10). Drug-containing solutions were prepared immediately before each experiment. The strips were exposed to cumulative doses from 108 to 104 mol/L of one of the three local anesthetics for 30 min at each dose level. Myometrial isometric contractions were measured continuously with a force transducer (FDT 10-A, Commat Ltd.), connected to a computer-based data acquisition system (TDA 97, Commat Ltd.). The contraction force after the application of oxytocin but before the addition of any local anesthetic was taken as 100%. The characteristics of the contractions analyzed over 1800-s intervals immediately before and after the addition of drugs included frequency and force of each contraction. Data are presented as mean standard deviation and analyzed using analysis of variance. P < 0:05 is considered to be statistically significant.
RESULTS In most myometrial strips, the tone was unaffected by the lowest concentration of the study drugs. Bupivacaine effects: A representative recording of a strip treated with bupivacaine is shown in Fig. 1a, and mean changes in amplitude of contractions are shown in Fig. 1b. Force of contractions decreased with increasing concentrations of bupivacaine, reaching statistical significance at a concentration of 104 mol/L, when contractility was 79.6 12.6% of baseline ðP ¼ 0:005Þ. The inhibitory effect of bupivacaine at 104 mol/L concentration was significantly different from that of other concentrations ðP ¼ 0:001Þ (Fig. 1). Bupivacaine was found to have no effect on frequency of contractions. Ropivacaine effects: Ropivacaine, like bupivacaine, caused a dose-dependent depression of uterine contractility (Fig. 2). The force of contractions decreased with increasing concentrations of ropivacaine. Contractility was 90.5 6.1% of baseline at a 104 mol/L ðP ¼ 0:005Þ. The inhibitory effect of ropivacaine 104 mol/L was significantly different from that of other concentrations ðP ¼ 0:005Þ (Fig. 2). Ropivacaine had no effect on the frequency of contractions. Mepivacaine effects: Exposure to mepivacaine at cumulative concentrations of 108 –104 mol/L increased the contractility of myometrial strips (Fig. 3). The effects were concentration-dependent, reaching statistical significance at a concentration of 104 mol/L ðP ¼ 0:012Þ. Contractility was 133.07 23.80% of baseline at
Fig. 1 (a) Representative trace showing contractions induced by bupivacaine at cumulative concentrations (108 –104 mol/L) in isolated rat myometrium. (b) Mean effects of cumulative concentrations of bupivacaine on uterine contraction, presented as a percentage of the initial contraction. Vertical bars represent standard deviations.
a 104 mol/L. Mepivacaine had no effect on frequency of contractions. Comparison of local anesthetics: Bupivacaine had a significantly greater inhibitory effect on contractility than ropivacaine at a concentration of 3 105 mol/L ðP ¼ 0:014Þ. The maximum inhibitory effect was also greater for bupivacaine than for ropivacaine. By contrast, mepivacaine, increased the contractility over similar concentrations (Fig. 4).
DISCUSSION Neuraxial blockade is used in obstetric patients to produce pain relief or complete anesthesia within a limited segmental distribution. The side effects that result may be affected by the local anesthetic that is used.5 We therefore compared the effects of three local anesthetics: bupivacaine, ropivacaine and mepivacaine on contractility of pregnant rat myometrium in vitro. While some in vivo clinical studies suggested that bupivacaine has no effect on uterine contractility,5–7 others have shown decreased contractility following epidural bupivacaine.2;8–10 The latter findings are in accord with those of our own in vitro study and that of
Local anesthetics on rat myometrium 97
Karsli et al.1 who demonstrated that cumulative concentrations of bupivacaine produced a decrease both in the spontaneous contractile activity and in the contraction amplitude of myometrial strips. Many studies have demonstrated that bupivacaine decreases contractility in other types of smooth and striated muscle.11–16 For example, it produced dose-dependent depression of contraction in the isolated dog papillary muscle,13 in bladder smooth muscle14;15 and in tracheal smooth muscle.16 The chemical properties of ropivacaine are similar to those of bupivacaine, although lipid solubility of ropivacaine is lower.17 Kopac et al.18 showed that ropivacaine produces cutaneous vasoconstriction in pigs, whereas bupivacaine at high concentrations produces vasodilatation. Iida et al.17 reported that topical application of ropivacaine constricted spinal pial arterioles and venules in a concentration-dependent manner, whereas the topical application of bupivacaine caused vasodilatation. Several investigators have speculated that local anesthetics cause changes in vessels via several mechanisms, one of which is direct smooth muscle activation of pre-capillary or post-capillary vessels.19–21 Mitochondria provide energy in the form of adenosine triphosphate (ATP) for essential cell functions. The
Fig. 3 (a) Representative trace showing contractions induced by mepivacaine at cumulative concentrations (108 –104 ) in isolated rat myometrium. (b) Effects of cumulative concentrations of mepivacaine on uterine contraction, presented as a percentage of the initial concentration. Vertical bars represent standard deviations.
bupivacaine
ropivacaine
mepivacaine
140 130 Contraction (%)
Fig. 2 (a) Representative trace showing contractions induced by ropivacaine at cumulative concentrations (108 –104 mol/L) in isolated rat myometrium. (b) Mean effects of cumulative concentrations of ropivacaine on uterine contraction, presented as a percentage of the initial concentration. Vertical bars represent standard deviations.
120 110 100 90 80 70
-8
10
-8
3×10
-7
10
-7
3×10
-6
10
-6
3×10
-5
10
-
3×10
-4
10
Concentration (mol/L)
Fig. 4 Comparison of the effects of bupivacaine, ropivacaine and mepivacaine on uterine contractility.
mitochondrial respiratory chain is divided into four enzymatic complexes, catalyzing oxidation-reduction reactions leading to the oxidation of respiratory substrates (e.g. pyruvate, glutamate, succinate) and to the reduction of oxygen to water. The transfer of electrons along the respiratory chain generates a proton gradient across the inner mitochondrial membrane that is used for ATP synthesis. Two mechanisms have been described for the
98 International Journal of Obstetric Anesthesia interactions of local anesthetics with mitochondrial metabolism: (1) an uncoupling effect between oxygen consumption and ATP synthesis by increasing proton membrane permeability, thus dissipating the proton gradient22–26 and (2) a direct inhibitory effect of local anesthetics (at higher concentrations) on mitochondrial enzyme complexes.27 All these effects lead to a decrease in ATP synthesis and to a depletion in the ATP content of the cell.28 The pharmacological properties of mepivacaine are similar to those of lidocaine, but it is more toxic to the neonate and is not used in obstetrical anesthesia.29 Like bupivacaine, mepivacaine has been found to depress cardiac function,30;31 and to inhibit contractions in tracheal smooth muscle.16 To our surprise, however, we found that exposure to mepivacaine at cumulative concentrations of 108 –104 mol/L increased myometrial contractility. In summary, both bupivacaine and ropivacaine had a depressant effect on uterine contractility in the higher concentrations that were studied. The effect was greater with bupivacaine. Mepivacaine on the other hand caused a significant increase in contractility. The choice of drug for obstetric pain relief, however, cannot be decided solely on the basis of in vitro studies, but must be evaluated in controlled clinical trials.
REFERENCES 1. Karsli B, Kayacan N, Kucukyavuz Z, Mimarolu C. Effects of local anesthetics on pregnant uterine muscles. Pol J Pharmacol 2003; 55: 51–56. 2. Willdeck-Lund G, Nilsson B A. The effect of local anaesthetic agents on the contractility of human myometrium in late pregnancy. Acta Anaesthesiol Scand 1979; 23: 78–88. 3. Holdcroft A, Thomas T A. Regional anaesthetic techniques. In: Principles and Practice of Obstetric Anaesthesia and Analgesia. London: Blackwell Science, 2000: 266–268. 4. Yentis S M, Brighouse D, May A, Bogod D, Elton C. Local anaesthetics. In: Analgesia, Anaesthesia and Pregnancy: A practical Guide. London: WB Saunders, 2001: 47–49. 5. Guidozzi F, Graham K M, Buchmann E J, Christophers G J. The effect of continuous low-dose epidural analgesia on uterine work during the active phase of the first stage of labor. S Afr Med J 1992; 81: 361–362. 6. Schull T J, Hemmings G T, Weeks S K, Mazza L, Zingg H H. Epidural analgesia in early labour blocks the stress response but uterine contractions remain unchanged. Can J Anaesth 1988; 45: 626–630. 7. Nielsen P E, Abouleish E, Meyer B A, Parisi V M. Effect of epidural analgesia on fundal dominance during spontaneous active-phase nulliparous labor. Anesthesiology 1996; 84: 540–544. 8. Raabe N, Belfrage P. Epidural analgesia in labour. IV. Influence on uterine activity and fetal heart rate. Acta Obstet Gynecol Scand 1976; 55: 305–308. 9. Littlewood D G, Scott D B, Wilson J, Covino B G. Comparative anaesthetic properties of various local anaesthetic agents in extradural block for labour. Br J Anaesth 1977; 49: 75–79. 10. Schellenberg J C. Uterine activity during lumbar epidural analgesia with bupivacaine. Am J Obstet Gynecol 1977; 127: 26–31.
11. Nakamura T, Toda H, Kakuyama M et al. Direct vascular effect of ropivacaine in femoral artery and vein of the dog. Acta Anaesthesiol Scand 1993; 37: 269–273. 12. Szocik J F, Gardner C A, Webb R C. Inhibitory effects of bupivacaine and lidocaine on adrenergic neuroeffector junctions in rat tail artery. Anesthesiology 1993; 78: 911–917. 13. Shibuya N, Momose Y, Ito Y. Effects of bupivacaine on contraction and membrane potential in isolated canine papillary muscles. Pharmacology 1993; 47: 158–166. 14. McInnerney P D, Grant A, Chawla J, Stephenson T P. The effect of intravesical Marcaine instillation on hyperreflexic detrusor contractions. Paraplegia 1992; 30: 127–130. 15. Oh S J, Kim S J, Park E C, Chung H K, Kim K W, Choi H. Effects of local anesthetics on the contractility of rat bladders. J Urol 2001; 165: 2044–2050. 16. Wali F A. Local anaesthetics inhibit cholinergic and non-cholinergic neural and muscular contractions in avian tracheal smooth muscle. Acta Anaesthesiol Scand 1987; 31: 148–153. 17. Iida H, Watanabe Y, Dohi S, Ishiyama T. Direct effects of ropivacaine and bupivacaine on spinal pial vessels in canine. Anesthesiology 1997; 87: 75–81. 18. Kopacz D J, Carpenter R L, Mackey D C. Effect of ropivacaine on cutaneous capillary blood flow in pigs. Anesthesiology 1989; 71: 69–74. 19. Johns R A, Seyde W C, DiFazio C A, Longnecker D E. Dose-dependent effects of bupivacaine on rat muscle arterioles. Anesthesiology 1986; 65: 186–191. 20. Johns R A, DiFazio C A, Longnecker D E. Lidocaine constricts or dilates rat arterioles in dose-dependent manner. Anesthesiology 1985; 62: 141–144. 21. Kozody R, Ong B, Palahniuk R J, Wade J G, Cumming M O, Pucci W R. Subarachnoid bupivacaine decreases spinal cord blood flow in dogs. Can J Anaesth 1985; 32: 216–222. 22. Garlid K D, Nakashima R A. Studies on the mechanism of uncoupling by amine local anesthetics. Evidence for mitochondrial proton transport mediated by lipophilic ion pairs. J Biol Chem 1983; 258: 7974–7980. 23. Dabadie P, Benriss P, Erny P, Mazat J P. Uncoupling effects of local anesthetics on rat liver mitochondria. FEBS Lett 1987; 226: 77–82. 24. Terada H, Shima O, Yoshida K, Shinohara Y. Effects of the local anesthetic bupivacaine on oxidative phosphorylation in mitochondria. Change from decoupling to uncoupling by formation of a leakage type ion pathway specific for Hþ in cooperation with hydrophoric anions. J Biol Chem 1990; 265: 7837–7842. 25. Schonfeld P, Sztark F, Slimani M, Dabadie P, Mazat J P. Is bupivacaine a decoupler, a protonophore or a proton-leak-inducer? FEBS Lett 1992; 304: 273–276. 26. Sun X, Garlid K D. On the mechanism by which bupivacaine conducts protons across the membranes of mitochondria and liposomes. J Biol Chem 1992; 267: 19147–19154. 27. Chazotte B, Vanderkooi G. Multiples sites of inhibition of mitochondrial electron transport by local anesthetics. Biochim Biophys Acta 1981; 636: 153–161. 28. Sztark F, Tueux O, Erny P, Dabadie P, Georgescaud D, Mazat J P. Effects of bupivacaine on cellular oxygen consumption and adenine nucleotide metabolism. Anesth Analg 1994; 78: 335–339. 29. Catteral W, Mackie K. Local anesthetics. In: Hadman J G, Limbird L E, Molinof P B, Rundon R W, Goodman Gilman A (eds). The Pharmacological Basis of Therapeutics, 9th Ed. New York: McGraw-Hill, 1996: 331–347. 30. Park W K, Suh C K. Mechanical and electrophysiological effects of mepivacaine on direct myocardial depression in vitro. Br J Anaesth 1998; 81: 244–246. 31. Takamura T, Sakamoto A, Ogawa R. Bupivacaine combined with isoflurane synergistically depressed myocardial contractility in rat working heart preparation. Nippon Ika Daigaku Zasshi 1997; 64: 292–297.
ORIGINAL ARTICLE
The effects of bupivacaine, ropivacaine and mepivacaine on the contractility of rat myometrium G. Arici, B. Karsli, N. Kayacan, M. Akar* Akdeniz University Faculty of Medicine, Departments of Anesthesiology and Reanimation, and Department of Obstetric and Gynecology, Antalya, Turkey SUMMARY. Local anesthetic agents are commonly used for obstetric anesthesia and analgesia. We determined the effects of bupivacaine, ropivacaine and mepivacaine on the contractility of isolated pregnant rat uterine muscle strips. Uterine specimens were obtained from 18- to 21-day pregnant Wistar rats ðn ¼ 28Þ. Myometrial strips were obtained from the uterine horns after removing the fetuses and non-uterine tissue, incubated in organ baths and contractions stimulated with oxytocin. When contractions became regular, strips were exposed to increasing concentrations of the study drugs. Mepivacaine ðn ¼ 8Þ, ropivacaine ðn ¼ 10Þ and bupivacaine ðn ¼ 10Þ were used at cumulative doses from 108 to 104 mol/L. Two of the local anesthetics, bupivacaine most, ropivacaine least, caused a dose-dependent inhibition of uterine contractility. In contrast, mepivacaine significantly increased uterine contractility. Bupivacaine, ropivacaine and mepivacaine were found to have no effect on frequency of uterine contractions. These results demonstrate that bupivacaine and ropivacaine may inhibit myometrium contractility. Ó 2004 Elsevier Ltd. All rights reserved. Keywords: Bupivacaine; Ropivacaine; Mepivacaine; Uterine contractility; Rat
INTRODUCTION
METHODS
Regional anesthesia and analgesia have come into widespread use in obstetrics, and local anesthetics are often used for managing labor pain. Any effect they might have on the spontaneous contractility of the pregnant uterus is therefore potentially undesirable, since increased or decreased uterine contraction can be a significant limiting factor in the success of labor. Previous studies have suggested that some local anesthetics may alter the spontaneous contractility of uterine muscle.1–3 Bupivacaine is the most commonly used local anesthetic in obstetric procedures. In vivo clinical studies suggested that bupivacaine had no effect on uterine contractility, but its effects in vitro are not well documented.4 We have compared the effects of bupivacaine on contractions of isolated rat pregnant uterine muscle strips with those of mepivacaine and ropivacaine.
The study procedures were approved by the Faculty Animal Care and Use Committee. Pregnant Wistar rats at 18–21 days gestation were cared for in accordance with the guidelines of the Animal Care Center. A total of 30 rats were killed for the study, but two were excluded because full thickness myometrial strips were not obtained. Animals were sacrificed by cervical subluxation. The uterine horns were rapidly excised, carefully cleaned of surrounding connective tissue and opened longitudinally along the mesometrial border. Fetuses were removed and non-uterine tissues were dissected away and discarded. Full-thickness longitudinal myometrial muscle strip (approximately 3 10 mm) were obtained from each animal, mounted vertically and incubated in a 10-mL organ bath containing modified Krebs solution (composition in mmol/L: NaCl 154, KCl 5.6, CaCl2 1.9, MgCl2 0.95, NaHCO3 5.95, glucose 2.78) and aerated continuously at 37°C with 5% carbon dioxide in oxygen. Each myometrial strip was allowed to equilibrate at 1 g tension for 20 min, after which the preparation was challenged twice by administration of a maximally effective concentration of oxytocin (1 mU/ mL). Uterine strips were then allowed to equilibrate for
––––––––––––––––––––––––––––––––––––––––––––––––––––––––– Accepted October 2003 Correspondence to: Dr. Bilge Karsli, Akdeniz University Faculty of Medicine, Departments of Anesthesiology and Reanimation, Antalya, Turkey. Tel.: +90-242-2274343; fax: +90-242-2278836; E-mail: [email protected] 95
96 International Journal of Obstetric Anesthesia a further 60 min and, when the contractions became regular, they were exposed to cumulative concentrations of mepivacaine (Mepihexal, Hexal; n ¼ 8), ropivacaine (Naropin, Astra; n ¼ 10) or bupivacaine (Marcaine, Astra; n ¼ 10). Drug-containing solutions were prepared immediately before each experiment. The strips were exposed to cumulative doses from 108 to 104 mol/L of one of the three local anesthetics for 30 min at each dose level. Myometrial isometric contractions were measured continuously with a force transducer (FDT 10-A, Commat Ltd.), connected to a computer-based data acquisition system (TDA 97, Commat Ltd.). The contraction force after the application of oxytocin but before the addition of any local anesthetic was taken as 100%. The characteristics of the contractions analyzed over 1800-s intervals immediately before and after the addition of drugs included frequency and force of each contraction. Data are presented as mean standard deviation and analyzed using analysis of variance. P < 0:05 is considered to be statistically significant.
RESULTS In most myometrial strips, the tone was unaffected by the lowest concentration of the study drugs. Bupivacaine effects: A representative recording of a strip treated with bupivacaine is shown in Fig. 1a, and mean changes in amplitude of contractions are shown in Fig. 1b. Force of contractions decreased with increasing concentrations of bupivacaine, reaching statistical significance at a concentration of 104 mol/L, when contractility was 79.6 12.6% of baseline ðP ¼ 0:005Þ. The inhibitory effect of bupivacaine at 104 mol/L concentration was significantly different from that of other concentrations ðP ¼ 0:001Þ (Fig. 1). Bupivacaine was found to have no effect on frequency of contractions. Ropivacaine effects: Ropivacaine, like bupivacaine, caused a dose-dependent depression of uterine contractility (Fig. 2). The force of contractions decreased with increasing concentrations of ropivacaine. Contractility was 90.5 6.1% of baseline at a 104 mol/L ðP ¼ 0:005Þ. The inhibitory effect of ropivacaine 104 mol/L was significantly different from that of other concentrations ðP ¼ 0:005Þ (Fig. 2). Ropivacaine had no effect on the frequency of contractions. Mepivacaine effects: Exposure to mepivacaine at cumulative concentrations of 108 –104 mol/L increased the contractility of myometrial strips (Fig. 3). The effects were concentration-dependent, reaching statistical significance at a concentration of 104 mol/L ðP ¼ 0:012Þ. Contractility was 133.07 23.80% of baseline at
Fig. 1 (a) Representative trace showing contractions induced by bupivacaine at cumulative concentrations (108 –104 mol/L) in isolated rat myometrium. (b) Mean effects of cumulative concentrations of bupivacaine on uterine contraction, presented as a percentage of the initial contraction. Vertical bars represent standard deviations.
a 104 mol/L. Mepivacaine had no effect on frequency of contractions. Comparison of local anesthetics: Bupivacaine had a significantly greater inhibitory effect on contractility than ropivacaine at a concentration of 3 105 mol/L ðP ¼ 0:014Þ. The maximum inhibitory effect was also greater for bupivacaine than for ropivacaine. By contrast, mepivacaine, increased the contractility over similar concentrations (Fig. 4).
DISCUSSION Neuraxial blockade is used in obstetric patients to produce pain relief or complete anesthesia within a limited segmental distribution. The side effects that result may be affected by the local anesthetic that is used.5 We therefore compared the effects of three local anesthetics: bupivacaine, ropivacaine and mepivacaine on contractility of pregnant rat myometrium in vitro. While some in vivo clinical studies suggested that bupivacaine has no effect on uterine contractility,5–7 others have shown decreased contractility following epidural bupivacaine.2;8–10 The latter findings are in accord with those of our own in vitro study and that of
Local anesthetics on rat myometrium 97
Karsli et al.1 who demonstrated that cumulative concentrations of bupivacaine produced a decrease both in the spontaneous contractile activity and in the contraction amplitude of myometrial strips. Many studies have demonstrated that bupivacaine decreases contractility in other types of smooth and striated muscle.11–16 For example, it produced dose-dependent depression of contraction in the isolated dog papillary muscle,13 in bladder smooth muscle14;15 and in tracheal smooth muscle.16 The chemical properties of ropivacaine are similar to those of bupivacaine, although lipid solubility of ropivacaine is lower.17 Kopac et al.18 showed that ropivacaine produces cutaneous vasoconstriction in pigs, whereas bupivacaine at high concentrations produces vasodilatation. Iida et al.17 reported that topical application of ropivacaine constricted spinal pial arterioles and venules in a concentration-dependent manner, whereas the topical application of bupivacaine caused vasodilatation. Several investigators have speculated that local anesthetics cause changes in vessels via several mechanisms, one of which is direct smooth muscle activation of pre-capillary or post-capillary vessels.19–21 Mitochondria provide energy in the form of adenosine triphosphate (ATP) for essential cell functions. The
Fig. 3 (a) Representative trace showing contractions induced by mepivacaine at cumulative concentrations (108 –104 ) in isolated rat myometrium. (b) Effects of cumulative concentrations of mepivacaine on uterine contraction, presented as a percentage of the initial concentration. Vertical bars represent standard deviations.
bupivacaine
ropivacaine
mepivacaine
140 130 Contraction (%)
Fig. 2 (a) Representative trace showing contractions induced by ropivacaine at cumulative concentrations (108 –104 mol/L) in isolated rat myometrium. (b) Mean effects of cumulative concentrations of ropivacaine on uterine contraction, presented as a percentage of the initial concentration. Vertical bars represent standard deviations.
120 110 100 90 80 70
-8
10
-8
3×10
-7
10
-7
3×10
-6
10
-6
3×10
-5
10
-
3×10
-4
10
Concentration (mol/L)
Fig. 4 Comparison of the effects of bupivacaine, ropivacaine and mepivacaine on uterine contractility.
mitochondrial respiratory chain is divided into four enzymatic complexes, catalyzing oxidation-reduction reactions leading to the oxidation of respiratory substrates (e.g. pyruvate, glutamate, succinate) and to the reduction of oxygen to water. The transfer of electrons along the respiratory chain generates a proton gradient across the inner mitochondrial membrane that is used for ATP synthesis. Two mechanisms have been described for the
98 International Journal of Obstetric Anesthesia interactions of local anesthetics with mitochondrial metabolism: (1) an uncoupling effect between oxygen consumption and ATP synthesis by increasing proton membrane permeability, thus dissipating the proton gradient22–26 and (2) a direct inhibitory effect of local anesthetics (at higher concentrations) on mitochondrial enzyme complexes.27 All these effects lead to a decrease in ATP synthesis and to a depletion in the ATP content of the cell.28 The pharmacological properties of mepivacaine are similar to those of lidocaine, but it is more toxic to the neonate and is not used in obstetrical anesthesia.29 Like bupivacaine, mepivacaine has been found to depress cardiac function,30;31 and to inhibit contractions in tracheal smooth muscle.16 To our surprise, however, we found that exposure to mepivacaine at cumulative concentrations of 108 –104 mol/L increased myometrial contractility. In summary, both bupivacaine and ropivacaine had a depressant effect on uterine contractility in the higher concentrations that were studied. The effect was greater with bupivacaine. Mepivacaine on the other hand caused a significant increase in contractility. The choice of drug for obstetric pain relief, however, cannot be decided solely on the basis of in vitro studies, but must be evaluated in controlled clinical trials.
REFERENCES 1. Karsli B, Kayacan N, Kucukyavuz Z, Mimarolu C. Effects of local anesthetics on pregnant uterine muscles. Pol J Pharmacol 2003; 55: 51–56. 2. Willdeck-Lund G, Nilsson B A. The effect of local anaesthetic agents on the contractility of human myometrium in late pregnancy. Acta Anaesthesiol Scand 1979; 23: 78–88. 3. Holdcroft A, Thomas T A. Regional anaesthetic techniques. In: Principles and Practice of Obstetric Anaesthesia and Analgesia. London: Blackwell Science, 2000: 266–268. 4. Yentis S M, Brighouse D, May A, Bogod D, Elton C. Local anaesthetics. In: Analgesia, Anaesthesia and Pregnancy: A practical Guide. London: WB Saunders, 2001: 47–49. 5. Guidozzi F, Graham K M, Buchmann E J, Christophers G J. The effect of continuous low-dose epidural analgesia on uterine work during the active phase of the first stage of labor. S Afr Med J 1992; 81: 361–362. 6. Schull T J, Hemmings G T, Weeks S K, Mazza L, Zingg H H. Epidural analgesia in early labour blocks the stress response but uterine contractions remain unchanged. Can J Anaesth 1988; 45: 626–630. 7. Nielsen P E, Abouleish E, Meyer B A, Parisi V M. Effect of epidural analgesia on fundal dominance during spontaneous active-phase nulliparous labor. Anesthesiology 1996; 84: 540–544. 8. Raabe N, Belfrage P. Epidural analgesia in labour. IV. Influence on uterine activity and fetal heart rate. Acta Obstet Gynecol Scand 1976; 55: 305–308. 9. Littlewood D G, Scott D B, Wilson J, Covino B G. Comparative anaesthetic properties of various local anaesthetic agents in extradural block for labour. Br J Anaesth 1977; 49: 75–79. 10. Schellenberg J C. Uterine activity during lumbar epidural analgesia with bupivacaine. Am J Obstet Gynecol 1977; 127: 26–31.
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