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Anesth Analg 2001;93:1552-1556
© 2001 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

The Differential Effects of Stereoisomers of Ropivacaine and Bupivacaine on Cerebral Pial Arterioles in Dogs

Hiroki Iida, MD*, Hiroto Ohata, MD*, Mami Iida, MD{dagger}, Kiyoshi Nagase, MD*, Masayoshi Uchida, MD*, and Shuji Dohi, MD*

*Department of Anesthesiology and Critical Care Medicine and {dagger}Second Department of Internal Medicine, Gifu University School of Medicine, Gifu City, Gifu, Japan

Address correspondence and reprint requests to Hiroki Iida, MD, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, 40 Tsukasamachi, Gifu City, Gifu 500-8705, Japan. Address e-mail to iida{at}cc.gifu-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We investigated whether the stereoisomers of ropivacaine and bupivacaine exert differential effects on the cerebral microcirculation. Pentobarbital-anesthetized dogs (n = 16) were prepared for measurement of cerebral pial vessel diameters by using a closed cranial window preparation. We administered three different concentrations (10-7, 10-5, and 10-3 M) of each of three drug solutions [R(+), racemic, and S(-) forms of ropivacaine (n = 8) or bupivacaine (n = 8)] under the window in a randomized manner and measured cerebral pial arteriolar diameters. Various physiologic data were obtained before and after topical application of each test solution. All three forms of ropivacaine constricted cerebral pial arterioles, each in a concentration-dependent manner. The rank order for degree of vasocon- striction was S(-) ropivacaine > racemic ropivacaine > R(+) ropivacaine. In contrast, R(+) and racemic bupivacaine dilated, but S(-) bupivacaine constricted, cerebral pial arterioles, each in a concentration-dependent manner. We could find no difference in vascular reactivity to these drugs between large (>=100 µm) and small (<100 µm) arterioles. Topical application of these drugs induced no changes in mean blood pressure or heart rate. The observed differences in the microvascular alterations induced by the stereoisomers of ropivacaine and bupivacaine suggest that the vasoactive effects of these drugs on cerebral arterioles could, at least in part, depend on their chirality.

IMPLICATIONS: The differential effects of the stereoisomers of ropivacaine and bupivacaine on cerebral pial vessels could, at least in part, depend on their chirality.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
A lthough it is clear that amide local anesthetics affect vascular tone, their exact peripheral vas cular effects are controversial, with both vasodilation and vasoconstriction having been reported (1–6). Chiral local anesthetics, such as ropivacaine [S(-) ropivacaine] and levobupivacaine [S(-) bupivacaine], have been introduced into clinical anesthesia because of their potential advantage over racemic mixtures in terms of reduced toxic effects (7–10). We previously reported that although S(-) ropivacaine produced a concentration-dependent vasoconstriction of spinal and cerebral pial vessels in dogs (11,12), racemic bupivacaine produced a concentration-dependent vasodilation of spinal pial vessels (11). We speculated that the vasoactive effect of S(-) ropivacaine on spinal and cerebral vessels might be related to its chirality (11), although the mechanisms by which ropivacaine and bupivacaine affect vascular tone in the cerebral and spinal beds are not clearly understood. In this study, we evaluated the differential effects of the stereoisomers of ropivacaine and bupivacaine on cerebral pial vascular diameters by using a closed cranial window technique.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The procedures used in this study conformed with the Guideline Principles in the Care and Use of Animals as approved by the Council of the American Physiologic Society. The experimental protocols were approved by our Institutional Committee for Animal Care. The experiments were performed in 16 anesthetized dogs weighing from 6 to 10 kg. Anesthesia was induced with pentobarbital sodium (20 mg/kg, IV) and maintained with a continuous infusion of the same drug (2 mg · kg-1 · min-1). After tracheal intubation, each dog was mechanically ventilated with oxygen-enriched room air. The tidal volume and respiratory rate were adjusted to maintain an end-tidal CO2 of 35–40 mm Hg. A polyvinyl chloride catheter was placed in a femoral vein for the administration of drugs and fluids, and another was placed in a femoral artery for blood pressure monitoring and blood sampling. Rectal temperature was maintained between 36.5° and 37.5°C with the aid of a warming blanket.

A closed cranial window was used to observe the pial microcirculation. The animal was placed in the sphinx position with the head immobilized in a stereotactic frame. The scalp was retracted, the temporal muscle was removed, and a hole 2 cm in diameter was made in the parietal bone. After electrocoagulation of dural vessels, the dura and arachnoid membrane were cut and retracted over the bone. A ring fitted with a cover glass was placed over the hole and secured with dental acrylic. The ends of four polyvinyl chloride catheters were inserted through the ring. The space under the window was filled with artificial cerebrospinal fluid (aCSF) of the following composition: Na+, 151 mEq/L; K+, 4 mEq/L; Ca2+, 3 mEq/L; Mg2+, 1.3 mEq/L; Cl-, 110 mEq/L; HCO3-, 25 mEq/L; urea, 40 mg/dL; and glucose, 67 mg/dL. The pH was adjusted to 7.48. The solution was freshly prepared each day and bubbled with 5% CO2 in air at 37°C. One catheter was attached to a reservoir bottle containing aCSF to maintain a constant intrawindow pressure of 5 mm Hg. Two other catheters were used for infusion and drainage of aCSF and experimental drug solutions, and the final catheter was used for continuous monitoring of intrawindow pressure. The volume below the window was between 0.5 and 1 mL. Intrawindow temperature was monitored with a thermometer (Model 6510; Mallinckrodt Medical, St. Louis, MO) and was between 36.5 and 37.5°C.

All in vivo experiments were performed in the following manner. The R(+), racemic, and S(-) forms of ropivacaine (Astra, Södertälje, Sweden) and bupivacaine (Sigma, St. Louis, MO and Chiroscience, Cambridge, UK) were freshly dissolved in aCSF, making three different concentrations (10-7, 10-5, and 10-3 M) of each drug. Meanwhile, the animals were allowed to recover from the surgical procedures for at least 30 min. We confirmed the carbon dioxide reactivity of pial vessels prepared with the cranial window before and after the experiment by comparing it with our previous data (13) (in the hypercapnic condition [partial pressure of carbon dioxide in arterial blood, 55–60 mm Hg], the diameter of pial arterioles was increased more than 5% compared with normocapnia; no animal was excluded in this study). Pial arteriolar diameters, mean arterial pressure, heart rate, arterial blood gas tensions, pH, blood sugar, and serum electrolytes were measured before and after topical application of each test solution into the cranial window. To establish the baseline size of the various vessels, the window was continuously flushed with aCSF at a rate of 0.5 to 1 mL/min for 20 min. This was also done after each measurement. Twenty minutes after the last administration of the study solutions, the cerebral pial vascular diameters had returned to baseline values.

In each dog, the diameters of four pial arterioles (two >=100 µm and two <100 µm) were measured after the administration of each solution. The three concentrations of the three stereoisomers of a given drug were applied in a randomized manner, and a given dog received only one drug (ropivacaine or bupivacaine). The data from each view were stored on videotape for later playback and analysis. Diameter measurements were made with a videomicrometer (Olympus Flovel videomicrometer, model VM-20; Flovel, Tokyo, Japan) attached to a microscope (Model SZH-10; Olympus, Tokyo, Japan).

All variables used to assess the concentration-dependent effects of the experimental drugs were tested by a one-way analysis of variance (ANOVA) for repeated measures and a paired Student’s t-test with a Bonferroni correction for post hoc comparisons. Differences among drugs at the same concentration were tested by a one-way ANOVA followed by an unpaired Student’s t-test with a Bonferroni correction. Significance was set at P < 0.05. All results are expressed as mean ± SD.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Neither mean arterial pressure nor heart rate changed significantly after thetopical administration of any drug [R(+), racemic, or S(-) forms of ropivacaine or bupivacaine] at any of three concentrations used (Tables 1 and 2). Moreover, arterial blood gas tensions, pH, serum electrolytes, and blood sugar were all unchanged by any concentration of these drugs in either set of experiments. The baseline diameters were 152 ± 47 µm for large cerebral arterioles and 58 ± 17 µm for small cerebral arterioles.


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  		Table 1. Hemodynamic Measurements (Ropivacaine Group)
 

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  		Table 2. Hemodynamic Measurements (Bupivacaine Group)
 
Each of the three forms of ropivacaine constricted cerebral pial arterioles in a concentration-dependent manner (Fig. 1). The rank order for the degree of vasoconstriction was S(-) ropivacaine > racemic ropivacaine > R(+) ropivacaine. In contrast, R(+) bupivacaine and racemic bupivacaine dilated, whereas S(-) bupivacaine constricted, cerebral pial arterioles, each in a concentration-dependent manner (Fig. 2). We could detect no difference in vascular reactivity to these drugs between large (>=100 µm) and small (<100 µm) arterioles.



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  		Figure 1. Concentration-related effects of three stereoisomers of ropivacaine on the diameter of large (>=100 µm) and small (<100 µm) cerebral pial arterioles in eight dogs. Data are expressed as percentage change in diameter. A concentration-dependent decrease in diameter was observed after topical administration of each stereoisomer. At the concentrations tested, S(-) ropivacaine caused significantly larger arteriolar constrictions than either racemic or R(+) ropivacaine. There was no clear difference in vascular reactivity to these drugs between large and small arterioles. Values are mean ± SD. {dagger}P < 0.05 compared with the corresponding value at 10-7 M. §P < 0.05 compared with the corresponding value at 10-5 M. *P < 0.05 between the indicated values. NS = not significant.

 


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  		Figure 2. Concentration-related effects of three stereoisomers of bupivacaine on the diameter of large (>=100 µm) and small (<100 µm) cerebral pial arterioles in eight dogs. Data are expressed as percentage change in diameter. A concentration-dependent increase in diameter was observed after topical administration of R(+) and racemic bupivacaine, whereas a concentration-dependent decrease in diameter was observed after the topical administration of S(-) bupivacaine. There was no clear difference in vascular reactivity to these drugs between large and small arterioles. Values are mean ± SD. {dagger}P < 0.05 compared with the corresponding value at 10-7 M. §P < 0.05 compared with the corresponding value at 10-5 M. *P < 0.05 between the indicated values. NS = not significant.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The major findings of this study were that on topical application, each of the three forms of ropivacaine constricted cerebral pial arterioles in a concentration-dependent manner, with the rank order being S(-) ropivacaine > racemic ropivacaine > R(+) ropivacaine, whereas R(+) bupivacaine and racemic bupivacaine dilated these vessels and S (-) bupivacaine constricted them, each in a concentration-dependent manner. Large and small arterioles did not differ in their vascular reactivity to these drugs. Thus, the differences between ropivacaine and bupivacaine in terms of the effects of their stereoisomers on cerebral pial arterioles could, at least in part, depend on their chirality.

It is generally accepted that the effect of a given local anesthetic on the vasculature influences its in vivo potency and duration of action. The vasoconstriction of cerebral vessels induced by S(-) bupivacaine in this study is consistent with previous reports that S(-) bupivacaine was more of a vasoconstrictor than R(+) bupivacaine in intradermal tests (14,15). A slower absorption of S(-) bupivacaine than of R(+) bupivacaine from the site of administration in the central nervous system (such as during epidural or spinal anesthesia) might be indicated by our results and contribute to the differences in toxicity between them.

One article indicates that cerebral blood flow (CBF) increases during local anesthetic-induced convulsions (16), and also it has been observed that CBF increases and cerebral arterioles dilate during seizures induced by bicuculline (17) and pentylenetetrazole (18). Thus, in view of the coupling between metabolism and blood flow, it may be considered a potential hazard that a toxic dose of S(-) ropivacaine and S(-) bupivacaine given systemically would presumably decrease CBF (as a result of the vasoconstriction induced) during convulsions, although cerebral metabolic demand for oxygen is increased (19). Further studies are needed to clarify whether the convulsive doses of the S(-) enantiomers of local anesthetics do indeed have such effects when given systematically or whether they in some way alter the relationship between metabolism and blood flow in the brain, spinal cord, or both.

The mechanisms by which the stereoisomers of ropivacaine and bupivacaine alter the caliber of cerebral pial vessels are not clear. A number of investigators have speculated on the mechanisms by which local anesthetics might cause changes in vessel diameters. These putative mechanisms include a direct activation of smooth muscle in precapillary vessels, postcapillary vessels, or both (1), an indirect release of vasoactive substances or a blockade of the release of vasoactive substances (20), a blockade of the sympathetic nerves innervating the vessels (21), an increase in cytoplasmic calcium (vasoconstriction) or a calcium-channel blockade (vasodilation) (4), and a decrease in the tissue’s metabolic demands (21,22). None of these mechanisms is completely consistent with the results of this study, and we also do not clarify whether the vasoactivity of ropivacaine and bupivacaine is related to a direct or an indirect effect on cerebral vessels. In this study, the two R(+) enantiomers had opposite effects on cerebral pial vessels, whereas the two S(-) enantiomers had similar (vasoconstrictor) effects. This phenomenon cannot be explained simply by differences in the vasoactivity of ropivacaine and bupivacaine. The results of this study seem to indicate that each local anesthetic has a basic vasoactive effect on pial arterioles (vasoconstriction for ropivacaine and vasodilation for bupivacaine) that is modified by effects caused by chiral differences.

Because the basal anesthetic state with pentobarbital might affect the tone of the cerebral arterioles, we cannot exclude the possibility that the observed effects on pial arteriolar tone induced by the stereoisomers of ropivacaine and bupivacaine could have been modulated by the presence of pentobarbital.

In conclusion, the differences in the observed cerebral microvascular effects of the stereoisomers of ropivacaine and bupivacaine suggest that the actual effects of these drugs on cerebral vessels could, at least in part, depend on their chirality, although the precise underlying mechanisms remain unknown.


   Acknowledgments
 
Supported by Grants-in-Aid 11671489 and 13671570 for Scientific Research from the Ministry of Education, Science, and Culture, Japan.


   Footnotes
 
Presented in part at the XIX International Symposium on Cerebral Blood Flow and Metabolism, Copenhagen, June 15–19, 1999.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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  3. Cederholm I, Evers H, Lofstrom JB. Effect of intradermal injection of saline or a local anaesthetic agent on skin blood flow: a methodological study in man. Acta Anaesthesiol Scand 1991; 35: 208–15.[Web of Science][Medline]
  4. Johns RA, Seyde WC, DiFazio CA, Longnecker DE. Dose-dependent effects of bupivacaine on rat muscle arterioles. Anesthesiology 1986; 65: 186–91.[Web of Science][Medline]
  5. Santos AC, Arthur GR, Roberts DJ, et al. Effect of ropivacaine and bupivacaine on uterine blood flow in pregnant ewes. Anesth Analg 1992; 74: 62–7.[Abstract/Free Full Text]
  6. Johns RA, DiFazio CA, Longnecker DE. Lidocaine constricts or dilates rat arterioles in a dose-dependent manner. Anesthesiology 1985; 62: 141–4.[Web of Science][Medline]
  7. Nancarrow C, Rutten AJ, Runciman WB, et al. Myocardial and cerebral drug concentrations and the mechanisms of death after fatal intravenous doses of lidocaine, bupivacaine, and ropivacaine in the sheep. Anesth Analg 1989; 69: 276–83.[Abstract/Free Full Text]
  8. Scott DB, Lee A, Fagan D, et al. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg 1989; 69: 563–9.[Abstract/Free Full Text]
  9. Denson DD, Behbehani MM, Gregg RV. Enantiomer-specific effects of an intravenously administered arrhythmogenic dose of bupivacaine on neurons of the nucleus tractus solitarius and the cardiovascular system in the anesthetized rat. Reg Anesth 1992; 17: 311–6.[Web of Science][Medline]
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  12. 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]
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  19. Drummond JC, Patel PM. Cerebral physiology and the effects of anesthetics and techniques. In: Miller RD, ed. Anesthesia. 5th ed. Philadelphia: Churchill Livingstone, 2000: 695–733.
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Accepted for publication July 18, 2001.




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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