Abstract
Autoregulation, an important feature of the cerebral circulation, is affected in many diseases. Since genetically modified mice are a fundamental tool in biomedical research, including neuro(bio)logy also in this specie measurements of cerebral autoregulation (CA) are mandatory. However, this requires anesthesia that unfortunately significantly impacts cerebral perfusion and consequently might distort CA measurements directly or by altering arterial pCO2. The latter can be avoided by artificial ventilation but requires several control measurements of blood gases, each consuming at least 100 μl of blood or 5% of a mouse’s blood volume. To avoid such diagnostic hemorrhage, we systematically analyzed the effect of different common anesthetic protocols used for rodents in spontaneously breathing mice on CA measured with Laser speckle perfusion imaging. Halothane, Isoflurane and Pentobarbital abrogated CA and Ketamin/Xylazine as well as Chloralose had a moderate reproducibility. In contrast, the rather rarely used anesthetic Ethomidate applied in low doses combined with local anesthetics had the best reproducibility. Although with this anesthesia the lower CA limit was lower than with Ketamin/Xylazine and Chloralose as reported in the handful of papers so far dealing with CA in mice, we suggest Ethomidate as the anesthetic of choice for CA measurements in spontaneously breathing mice.
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References
Ayata C, Dunn AK, Gursoy OY, Huang Z, Boas DA, Moskowitz MA (2004) Laser speckle flowmetry for the study of cerebrovascular physiology in normal and ischemic mouse cortex. J Cereb Blood Flow Metab 24:744–755
Bosnjak ZJ, Aggarwal A, Turner LA, Kampine JM, Kampine JP (1992) Differential effects of halothane, enflurane, and isoflurane on Ca2 + transients and papillary muscle tension in guinea pigs. Anesthesiology 76:123–131
Campen MJ, Tagaito Y, Li J, Balbir A, Tankersley CG, Smith P, Schwartz A, O’Donnell CP (2004) Phenotypic variation in cardiovascular responses to acute hypoxic and hypercapnic exposure in mice. Physiol Genomics 20:15–20
Famewo CE, Odugbesan CO (1978) Further experience with etomidate. Can Anaesth Soc J 25:130–132
Faraci FM, Heistad DD (1998) Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev 78:53–97
Foley LM, Hitchens TK, Kochanek PM, Melick JA, Jackson EK, Ho C (2005) Murine orthostatic response during prolonged vertical studies: effect on cerebral blood flow measured by arterial spin-labeled MRI. Magn Reson Med 54:798–806
Harper SL (1987) Antihypertensive drug therapy prevents cerebral microvascular abnormalities in hypertensive rats. Circ Res 60:229–237
Hu K, Peng CK, Czosnyka M, Zhao P, Novak V (2008) Nonlinear assessment of cerebral autoregulation from spontaneous blood pressure and cerebral blood flow fluctuations. Cardiovasc Eng 8:60–71
Immink RV, van den Born BJ, van Montfrans GA, Koopmans RP, Karemaker JM, van Lieshout JJ (2004) Impaired cerebral autoregulation in patients with malignant hypertension. Circulation 110:2241–2245
Janssen PA, Niemegeers CJ, Marsboom RP (1975) Etomidate, a potent non-barbiturate hypnotic. Intravenous etomidate in mice, rats, guinea-pigs, rabbits and dogs. Arch Int Pharmacodyn Ther 214:92–132
Joutel A, Monet-Lepretre M, Gosele C, Baron-Menguy C, Hammes A, Schmidt S, Lemaire-Carrette B, Domenga V, Schedl A, Lacombe P, Hubner N (2010) Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease. J Clin Invest 120:433–445
Kumaria A, Tolias CM (2009) Normobaric hyperoxia therapy for traumatic brain injury and stroke: a review. Br J Neurosurg 23:576–584
Kuschinsky W (1982) Role of hydrogen ions in regulation of cerebral blood flow and other regional flows. Adv Microcirc 11:1–19
Kuschinsky W (1990) Coupling of blood flow and metabolism in the brain. J Basic Clin Physiol Pharmacol 1:191–201
Kuschinsky W (1991) Coupling of function, metabolism, and blood flow in the brain. Neurosurg Rev 14:163–168
Kuschinsky W (1997) Neuronal-vascular coupling. A unifying hypothesis. Adv Exp Med Biol 413:167–176
Lacombe P, Oligo C, Domenga V, Tournier-Lasserve E, Joutel A (2005) Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy. Stroke 36:1053–1058
Lo MT, Hu K, Liu Y, Peng CK, Novak V (2008) Multimodal Pressure Flow Analysis: Application of Hilbert Huang Transform in Cerebral Blood Flow Regulation. EURASIP J Appl Signal Processing 2008:785243
McCulloch TJ, Boesel TW, Lam AM (2005) The effect of hypocapnia on the autoregulation of cerebral blood flow during administration of isoflurane. Anesth Analg 100:1463–1467 table of contents
Merzeau S, Preckel MP, Fromy B, Leftheriotis G, Saumet JL (2000) Differences between cerebral and cerebellar autoregulation during progressive hypotension in rats. Neurosci Lett 280:103–106
Niwa K, Kazama K, Younkin L, Younkin SG, Carlson GA, Iadecola C (2002) Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein. Am J Physiol Heart Circ Physiol 283:H315–H323
Novak V, Yang AC, Lepicovsky L, Goldberger AL, Lipsitz LA, Peng CK (2004) Multimodal pressure-flow method to assess dynamics of cerebral autoregulation in stroke and hypertension. Biomed Eng Online 3:39
Ogoh S, Nakahara H, Ainslie PN, Miyamoto T (2010) The effect of oxygen on dynamic cerebral autoregulation: critical role of hypocapnia. J Appl Physiol 108:538–543
Panerai RB (2008) Cerebral autoregulation: from models to clinical applications. Cardiovasc Eng 8:42–59
Paterno R, Heistad DD, Faraci FM (2000) Potassium channels modulate cerebral autoregulation during acute hypertension. Am J Physiol Heart Circ Physiol 278:H2003–H2007
Paulson OB, Strandgaard S, Edvinsson L (1990) Cerebral autoregulation. Cerebrovasc Brain Metab Rev 2:161–192
Pedersen TF, Paulson OB, Nielsen AH, Strandgaard S (2003) Effect of nephrectomy and captopril on autoregulation of cerebral blood flow in rats. Am J Physiol Heart Circ Physiol 285:H1097–H1104
Rosengarten B, Hecht M, Kaps M (2006) Carotid compression: investigation of cerebral autoregulative reserve in rats. J Neurosci Methods 152:202–209
Schubert GA, Schilling L, Thome C (2008) Clazosentan, an endothelin receptor antagonist, prevents early hypoperfusion during the acute phase of massive experimental subarachnoid hemorrhage: a laser Doppler flowmetry study in rats. J Neurosurg 109:1134–1140
Schuler B, Rettich A, Vogel J, Gassmann M, Arras M (2009) Optimized surgical techniques and postoperative care improve survival rates and permit accurate telemetric recording in exercising mice. BMC Vet Res 5:28
Schuler B, Arras M, Keller S, Rettich A, Lundby C, Vogel J, Gassmann M (2010) Optimal hematocrit for maximal exercise performance in acute and chronic erythropoietin-treated mice. Proc Natl Acad Sci USA 107:419–423
Strandgaard S (1976) Autoregulation of cerebral blood flow in hypertensive patients. The modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug-induced hypotension. Circulation 53:720–727
Tonnesen J, Pryds A, Larsen EH, Paulson OB, Hauerberg J, Knudsen GM (2005) Laser Doppler flowmetry is valid for measurement of cerebral blood flow autoregulation lower limit in rats. Exp Physiol 90:349–355
Verhaegen MJ, Todd MM, Hindman BJ, Warner DS (1993) Cerebral autoregulation during moderate hypothermia in rats. Stroke 24:407–414
Vogel J, Kuschinsky W (1996) Decreased heterogeneity of capillary plasma flow in the rat whisker barrel cortex during functional hyperemia. J Cereb Blood Flow Metab 16:1300–1306
Vorstrup S, Barry DI, Jarden JO, Svendsen UG, Braendstrup O, Graham DI, Strandgaard S (1984) Chronic antihypertensive treatment in the rat reverses hypertension-induced changes in cerebral blood flow autoregulation. Stroke 15:312–318
Waschke KF, Krieter H, Hagen G, Albrecht DM, Van-Ackern K, Kuschinsky W (1994) Lack of dependence of cerebral blood flow on blood viscosity after blood exchange with a Newtonian O2 carrier. J Cereb Blood Flow Metab 14:871–876
Werber AH, Fitch-Burke MC, Harrington DG, Shah J (1990) No rarefaction of cerebral arterioles in hypertensive rats. Can J Physiol Pharmacol 68:476–479
Yasuda N, Targ AG, Eger EI 2nd (1989) Solubility of I-653, sevoflurane, isoflurane, and halothane in human tissues. Anesth Analg 69:370–373
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J. V. is supported by the Swiss National Science Foundation (310000_120321/1).
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Wang, Z., Schuler, B., Vogel, O. et al. What is the optimal anesthetic protocol for measurements of cerebral autoregulation in spontaneously breathing mice?. Exp Brain Res 207, 249–258 (2010). https://doi.org/10.1007/s00221-010-2447-4
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DOI: https://doi.org/10.1007/s00221-010-2447-4