Disproportional cardiovascular depressive effects of isoflurane: Serendipitous findings from a comprehensive re-visit in mice

Abstract

Employment of anesthetics, including isoflurane, though mandatory in animal experiments, is often regarded as a major limitation because results obtained with anesthetics may be different from those obtained under a conscious state. This study re-visits two issues related to the use of isoflurane. First, does isoflurane exert depression equally on all aspects of cardiovascular functions and their regulations? Second, is the circulatory supply of oxygen to brain tissues sufficient under isoflurane anesthesia? We determined in male C57BL/6J mice the temporal effects of 1.5% (vol/vol) isoflurane on blood pressure (BP), heart rate (HR), cardiac performance, baroreflex-mediated sympathetic vasomotor tone, cardiac vagal baroreflex, functional connectivity within the baroreflex neural circuits, carotid or cerebral blood flow, cortical tissue oxygen level, respiratory rate and blood gas. Over 150 min after exposure to 1.5% isoflurane, BP and HR were sustained at 71% and 79% of their awake levels amid a trend of progressive increase. Cardiac performance was within physiological ranges. Baroreflex-mediated sympathetic vasomotor tone gradually reversed from an 85% reduction toward the conscious level, alongside a parallel decrease in inhibitory connectivity between nucleus tractus solitarii (NTS) and rostral ventrolateral medulla. A decline in excitatory connectivity between NTS and nucleus ambiguus accompanied the decrease in cardiac vagal baroreflex. There were progressive increases in carotid or cerebral blood flow and tissue oxygen tension in cerebral cortex, alongside gradual hypoventilation, mild respiratory acidosis and hypercapnia. We conclude that, by eliciting disproportional depressive actions on cardiovascular functions and their regulations, which sustain circulatory supply of oxygen to brain tissues, 1.5% isoflurane is sufficient to maintain optimal cardiovascular functions in mice.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Experimental set up.
Fig. 2: Temporal changes in mean arterial pressure (MAP), HR, power density of the low-frequency component in the systolic BP spectrum (BLF), baroreflex sensitivity (BRS), RR and baroreflex effectiveness index (BEI) in mice from an awake, resting state (C) to under 1.5% (vol/vol) isoflurane for 150 min.
Fig. 3: Temporal changes in functional connectivity within baroreflex neural circuits in mice under 1.5% (vol/vol) isoflurane for 150 min.
Fig. 4: Temporal changes in carotid blood flow (CBF), tissue oxygen tension (PO2), tissue perfusion (Flow) and tissue temperature in the cerebral cortex of mice subjected to 1.5% (vol/vol) isoflurane for 150 min.

Data availability

The data that support the findings of this study may be sought from the corresponding author under the author’s discretion.

References

  1. 1.

    Cesarovic, N. et al. Isoflurane and sevoflurane provide equally effective anaesthesia in laboratory mice. Lab Anim. 44, 329–336 (2010).

    CAS  Article  Google Scholar 

  2. 2.

    Lindsey, M. L. et al. Guidelines for measuring cardiac physiology in mice. Am. J. Physiol. Heart Circ. Physiol. 314, H733–H752 (2018).

    Article  Google Scholar 

  3. 3.

    Bosnjak, Z. J. & Kampine, J. P. Effects of halothane, enflurane, and isoflurane on the SA node. Anesthesiology 58, 314–321 (1983).

    CAS  Article  Google Scholar 

  4. 4.

    Sousa, M. G. et al. Effects of isoflurane on echocardiographic parameters in healthy dogs. Vet. Anaesth. Analg. 35, 185–190 (2008).

    CAS  Article  Google Scholar 

  5. 5.

    Akata, T. et al. Effects of volatile anesthetics on acetylcholine-induced relaxation in the rabbit mesenteric resistance artery. Anesthesiology 82, 188–204 (1995).

    CAS  Article  Google Scholar 

  6. 6.

    Yamazaki, M. et al. Effects of volatile anesthetic agents on in situ vascular smooth muscle transmembrane potential in resistance- and capacitance-regulating blood vessels. Anesthesiology 88, 1085–1095 (1998).

    CAS  Article  Google Scholar 

  7. 7.

    Saeki, Y. et al. The effects of sevoflurane, enflurane, and isoflurane on baroreceptor-sympathetic reflex in rabbits. Anesth. Analg. 82, 342–348 (1996).

    CAS  PubMed  Google Scholar 

  8. 8.

    Seagard, J. L. et al. Effects of isoflurane on the baroreceptor reflex. Anesthesiology 59, 511–520 (1983).

    CAS  Article  Google Scholar 

  9. 9.

    Lee, J. S. et al. Isoflurane depresses baroreflex control of heart rate in decerebrate rats. Anesthesiology 96, 1214–1222 (2002).

    CAS  Article  Google Scholar 

  10. 10.

    Dampney, R. A. Functional organization of central pathways regulating the cardiovascular system. Physiol. Rev. 74, 323–364 (1994).

    CAS  Article  Google Scholar 

  11. 11.

    Strebel, S. et al. Dynamic and static cerebral autoregulation during isoflurane, desflurane, and propofol anesthesia. Anesthesiology 83, 66–76 (1995).

    CAS  Article  Google Scholar 

  12. 12.

    Tiecks, F. P. et al. Comparison of static and dynamic cerebral autoregulation measurements. Stroke 26, 1014–1019 (1995).

    CAS  Article  Google Scholar 

  13. 13.

    Paulson, O. B., Strandgaard, S. & Edvinsson, L. Cerebral autoregulation. Cerebrovasc. Brain Metab. Rev. 2, 161–192 (1990).

    CAS  PubMed  Google Scholar 

  14. 14.

    Armstead, W. M. Cerebral blood flow autoregulation and dysautoregulation. Anesthesiol. Clin. 34, 465–477 (2016).

    Article  Google Scholar 

  15. 15.

    Steffey, E. P. & Howland, D. Jr. Comparison of circulatory and respiratory effects of isoflurane and halothane anesthesia in horses. Am. J. Vet. Res. 41, 821–825 (1980).

    CAS  PubMed  Google Scholar 

  16. 16.

    Kato, K. et al. Different sensitivity to the suppressive effects of isoflurane anesthesia on cardiorespiratory function in SHR/Izm, WKY/Izm, and Crl:CD (SD) rats. Exp. Anim. 65, 393–402 (2016).

    CAS  Article  Google Scholar 

  17. 17.

    Constantinides, C., Mean, R. & Janssen, B. J. Effects of isoflurane anesthesia on the cardiovascular function of the C57BL/6 mouse. ILAR J. 52, e21–e31 (2011).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Tsai, C.-Y. et al. Anomalous baroreflex functionality inherent in floxed and Cre-Lox mice: an overlooked physiological phenotype. Am. J. Physiol. Heart Circ. Physiol. 313, H700–H707 (2017).

    CAS  Article  Google Scholar 

  19. 19.

    Li, P. L. et al. Potentiation of baroreceptor reflex response by heat shock protein 70 in nucleus tractus solitarii confers cardiovascular protection during heatstroke. Circulation 103, 2114–2119 (2001).

    CAS  Article  Google Scholar 

  20. 20.

    Poon, Y.-Y. et al. Endogenous nitric oxide derived from NOS I or II in thoracic spinal cord exerts opposing tonic modulation on sympathetic vasomotor tone via disparate mechanisms in anesthetized rats. Am. J. Physiol. Heart Circ. Physiol. 311, H555–H562 (2016).

    Article  Google Scholar 

  21. 21.

    Tsai, C.-Y. et al. Visualizing oxidative stress-induced depression of cardiac vagal baroreflex by MRI/DTI in a mouse neurogenic hypertension model. Neuroimage 82, 190–199 (2013).

    Article  Google Scholar 

  22. 22.

    Su, C.-H. et al. MRI/DTI of the brain stem reveals reversible and irreversible disruption of the baroreflex neural circuits: clinical implications. Theranostics 6, 837–848 (2016).

    CAS  Article  Google Scholar 

  23. 23.

    Tsai, C.-Y. et al. Baroreflex functionality in the eye of diffusion tensor imaging. J. Physiol. 597, 41–55 (2019).

    CAS  Article  Google Scholar 

  24. 24.

    Yang, X.-P. et al. Echocardiographic assessment of cardiac function in conscious and anesthetized mice. Am. J. Physiol. 277, H1967–H1974 (1999).

    CAS  Article  Google Scholar 

  25. 25.

    Tsutsumi, Y. M. et al. Isoflurane produces sustained cardiac protection after ischemia-reperfusion injury in mice. Anesthesiology 104, 495–502 (2006).

    CAS  Article  Google Scholar 

  26. 26.

    Yu, C.-M. et al. Tissue Doppler imaging. A new prognosticator for cardiovascular diseases. J. Am. Coll. Cardiol. 49, 1903–1914 (2007).

    Article  Google Scholar 

  27. 27.

    Geyer, H. et al. Assessment of myocardial mechanics using speckle tracking echocardiography: fundamentals and clinical applications. J. Am. Soc. Echocardiogr. 23, 351–369 (2010).

    Article  Google Scholar 

  28. 28.

    Cowley, A. W. Jr., Liard, J. F. & Guyton, A. C. Role of the baroreceptor reflex in daily control of arterial blood pressure and other variables in dogs. Circ. Res. 32, 564–576 (1973).

    Article  Google Scholar 

  29. 29.

    Thrasher, T. N. Baroreceptors and the long-term control of blood pressure. Exp. Physiol. 89, 331–335 (2004).

    Article  Google Scholar 

  30. 30.

    Lyons, D. G., Parpaleix, A., Roche, M. & Charpax, S. Mapping oxygen concentration in the awake mouse brain. eLife 5, e12024 (2016).

    Article  Google Scholar 

  31. 31.

    Ogoh, S. & Ainslie, P. N. Cerebral blood flow during exercise: mechanisms of regulation. J. Appl. Physiol. 107, 1370–1380 (2009).

    CAS  Article  Google Scholar 

  32. 32.

    Loepke, A. W. et al. The physiologic effects of isoflurane anesthesia in neonatal mice. Anesth. Analg. 102, 75–80 (2006).

    CAS  Article  Google Scholar 

  33. 33.

    Mukda, S. et al. Pinin protects astrocytes from cell death after acute ischemic stroke via maintenance of mitochondrial anti-apoptotic and bioenergetics functions. J. Biomed. Sci. 26, e43 (2019).

    Article  Google Scholar 

  34. 34.

    Tsai, C.-Y. et al. VEGF tonically sustains myocardial performance via fetal liver kinase-1 in the heart. Int. J. Cardiol. 177, 727–730 (2014).

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported in part by research grants MOST-107-2320-B-182A-024, MOST-108-2320-B-182A-007 and MOST-109-2320-B-182A-019 to S.H.H.C. from the Ministry of Science and Technology, Taiwan.

Author information

Affiliations

Authors

Contributions

Y.-Y.P., C.-Y.T., S.H.H.C. and J.Y.H.C. conceived and designed the study. Y.-H.H. and J.C.C.W. collected the data. Y.-Y.P., C.-Y.T., Y.-H.H. and J.C.C.W. analyzed the data. All authors wrote the manuscript.

Corresponding authors

Correspondence to Samuel H. H. Chan or Julie Y. H. Chan.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Poon, YY., Tsai, CY., Huang, Y. et al. Disproportional cardiovascular depressive effects of isoflurane: Serendipitous findings from a comprehensive re-visit in mice. Lab Anim 50, 26–31 (2021). https://doi.org/10.1038/s41684-020-00684-w

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing