Isoflurane-induced Cerebral Hyperemia Is Partially Mediated by Nitric Oxide and Epoxyeicosatrienoic Acids in Mice In Vivo

Background Despite intense investigation, the mechanism of isoflurane-induced cerebral hyperemia is unclear. The current study was designed to determine the contributions of neuronal nitric oxide synthase, prostaglandins, and epoxyeicosatrienoic acids to isoflurane-induced cerebral hyperemia. Methods Regional cerebral cortical blood flow was measured with laser Doppler flowmetry during stepwise increases of isoflurane from 0.0 to 1.2, 1.8, and 2.4 vol% end-tidal concentration in &agr;-chloralose–urethane-anesthetized, C57BL/6 mice before and 45 min after administration of the neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI, 40 mg/kg, intraperitoneal), the cyclooxygenase inhibitor indomethacin (INDO, 10 mg/kg, intravenous), and the cytochrome P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-proparglyoxyphenyl)hexanoic acid (PPOH, 20 mg/kg, intravenous). Results Isoflurane increased regional cerebral cortical blood flow by 9 ± 3, 46 ± 21, and 101 ± 26% (SD) at 1.2, 1.8, and 2.4 vol%, respectively. The increases in regional cerebral cortical blood flow were significantly (*P < 0.05) smaller after 7-NI (5 ± 6, 29 ± 19*, 68 ± 15%*) or PPOH (4 ± 8, 27 ± 17*, 67 ± 30%*), but not after administration of INDO (4 ± 4, 33 ± 18 [NS], 107 ± 35% [NS]). The effect of combined treatment with 7-NI, PPOH, and INDO was not additive and was equal to that of either 7-NI or PPOH alone (5 ± 5, 30 ± 12*, 76 ± 24%*). Chronic treatment of mice for 5 days with 7-NI (2 × 40 mg/kg, intraperitoneal) produced similar decreases in regional cerebral cortical blood flow as those seen with acute administration. Neither PPOH nor INDO conferred a significant additional block of the hyperemia in these animals. Conclusions Nitric oxide and epoxyeicosatrienoic acids contribute to isoflurane-induced hyperemia. However, only approximately one third of the cerebral hyperemic response to isoflurane is mediated by autacoids. The remaining part of this response appears to be mediated by a direct action of isoflurane on smooth muscle by some yet-unknown mechanism.

[1]  J. Falck,et al.  Kinetic profile of the rat CYP4A isoforms: arachidonic acid metabolism and isoform-specific inhibitors. , 1999, American journal of physiology. Regulatory, integrative and comparative physiology.

[2]  D. Pelligrino,et al.  Cyclic nucleotide crosstalk and the regulation of cerebral vasodilation , 1998, Progress in Neurobiology.

[3]  M. Moskowitz,et al.  Isoflurane‐induced Cerebral Hyperemia in Neuronal Nitric Oxide Synthase Gene Deficient Mice , 1997, Anesthesiology.

[4]  A. Hudetz,et al.  Neuronal NOS-derived NO plays permissive role in cerebral blood flow response to hypercapnia. , 1997, The American journal of physiology.

[5]  A. Loeb,et al.  Isoflurane enhances glutamatergic agonist-stimulated nitric oxide synthesis in cultured neurons , 1996, Brain Research.

[6]  R. Roman,et al.  Molecular characterization of an arachidonic acid epoxygenase in rat brain astrocytes. , 1996, Stroke.

[7]  B. Matta,et al.  Direct Cerebrovasodilatory Effects of Halothane, Isoflurane, and Desflurane during Propofol‐induced Isoelectric Electroencephalogram in Humans , 1995, Anesthesiology.

[8]  M. Moskowitz,et al.  Cerebrovascular Responses under Controlled and Monitored Physiological Conditions in the Anesthetized Mouse , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[9]  A. Hudetz,et al.  The role of nitric oxide in cerebrocortical laser Doppler flow response to halothane in the rat. , 1995, Journal of neurosurgical anesthesiology.

[10]  R. Johns,et al.  Inhalational anesthetics do not alter nitric oxide synthase activity. , 1995, The Journal of pharmacology and experimental therapeutics.

[11]  R. Busse,et al.  Characterization of endothelium‐derived hyperpolarizing factor as a cytochrome P450‐derived arachidonic acid metabolite in mammals. , 1994, The Journal of physiology.

[12]  A. Hudetz,et al.  The effects of halothane and isoflurane on cerebrocortical microcirculation and autoregulation as assessed by laser-Doppler flowmetry. , 1994, Anesthesia and analgesia.

[13]  M. Carlberg.  Assay of neuronal nitric oxide synthase by HPLC determination of citrulline , 1994, Journal of Neuroscience Methods.

[14]  R. Traystman,et al.  Nitric Oxide and Prostanoids Contribute to Isoflurane‐induced Cerebral Hyperemia in Pigs , 1994, Anesthesiology.

[15]  R. Albrecht,et al.  Role of nitric oxide and endothelium in rat pial vessel dilation response to isoflurane. , 1994, Anesthesia and analgesia.

[16]  R. Traystman,et al.  N omega-nitro-L-arginine methyl ester prevents cerebral hyperemia by inhaled anesthetics in dogs. , 1993, Anesthesia and analgesia.

[17]  D. Reis,et al.  Synthesis of nitric oxide in CNS glial cells , 1993, Trends in Neurosciences.

[18]  X. Xu,et al.  Role of nitric oxide synthase-containing vascular nerves in cerebrovasodilation elicited from cerebellum. , 1993, The American journal of physiology.

[19]  R. Albrecht,et al.  Halothane vasodilation and nitric oxide in rat pial vessels. , 1992, Journal of neurosurgical anesthesiology.

[20]  Richard Graham Knowles,et al.  Nitric oxide as a signal in blood vessels. , 1992, Trends in biochemical sciences.

[21]  N. Toda,et al.  Role of nitric oxide in neurally induced cerebroarterial relaxation. , 1991, The Journal of pharmacology and experimental therapeutics.

[22]  Y. Yamamoto,et al.  Hyperpolarization of arterial smooth muscle induced by endothelial humoral substances. , 1991, The American journal of physiology.

[23]  S. Snyder,et al.  Localization of nitric oxide synthase indicating a neural role for nitric oxide , 1990, Nature.

[24]  B. Johansson,et al.  Regional cerebral blood flow in acute hypertension induced by adrenaline, noradrenaline and phenylephrine in the conscious rat. , 1989, Acta physiologica Scandinavica.

[25]  S. Moncada,et al.  Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor , 1987, Nature.

[26]  M. Todd,et al.  A Comparison of the Direct Cerebral Vasodilating Potencies of Halothane and Isoflurane in the New Zealand White Rabbit , 1986, Anesthesiology.

[27]  S Gelman,et al.  Regional Blood Flow during Isoflurane and Halothane Anesthesia , 1984, Anesthesia and analgesia.