Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Sevoflurane reduces endothelium-dependent vasorelaxation: role of Superoxide anion and endothelin

Le sévoflurane réduit la vasorelaxation provenant de l’endothélium: le rôle de l’anion superoxyde et de l’endothéline

  • 266 Accesses

  • 12 Citations



There are several reports suggesting that volatile anesthetics alter vascular endothelial function. We analyzed the effect of sevoflurane, a fluorinated volatile anesthetic, on nitric oxide (NO)-dependent relaxation, evaluating the role of the endotheliumderived vasoconstrictor endothelin-1 (ET-1).


The experiments were performed in rat isolated aortic segments aerated in the absence and in the presence of sevoflurane (2%).


Acetylcholine-induced relaxation was reduced in aortic segments aerated with sevoflurane. Sevoflurane failed to modify relaxatation in response to an exogenous NO donor, sodium nitroprusside. Superoxide dismutase, a scavenger of Superoxide anion, partially restored the impaired vasorelaxation induced by sevoflurane, an effect that was associated with the release of Superoxide anion. The presence of BQ-123, an antagonist of endothelin ETA-type receptors, normalized the vasorelaxing response to acetylcholine in the presence of sevoflurane. In addition, BQ-123 also reduced the ability of the sevoflurane-incubated vascular wall to release Superoxide anion.


Our results suggest that sevoflurane impairs the endothelium-dependent vasorelaxation but that the endotheliumindependent response remains intact. ET-1 and Superoxide anion are involved in the endothelial dysfunction induced by sevoflurane. Further studies are needed to associate the endothelial dysfunction related to sevoflurane shown herein and its reported preconditioning properties on the myocardium.



Certains articles suggèrent que les anesthésiques volatils modifient la fonction endothéliale vasculaire. Nous avons analysé l’effet du sévoflurane, un anesthésique volatil fluoré, sur la relaxation liée à l’oxyde nitrique (NO) en évaluant le rôle de l’endothéline-1 (ET-1) vasoconstrictrice d’origine endothéliale.


Les expériences ont été réalisées sur des segments aortiques isolés de rat aérés en l’absence et en présence de sévoflurane à 2 %.


La relaxation induite par l’acétylcholine a été réduite dans les segments aérés avec le sévoflurane. Le sévoflurane n’a pas modifié la relaxation en réponse à un donneur de NO exogène, le nitroprussiate de sodium. La superoxyde dismutase, un piégeur de l’anion superoxyde, a partiellement restauré la vasorelaxation modifiée induite par le sévoflurane, un effet qui est associé à la libération de l’anion superoxyde. La présence de BQ-123, un antagoniste des récepteurs de type endothéline ETA, a normalisé la réponse vasorelaxante à l’acétylcholine en présence du sévoflurane. Le BQ-123 a aussi réduit la capacité de la paroi vasculaire mise en incubation dans le sévoflurane à libérer l’anion superoxyde.


Nos résultats laissent croire que le sévoflurane affecte la vasorelaxation d’origine endothéliale mais que la réponse indépendante de l’endothélium demeure intacte. LET-1 et l’anion superoxyde sont impliqués dans le dérèglement endothélial induit par le sévoflurane. D’autres études seront nécessaires pour pouvoir associer le dérèglement endothélial relié au sévoflurane démontré ici et ses propriétés mentionnées de préconditionnement sur le myocarde.


  1. 1

    Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43: 109–42.

  2. 2

    Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329: 2002–12.

  3. 3

    López-Farré A, Caramelo C, Esteban A, et al. Effects of aspirin on platelet-neutrophil interactions. Role of nitric oxide and endothelin-1. Circulation 1995; 91: 2080–8.

  4. 4

    Trachtman H, Futterweit S, Singhal P. Nitric oxide modulates the synthesis of extracellular matrix proteins in cultured rat mesangial cells. Biochem Biophys Res Commun 1995; 207: 120–5.

  5. 5

    Sessa WC. The nitric oxide synthase family of proteins. J Vasc Res 1994; 31: 131–43.

  6. 6

    Katsuki S, Arnold W, Mittal C, Murad F. Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerine and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxilamine. J Cyclic Nucleotide Res 1977; 3: 23–35.

  7. 7

    Moncada S, Palmer RMJ, Gryglewski RJ. Mechanism of action of some inhibitors of endothelium-derived relaxing factor. Proc Natl Acad Sci USA 1986; 83: 9164–8.

  8. 8

    López-Farré A, Riesco A, Digiuni E, et al. Aspirin-stimulated nitric oxide production by neutrophils after acute myocardial ischemia in rabbits. Circulation 1996; 94: 83–7.

  9. 9

    Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–5.

  10. 10

    Wallin RF, Regan BM, Napoli MD, Stern IJ. Sevoflurane: a new inhalational anesthetic agent. Anesth Analg 1975; 54: 758–66.

  11. 11

    Holaday DA, Smith FR. Clinical characteristics and biotransformation of sevoflurane in healthy human volunteers. Anesthesiology 1981; 54: 100–6.

  12. 12

    Stone DJ, Johns RA. Endothelium-dependent effects of halothane, enflurane, and isoflurane on isolated rat aortic vascular rings. Anesthesiology 1989; 71: 126–32.

  13. 13

    Gallego MJ, García-Villalón AL, López Farré AJ, et al. Mechanisms of the endothelial toxicity of cyclosporin A. Role of nitric oxide, cGMP, and Ca2+. Circ Res 1994; 74: 477–84.

  14. 14

    Yamaguchi A, Okabe E. Effect of sevoflurane on the vascular reactivity of rabbit mensenteric artery. Br J Anaesth 1995; 74: 576–82.

  15. 15

    Yoshida K, Okabe E. Selective impairment of endothelium-dependent relaxation by sevoflurane: oxygen free radicals participation. Anesthesiology 1992; 76: 440–7.

  16. 16

    Nakamura K, Terasako K, Toda H, et al. Mechanisms of inhibition of endothelium-dependent relaxation by halotane, isoflurane and sevoflurane. Can J Anaesth 1994; 41: 340–6.

  17. 17

    Hirata Y, Itoh K-I, Ando K, Endo M, Marumo F. Plasma endothelin levels during surgery (Letter). N Engl J Med 1989; 321: 1686.

  18. 18

    Pollock DM, Keith TL, Highsmith RF. Endothelin receptors and calcium signaling. FASEB J 1995; 9: 1196–204.

  19. 19

    Liu Y, Geisbuhler B, Jones AW. Activation of multiple mechanisms including phospholipase D by endothelin1 in rat aortic. Am J Physiol 1992; 262: C941–9.

  20. 20

    Haller H, Schaberg T, Lindschau C, Lode H, Distler A. Endothelin increases [Ca2+]i, protein phosphorylation, and O2production in human alveolar macrophages. Am J Physiol 1991; 261: L478–84.

  21. 21

    Bugajski P, Kalawski R, Balinski M, et al. Plasma-mediated stimulation of neutrophil Superoxide anion production during coronary artery bypass grafting: role of endothelin-1. Thorac Cardiovasc Surg 1999; 47: 144–7.

  22. 22

    Boulanger C, Lüscher TF. Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest 1990; 85: 587–90.

  23. 23

    Izumi K, Akata T, Takahashi S. The action of sevoflurane on vascular smooth muscle of isolated mesenteric resistance arteries (part 1). Anesthesiology 2000; 92: 1426–40.

  24. 24

    Toda H, Nakamura K, Hatano Y, Nishiwada M, Kakuyama M, Mori K. Halothane and isoflurane inhibit endothelium-dependent relaxation elicited by acetylcholine. Anesth Analg 1992; 75: 198–203.

  25. 25

    Muldoon SM, Hart JL, Bowen KA, Freas W. Attenuation of endothelium-mediated vasodilation by halothane. Anesthesiology 1988; 68: 31–7.

  26. 26

    Az-ma T, Fujii K, Yuge O. Inhibitory effect of sevoflurane on nitric oxide release from cultured endothelial cells. Eur J Pharmacol 1995; 289: 33–9.

  27. 27

    Dinerman JL, Mehta JL. Endothelial, platelet and leukocyte interactions in ischemic heart disease: insights into potential mechanisms and their clinical relevance. J Am Coll Cardiol 1990; 16: 207–22.

  28. 28

    Pearson PJ, Schaff HV, Vanhoutte PM. Acute impairment of endothelium-dependent relaxations to aggregating platelets following reperfusion injury in canine coronary arteries. Cir Res 1990; 67: 385–93.

  29. 29

    Kersten JR, Orth KG, Pagel PS, Mei DA, Gross GJ, Warltier DC. Role of adenosine in isoflurane-induced cardioprotection. Anesthesiology 1997; 86: 1128–39.

  30. 30

    Buljubasic N, Marijic J, Stowe DF, Kampine JP, Bosnjak ZJ. Halothane reduces dysrhythmias and improves contractile function after global hypoperfusion in isolated hearts. Anesth Analg 1992; 74: 384–94.

  31. 31

    Yamazi M, Stekiel TA, Bosnjak ZJ, Kampine JP, Stekiel WJ. Effect of volatile anesthetic agents on in situ vascular smooth muscle transmembrane potential in resistance-and capacitance-regulating blood vessels. Anesthesiology 1998; 88: 1085–95.

Download references

Author information

Correspondence to Juan Carlos de la Pinta.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Arriero, M.M., Alameda, L.M., Lopez-Farré, A. et al. Sevoflurane reduces endothelium-dependent vasorelaxation: role of Superoxide anion and endothelin. Can J Anesth 49, 471–476 (2002).

Download citation


  • Sevoflurane
  • Aortic Ring
  • Volatile Anesthetic
  • Aortic Segment
  • Release Superoxide Anion