存在於動脈壓中的“生-死”訊號是源自延腦鼻端腹外側核 (rostral ventrolateral medulla, RVLM)，在腦幹死亡過程中其訊號增減反應中樞調控心血管功能的完整與否。延腦鼻端腹外側核也會接受內生性第二型血管張力素 (Angiotensin II, Ang II) 作用在其上的接受器 (第 I 型或第 II 型血管張力素接受器，AT1R 或 AT2R)，活化其 AT1R 會造成血壓上升；活化該處 AT2R 會抑制感壓反射的反應。本論文欲研究在美文松所引發腦幹死亡的模式裡，延腦鼻端腹外側核之 AT1R與 AT2R 及其訊息傳遞途徑調控”生-死”訊號增減反應中所扮演的角色。利用 Sprague-Dawley 大鼠給予靜脈注射美文松 640 μg/kg 會造成”生-死”訊號反應的增加 (定義為 pro-life phase) 以及隨後反應的降低 (定義為 pro-death phase)。以即時定量 PCR 分析 AT1R mRNA，其含量於 pro-life phase 有增加 10%；AT2R mRNA 於 pro-death phase 有顯著增加達 40%。西方點墨法分析 AT1R 蛋白質，發現其含量於 pro-life phase有增加 20%；AT2R 蛋白質含量在 pro-death phase 有顯著增加達 50%。在靜脈注射美文松前先給予 AT1R 拮抗劑 losartan (2 nmol) 至延腦鼻端腹外側核造成個體因血壓過低而馬上死亡，且發現會經由抑制 AT1R 後，同時也抑制了下游NADPH oxidase與其所生成的超氧陰離子。給予NADPH oxidase 抑制劑 DPI (1.5 nmol) 可抑制 NADPH oxidase 活性與其所生成的超氧陰離子以及”生-死”訊號，然而給予超氧陰離子清除劑 tempol (5 nmol) 在 pro-death phase 則可以維持血壓與”生-死”訊號。先前給予 AT2R 拮抗劑 PD123319 (2 nmol) 卻會提升了”生-死”訊號且抵抗在 pro-death phase 會有的低血壓情形，發現是經由抑制 AT2R 後，同時也抑制下游 protein phosphotase 2A (PP2A) 使 extracellular signal-regulated kinase 1/2 (ERK1/2) 活化。給予 PP2A 抑制劑 okadaic acid (0.5 fmol) 可抑制 PP2A 使 ERK1/2 活化，也提升了”生-死”訊號且抵抗在 pro-death phase 會有的低血壓情形與給予 AT2R 拮抗劑 PD123319 相似。以上結果顯示在美文松中毒引發腦幹死亡模式中，AT1R在延腦鼻端腹外側核經由下游 NADPH oxidase/超氧陰離子路徑維持血壓與”生-死”訊號而扮演著“生”的角色；AT2R 在延腦鼻端腹外側核則經由下游 PP2A/ERK 路徑抑制血壓與”生-死”訊號而扮演著“死”的角色，超氧陰離子在 pro-death phase 亦可能扮演“死”的角色。

The rostral ventrolateral medulla (RVLM) is the origin of a “life-and-death” signal identifies from systemic arterial blood pressure spectrum that reflects failure of central cardiovascular regulation during brain stem death. It is also a target site where endogenous angiotensin II acts on angiotensin II type 1 receptors (AT1R) to increase blood pressure (BP); or on type 2 receptors (AT2R) to inhibit baroreceptor reflex (BRR) response. This study investigated the roles of AT1R and AT2R and their signaling pathways in RVLM for “life-and-death” signal response during experimental brain stem death, using organophosphate mevinphos (Mev) as the experimental insult. In Sprague-Dawley rats, Mev (640 μg/kg, i.v.) elicited an increase (pro-life phase) followed by a decrease (pro-death phase). Real-time PCR analysis revealed that whereas AT1R level underwent a 10% increase at pro-life phase, AT2R exhibited a significance increase of up to 40% at pro-death phase. Western blot analysis revealed that whereas AT1R level underwent a 20% increase at pro-life phase, AT2R exhibited a significant increase of up to 50% at pro-death phase. Pretreatment with microinjection of an AT1R antagonist losartan (2 nmol) into RVLM elicited abrupt death because of drastic hypotension through inhibiting NADPH oxidase and its downstream superoxide anion. Pretreatment with NADPH oxidase inhibitor DPI (1.5 nmol) inhibited NADPH oxidase avtiviting and superoxide anion production and decreased “life-and-death” signal at pro-life phase; using superoxide anion inhibitor tempol (5 nmol) potentiated blood pressure and “life-and-death” signal at pro-death phase. However, pretreatment with an AT2R antagonist PD123319 (2 nmol) potentiated the “life-and-death” signal and antagonized hypotension during pro-death phase through inhibiting protein phosphotase 2A (PP2A) then activating extracellular signal-regulated kinase 1/2 (ERK1/2). Similar to AT2R antagonist PD123319, pretreatment with PP2A inhibitor okadaic acid (0.5 fmol) inhibit PP2A, leading to activation of ERK1/2, potentiate “life-and-death” signal and antagonized hypotension during pro-death phase. These results suggest that AT1R in RVLM plays a “pro-life” role through NADPH oxidase/superoxide anion during experimental brain stem death by maintaining BP and “life-and-death” signal; AT2R plays a “pro-death” role through PP2A/ERK1/2 by inhibiting BP and “life-and-death” signal, and superoxide may also plays a “pro-life and pro-death” role at pro-death phase.

中文摘要 1-3
英文摘要 4-6
第一章 緒論 7-17
第二章 研究動機與目的 18-20
第三章 實驗材料與方法 21-29
第四章 實驗結果 30-44
第五章 討論 45-53
第六章 結論 54-55
第七章 未來展望 56-58
參考文獻 59-74
附圖 75-118

Akselrod, S., 1988. Spectral analysis of fluctuations in cardiovascular parameters: a quantitative tool for the investigation of autonomic control. Trends Pharmacol. Sci. 9, 6-9.

Akselrod, S., Eliash, S., Oz, O., Cohen, S., 1987. Hemodynamic regulation in SHR: investigation by spectral analysis. Am. J. Physiol. 253, 176-183.

Akselrod, S., Gordon, D., Madwed, J.B., Snidman, N.C., Shannon, D.C., Cohen, R.J., 1985. Hemodynamic regulation: investigation by spectral analysis. Am. J. Physiol. 249, 867-875.

Allen, A.M., Moeller, I., Jenkins, T.A., Zhuo, J., Aldred, G.P., Chai, S.Y., Mendelsohn, F.A., 1998. Angiotensin receptors in the nervous system. Brain Res. Bul. 47, 17-28.

Arregui, A., Iversen, L.L., 1978. Angiotensin-converting enzyme: presence of high activity in choroid plexus of mammalian brain. Eur. J. Pharmacol. 52, 147-150.

Averill, D.B., Tsuchihashi, T., Khosla, M.C., Ferrario, C.M., 1994. Losartan, nonpeptide angiotensin II-type 1 (AT1) receptor antagonist, attenuates pressor and sympathoexcitatory responses evoked by angiotensin II and L-glutamate in rostral ventrolateral medulla. Brain Res. 665, 245-252.

Bardin, P.G., Van Eeden, S.F., 1990. Organophosphate poisoning: grading the severity and comparing treatment between atropine and glycopyrrolate. Crit. Care Med. 18, 956-960.

Barman, S.M., Gebber, G.L., 1985. Axonal projection pattern of ventrolateral medullospinal sympathoexcitatory neurons. J. Neurophysiol. 53, 1567-1582.

Blessing, W.W., Reis, D.J., 1982. Inhibitory cardiovascular functin of neurons in the caudal ventrolateral medulla of the rabbit: relationship to the area containing A1 noradrenergic cells. Brain Res. 253, 161-171.

Boveris, A., Alivarez, S., Navarro, A., 2002. The role of mitochondrial nitric oxide synthase in inflammation and septic shock. Free Radic. Biol. Med. 33, 1186-1193.

Braszko, J. J., Wlasienko, J., Koziolkiewicz, W., Janecka, A., Wisniewski, K., 1991. The 3-7 fragment of angiotensin II is probably responsible for its psychoactive properties. Brain Res. 542, 49-54.

Campagnole-Santos, M.J., Diz, D.I., Ferrario, C.M., 1988. Baroreceptor reflex modulation by angiotensin II at the nucleus tractus solitarii. Hypertension 11, 167-171.

Campbell, W. B., Habener, J. F., 1979. (7-Ile) Angiotensin III: a relatively selective antagonist of angiotensin steroidogenesis. Eur. J. Pharmacol. 54, 209-216.

Casto, R., Phillips, M.I., 1986. Angiotensin II attenuates baroreceptor reflexes at nucleus tractus solitarius of rats. Am. J. Physiol. 250, R193-R198.

Cerutti, C., Gustin, M.P., Paultre, C.Z., Lo, M., Julien, C., Vincent, M., Sassard, J., 1991. Autonomic nervous system and cardiovascular variability in rats: a spectral analysis approach. Am. J. Physiol. 261, H1292-H1299.

Chan, J.Y.H., Chan, S.H.H., Chang, A.Y.W., 2004. Differential contributions of NOS isoforms in the rostral ventrolateral medulla to cardiovascular responses associated with mevinphos intoxication in the rat. Neuropharmacology 46, 1184-1194.

Chan, J.Y.H., Chan, S.H.H., Li, F.C.H., Cheng, H.L., Chang, A.Y.W., 2005a. Phasic cardiovascular responses to mevinphos are mediated through differential activation of cGMP/PKG cascade and peroxynitrite via nitric oxide generated in the rat rostral ventrolateral medulla by NOS I and II isoforms. Neuropharmacology 48, 161-172.

Chan, J.Y.H., Chang, A.Y.W., Chan, S.H.H., 2005b. New insights on brain stem death: From bedside to bench. Prog. Neurobiol. 77, 396-425.

Chan, J.Y.H., Cheng, H.L., Chou, J.L.J., Li, F.C.H., Dai, K.Y., Chan, S.H.H., Chang, A.Y.W., 2007. Heat shock protein 60 or 70 activates NOS I- and inhibits NOS II-associated signaling, and depresses mitochondrial apoptotic cascade during brain stem death. J. Biol. Chem. 282, 4585-4600.

Chan, J.Y.H., Wang, L.L., Ou, C.C., Chan, S.H.H., 2003. Downregulation of angiotensin subtype 1 receptor in rostral ventrolateral medulla during endotoxemia. Hypertension 42, 103-109.

Chan, J.Y.H., Wang, S.H., Chan, S.H.H., 2001. Differential roles of iNOS and nNOS at rostral ventrolateral medulla during experimental endotoxemia in the rat. Shock 15, 65-72.

Chan, J.Y.H., Wu, C.H.Y., Tsai, C.Y., Cheng, H.L., Dai, K.Y., Chan, S.H.H., Chang, A.Y.W., 2007. Transcriptional up-regulation of nitric oxide synthase II by nuclear factor-kappaB at rostral ventrolateral medulla in a rat mevinphos intoxication model of brain stem death. J. Physiol. 581, 1293-1307.

Chan, R.K.W., Chan, Y.S., Wong, T.M., 1990. Cardiovascular responses to electrical stimulation of the ventrolateral medulla of the spontaneously hypertensive rat. Brain Res. 522, 99-106.

Chan, S.H.H., Hsu, K.S., Huang, C.C., Wang, L.L, Ou, C.C., Chan, J.Y.H., 2005. NADPH oxidase-derived superoxide anion mediates angiotensin II-induced pressor effect via activation of p38 mitogen-activated protein kinase in the rostral ventrolateral medulla. Circ. Res. 97, 772-780.

Chan, S.H.H., Wang, L.L., Ou, C.C., Chan, J.Y.H., 2002. Contribution of peroxynitrite to fatal cardiovascular depression induced by overproduction of nitric oxide in rostral ventrolateral medulla of the rat. Neuropharmacology 43, 889-898.

Chan, S.H.H., Wang, L.L., Tseng, H.L., Chan, J.Y.H., 2007. Upregulation of AT1 receptor gene on activation of protein kinase Cbeta/nicotinamide adenine dinucleotide diphosphate oxidase/ERK1/2/c-fos signaling cascade mediates long-term pressor effect of angiotensin II in rostral ventrolateral medulla. J. Hypertens. 25, 1845-1861.

Chan, S.H.H., Wang, L.L., Wang, S.H., Chan. J.Y.H., 2001. Differential cardiovascular responses to blockade of nNOS or iNOS in rostral ventrolateral medulla of the rat. Br. J. Pharmacol. 133, 606-614.

Chen, Y., Morris, M., 2001. Differentiation of brain angiotensin type 1a and 1b receptor mRNAs: a specific effect of dehydration. Hyperten-
sion 37, 692-697.

Choe, E.S., Parelkar, N.K., Kim, J.Y., Cho, H.W., Kang, H.S., Mao, L., Wang, J.Q., 2004. The protein phosphatase 1/2A inhibitor okadaic acid increases CREB and Elk-1 phosphorylation and c-fos expression in the rat striatum in vivo. J. Neurochem. 89, 383-390.

Chuang, F.R., Jang, S.W., Lin, J.L., Chern, M.S., Chen, J.B., Hsu, K.T., 1996. QTc prolongation indicates a poor prognosis in patients with organophosphate poisoning. Am. J. Emerg. Med. 14, 451-453.

Conci, F., Di Rienzo, M., Castiglioni, P., 2001. Blood pressure and heart rate variability and baroreflex sensitivity before and after brain death. J. Neurol. Neurosurg. Psychiatr. 71, 621-631.

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

Davisson, R.L., Oliverio, M.I., Coffman, T.M., Sigmund, C.D., 2000. Divergent functions of angiotensin II receptor isoforms in the brain. J. Clin. Invest. 106, 103-106.

DiBona, G., Jones, S.Y., 2001. Sodium intake influences hemodynamic and neural responses to angiotensin receptor blockade in rostral ventrolateral medulla. Hypertension 37, 1114-1123.

Dille, J.R., Smith, P.W., 1964. Central nervous system effects of chronic exposure to organophosphate insecticides. Aerospace Med. 35, 475-478.

Elton, T.S., Stephan, C.C., Taylor, G.R., Kimball, M.G., Martin, M.M., Durand, J.N., Oparil, S., 1992. Isolation of two distinct type I angiotensin II receptor genes. Biochem. Biophys. Res. Commun. 184, 1067-1073.

Epstein, A. N., Fitzsimons, J. T., Simons, B. J., 1970. Drinking induced by injection of angiotensin into the brain of the rat. J. Physio. 210, 457-474.

Ferguson, A.V., Washburn, D.L.S., Latchford, K.J., 2001. Hormonal and neurotransmitter roles for angiotensin in the regulation of central autonomicfunction. Proc. Soc. Exp. Biol. Med. 226, 85-96.

Fink, G.D., Bruner, C.A., 1985. Hypertension during chronic peripheral and central infusion of angiotensin III. Am. J. Physiol. 249, E201-E208.

Fink, M. P., 2001. Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis. Crit. Care. Clin. 17, 219-237.

Fontes, M.A.P., Silva, L.C.S., Campagnole-Santos, M.J., Khosla, M.C., Guertzensten, P.G., Santos, R.A.S., 1994. Evidence that angiotensin- (1-7) plays a role in the central control of blood pressure at the ventrolateral medulla acting through specific receptors. Brain Res. Rev. 665, 175-180.

Ganten, D., Fuxe, J., Phillips, M.I., Mann, J.F.E., 1978. The brain isorenin angiotensin system: biochemistry, localization and possible role in drinking and blood pressure regulations. In: Ganong WF, Martini L, (Eds.) Frontiers in endocrinology. New York: Raven Press, 61.

Gao, L., Wang, W.Z., Wang, W., Zucker, I.H., 2008. Imbalance of angiotensin type 1 receptor and angiotensin II type 2 receptor in the rostral ventrolateral medulla: potential mechanism for sympathetic overactivity in heart failure. Hypertension 52, 708-714.

Gohlke, P., Pees, C., Unger, T., 1998. AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension 31, 349-355.

Granata, A.R., Ruggiero, D.A., Park, D.H., Joh, T.H., Reis, D.J., 1985. Brain stem area with C1 epinephrine neurons mediates baroreflex vasodepressor response. Am. J. Physiol. 248, H547-H567.

Guertzenstein, P.G., Silver, A., 1974. Fall in blood pressure produced from discrete regions of the ventral surface of the medulla by glycine and lesions. J. Physiol. Lond. 242, 489-503.

Guyenet, P.G., Haselton, J.R., Sun, M.K., 1989. Sympathoexcitatory neurons of rostroventrolateral medulla and the origin of the sympathetic vasomotor tone. Prog. Brain Res. 81, 105-116.

Head, G.A., Williams, N.S., 1992. Hemodynamic effects of central angiotensin I, II and III in conscious rabbits. Am. J. Physiol. 263, R845-R851.

Hermann, K., Phillips, M.I., Hilgenfeldt, U., Raizada, M.K., 1988. Biosynthesis of angiotensinogen and angiotensins by brain cell in primary culture. J. Neurochem. 51, 398-405.

Herzig, T.C., Jobe, S.M., Aoki, H., Molkentin, J.D., Cowley, A.W.Jr., Izumo, S., Markham, B.E., 1997. Angiotensin II type1a receptor gene expression in the heart: AP-1 and GATA-4 participate in the response to pressure overload. Proc. Natl. Acad. Sci. U.S.A. 94, 7543-7548.

Hirooka, Y., Potts, P.D., Dampney, R.A.L., 1997. Role of angiotensin II receptor subtypes in mediating the sympathoexcitatory effects of exogenous and endogenous angiotensin peptides in the rostral ventrolateral medulla of the rabbit. Brain Res. 772, 107-114.

Howe, P.R.C., Kohn, D.M., Minson, J.B., Stead, B.H., Chalmers, J.P., 1983. Evidence for bulbospinal seretonergic pressor pathway in the rat brain. Brain Res. 270, 29-36.

Hu, L., Zhu, D.N., Yu, Z., Wang, J.Q., Sun, Z.J., Yao, T., 2002. Expression of angiotensin II type 1 AT(1) receptor in the rostral ventrolateral medulla in rats. J. Appl. Physiol. 92, 2153-2161.

Huang, X.C., Richards, E.M., Sumners, C., 1995. Angiotensin II type 2 receptormediated stimulation of protein phosphatase 2A in rat hypothalamic/brainstem neuronal cocultures. J. Neurochem. 65, 2131-2137.

Huang, X.C., Richards, E.M., Sumners, C., 1996. Mitogen-activated protein kinases in rat brain neuronal cultures are activated by angiotensin II type 1 receptors and inhibited by angiotensin II type 2 receptors. J. Biol. Chem. 271, 15635-15641.

Hughes, P., Dragunow, M., 1995. Induction of immediate-early genes and the control of neurotransmitter-regulated gene expression within the nervous system. Pharmacol. Rev. 47, 133-178.

Hutchinsón, J.S., Csicsmann, J., Korner, P.I., Johnston, C.I., 1978. Characterization of immunoreactive angiotensin in canine cerebrospinal fluid as Des-Asp1-angiotensin II. Clin. Sci. Mol. Med. 54, 147-151.

Inoue, K., Miyake, S., Kumashiro, M., Ogata, H., Ueta, T., Akatsu, T., 1991. Power spectral analysis of blood pressure variability in traumatic quadriplegic humans. Am. J. Physiol. 260, H842-H847.

Ito, S., Komatsu, K., Tsukamoto, K., Kanmatsuse, K., Sved, A.F., 2002. Ventrolateral medulla AT1 receptors support blood pressure in hypertensive rats. Hypertension 40, 552-559.

Ito, S., Sved, A.F., 2000. Pharmacological profile of depressor response elicited by sarthran in rat ventrolateral medulla. Am. J. Physiol. Heart Circ. Physiol. 279, H2961-H2966.

Iwai, N., Yamano, Y., Chak, S., Konishi, F., Bardham, S., Tibbetts, C., Sasaki, K., Hasegawa, M., Matsuda, Y., Inagami, T., 1991. Rat angiotensin II receptor: cDNA sequence and regulation of gene expression. Biochem. Biophys. Res. Comm. 177, 299-304.

Japundzic, N., Grichois, M.L., Zitoun, P., Laude, D., Elghozi, J.L., 1990. Spectral analysis of blood pressure and heart rate in conscious rats: effects of autonomic blockers. J. Auton. Nerv. Syst. 30, 91-100.

Julien, C., Zhang, Z.Q., Cerutti, C., Barres, C., 1995. Hemodynamic analysis of arterial pressure oscillations in conscious rats. J. Auton. Nerv. Syst. 50, 239-252.

Kambayashi, Y., Bardham, S., Takahashi, K., Tsuzuki, S., Inui, H., Hamakubo, T., Inagami, T., 1993. Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J. Biol. Chem. 268, 24543-24546.

Kitami, Y., Okura, T., Marumoto, K., Wakamiya, R., Hiwada, K., 1992. Differential gene expression and regulation of type-1 angiotensin II receptor subtypes in the rat. Biochem. Biophys. Res. Commun. 188, 446-452.

Kuo, T.B.J., Chan, S.H.H., 1993. Continuous, on-line, real-time spectral analysis of systemic arterial pressure signals. Am. J. Physiol. 264, H2208-H2213.

Kuo, T.B.J., Yang, C.C.H., Chan, S.H.H., 1996. Transfer function analysis of ventilatory influence on systemic arterial pressure in the rat. Am. J. Physiol. 271, H2108-H2115.

Kuo, T.B.J., Yang, C.C.H., Chan, S.H.H., 1997a. Selective activation of vasomotor component SAP spectrum by nucleus reticularis ventrolateralis in rats. Am. J. Physiol. 272, H485-H492.

Kuo, T.B.J., Yien, H.W., Hseu, S.S., Yang, C.C.H., Lin, Y.Y., Lee, L.C., Chan, S.H.H., 1997b. Diminished vasomotor component of systemic arterial pressure signals and baroreflex in brain death. Am. J. Physiol. 273, H1291-H1298.

Lenkei, Z., Corvol, P., Llorens-Cortes, C., 1995. The angiotensin receptor subtype AT1A predominates in rat forebrain areas involved in blood pressure, body fluid homeostasis and neuroendocrine control. Brain Res. Mol. Brain Res. 30, 53-60.

Li, J., Li, P.F., Dietz, R., von Harsdorf, R., 2002. Intracellular superoxide induces apoptosis in VSMCs: role of mitochondrial membrane potential, cytochrome c and caspases. Apoptosis 7, 511-517.

Li, P.L., Chao, Y.M., Chan, S.H.H., Chan, J.Y.H., 2001. Potentiation of baroreceptor reflex response by HSP70 in nucleus tractus solitarii confers cardiovascular protection during heatstroke. Circulation 103, 2114-2119.

Li, Z., Iwai, M., Wu, L., Shiuchi, T., Jinno, T., Cui, T.X. Horiuchi, M., 2003. Role of AT2 receptor in the brain in regulation of blood pressure and water intake. Am. J. Physiol. 284, H116-H121.

Lin, K.S., Chan, J.Y.H., Chan, S.H.H., 1988. Reduction in baroreceptor reflex response by angiotensin III and its modification by Ile7-angiotensin III and bestatin in the rat. Neurosci. Lett. 90, 172-176.

Lin, K.S., Chan, J.Y.H., Chan, S.H.H., 1997. Involvement of AT2 receptors at NRVL in tonic baroreflex suppression by endogenous angiotensins. Am. J. Physiol. 272, H2204-H2210.

Lin, K.S., Chan, S.H.H., Chan, J.Y.H., 2001. Tonic suppression of spontaneous baroreceptor reflex by endogenous angiotensins via AT2 subtype receptors at nucleus reticularis ventrolateralis in the rat. Synapse 40, 85-94.

Lind, R.W., Swanson, L.W., Ganten, D., 1985. Organization of angiotensin II immunoreactive cells and fibers in the rat central nervous system. Neuroendocrinol. 40, 2-24.

Liu, D., Gao, L., Roy, S.K., Cornish, K.G., Zucker, I.H., 2006. Neuronal angiotensin II type 1 receptor upregulation in heart failure: activation of activator protein 1 and Jun N-terminal kinase. Circ. Res. 99, 1004-1011.

Lossi, L., Merighi, A., 2003. In vivo cellular and molecular mechanisms of neuronal apoptosis in the mammalian CNS. Prog. Neurobiol. 69, 287-312.

Matsumura, Y., Hasser, E.M., Bishop, V.S., 1989. Central effect of angiotensin II on baroreflex regulation in conscious rabbits. Am. J. Physiol. Regul. Integr. Comp. Physiol. 256, R694-R700.

Matsuura, T., Kumagai, H., Onimaru, H., Kawai, A., Iigaya, K., Onami, T., Sakata, K., Oshima, N., Sugaya, T., Saruta, T., 2005. Electro- physiological properties of rostral ventrolateral medulla neurons in angiotensin II 1a receptor knockout mice. Hypertension 46, 349-354.

Minson, J.B., Chalmers, J.P., Caon, A.C., Renaud, B., 1987. Separate areas of rat medulla oblongata with populations of serotonin- and adrenaline-containing neurons alter blood pressure after L-glutamate stimulation. J. Auton. Nerv. Syst. 19, 39-50.

Moriguchi, A., Morris, M., Brosnihan, K.B., Ferrario, C.M., 1993. Angiotensin II and angiotensin (1-7) augment the local release of vasopressin from the paraventricular nucleus (PVN) and the supraoptic nucleus (SON). Hypertension 21, 587.

Morrison, S.F., Milner, T.A., Reis, D.J., 1988. Reticulospinal vasomotor neurons of the rat rostral ventrolateral medulla: relationship to sympathetic nerve activity and the C1 adrenergic cell group. J. Neurosci. 8, 1286-1301.

Mukoyama, M., Nakajiima, M., Horiuchi, M., Sasamura, H., Pratt, R.E., Dzau, V.J., 1993. Expression cloning of type-2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors. J. Biol. Chem. 268, 24539-24542.

Munoz, M.J., Braun-Mendendez, E., Fasciolo, J.D., Leloir, L.F., 1939. Hypertensin: The substance causing renal hypertension. Nature 144, 980.

Murakami, K., Tsuchiya, K., Naruse, M., Naruse, K., Demura, H., Arai, J., Nihei, H., 1997. Nitric oxide synthase I immunoreactivity in the macula densa of the kidney is angiotensin II dependent. Kidney Int. Suppl. 63, S208-S210.

Murphy, T.J., Alexander, R.W., Griendling, K.K., Runge, M.S., Bernstein, K.E., 1991. Isolation of a cDNA encoding the vascular type-1 angiotensin receptor. Nature 351, 233-236.

Pagani, M., Rimodli, O., Pizzinelli, P., Furlan, R., Crivellaro, W., Liberati, D., Cerutti, S., Malliani, A., 1991. Assessment of neural control of circulation during psychological stress. J. Auton. Nerv. Syst. 35, 33-42.

Page, I.H., Helmer, O.M., 1940. A crystaline pressor substance (angiotonin) resulting from the action between renin and renin-activator. J. Exp. Med. 71, 29-42.

Pawlak, R., Napiorkowska-Pawlak, D., Takada, Y., Urano, T., Nagai, N., Ihara, H., Takada, A., 2001. The differential effect of angiotensin II and angiotensin 1-7 on norepinephrine, epinephrine, and dopamine concentrations in rat hypothalamus: the involvement of angiotensin receptors. Brain Res. Bul. 54, 689-694.

Paxinos, G., Watson, C., 1998. The rat brain: in steroetaxic coordinates. Academic Press, Sydney, Australia.

Pelicano, H., Feng, L., Zhou, Y., Carew, J.S., Hileman, E.O., Plunkett, W., Keating, M.J., Huang, P., 2003. Inhibition of mitochondrial respiration. A novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J. Biol. Chem. 278, 37832-37839.

Phillips, M.I., Sumners, C., 1998. Angiotensin II in central nervous system physiology. Regul. Pept. 78, 1-11.

Pyner, S., Coote, J.H., 1999. Identification of an efferent projection from the paraventricular nucleus of the hypothalamus terminating close to spinally projecting rostral ventrolateral medullary neurons. Neuroscience 88, 949-957.

Raizada, M.K., Lu, D., Yang, H., Richards, E.M., Gelband, C.H., Sumners, C., 1999. Brain angiotensin receptor subtypes and their coupling to distinct signal transduction pathways. Adv. Mol. Cell. Endocrinol. 9, 75-101.

Reid, I.A., Day, R.P., Moffat, B., Hughes, H.G., 1977. Apparent angiotensin immunoreactivity in dog brain resulting from angiotensinase. J. Neurochem. 28, 435-438.

Revzin, A.M., 1973. Subtle changes in brain functions produced by single doses of mevinphos (Phosdrin). FAA Office of Aviation Medicine Report No. AM-73-3.

Rimoldi, O., Pierini, S., Ferrari, A., Cerutti, S., Pagani, M., Malliani, A., 1990. Analysis of short-term oscillations of R-R and arterial pressure in conscious dogs. Am. J. Physiol. 258, H967-H976.

Robbe, H.W.J., Mulder, L.J.M., Ruddel, H., Langewitz, W.A., Veldman, J.B.P., Mulder, G., 1987. Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension 10, 538-543.

Ross, C.A., Ruggiero, D.A., Park, D.H., Joh, T.H., Sved, A.F., Fernandez-Pardal, J., Saavedra, J.M., Reis, D.J., 1984. Tonic vasomotor control by the rostral ventrolateral medulla: effect of electrical or chemical stimulition of the area containing C1 adrenaline neurons on arterial pressure, heart rate, and plasma catecholamines and vasopressin. J. Neurosci. 4, 474-494.

Sandberg, K., Ji, H., Clark, A.J., Shapira, H., Catt, K.J., 1992. Cloning and expression of a novel angiotensin II receptor subtype. J. Biol. Chem. 267, 9455-9458.

Santos, R.A., Brosnihan, K.B., Chappell, M.C., Pesquero, J., Chernicky, C.L., Greene, L.J., Ferrario, C.M., 1988. Converting enzyme activity and angiotensin metabolism in the dog brainstem. Hypertension 11, 153-157.

Sasaki, S., Dampney, R.A.L., 1990. Tonic cardiovascular effects of angiotensin II in the ventrolateral medulla. Hypertension 15, 274-283.

Sasamura, H., Hein, L., Krieger, J.E., Pratt, R.E., Kobilka, B.K., Dzau, V.J., 1992. Cloning, characterization, and expression of two angiotensin receptor (AT-1) isoforms from the mouse genome. Biochem. Biophys. Res. Commun. 185, 253-259.

Sheh, Y.L., Hsu, C., Chan, S.H.H., Chan, J.Y.H., 2007. NADPH oxidase- and mitochondrion-derived superoxide at rostral ventrolateral medulla in endotoxin-induced cardiovascular depression. Free Radic. Biol. Med. 42, 1610-1623.

Shenoy, U.V., Richards, E.M., Huang, X.C., Sumners, C., 1999. Angiotensin II type 2 receptor-mediated apoptosis of cultured neurons from newborn rat brain. Endocrinology 140, 500-509.

Shih, T.M., 1982. Time course effects of soman on acetylcholine and choline levels in six discrete areas of the rat brain. Psychopharma- cology 78, 170-175.

Sirrett, N.E., McLean, A.S., Bray, J.J., Hubbard, J.I., 1977. Distribution of angiotensin II receptors in rat brain. Brain Res. 122, 299-312.

Spyer, K.M., 1994. Central nervous mechanisms contributing to cardiovascular control. J. Physiol. Lond. 474, 1-19.

Sveed, A.F., Ito, S., Madden, C.J., 2000. Baroreflex dependent and independent roles of the caudal ventrolateral medulla in cardiovascular regulation. Brain Res. Bul. 51, 120-133.

Triedman, J.K., Saul, J.P., 1994. Blood pressure modulation by central venous pressure and respiration: buffering effects of the heart rate reflexes. Circulation 89, 169-179.

Tsai, C.Y., Wu, C.H.Y., Chan, S.H.H., Chang, A.Y.W., 2007. Muscarinic receptor-independent activation of cyclic adenosine monophosphate dependent protein kinase in rostral ventrolateral medulla underlies the sympathoexcitatory phase of cardiovascular responses during mevinphos intoxication in the rat. Shock 27, 559-564.

Wakade, A.R., Wakade, T.D., 1983. Mechanism of negative feed-back inhibition of norepinephrine release by alpha-adrenergic agonists. Neuroscience 9, 673-677.

Wiemer, G., Schölkens, B.A., Wagner, A., Heitsch, H., Linz, W., 1993. The possible role of angiotensin II subtype AT2 receptors in endothelial cells and isolated ischemic rat hearts. J. Hypertens. Suppl. 11, S234-S235.

Wright, J.W., Morseth, S.L., Abhold, R.H., Harding, J.W., 1985. Pressor action and disogenicity induced by angiotensin II and III in rats. Am. J. Physiol. 249, R514-R521.

Yang, C.H., Shyr, M.H., Kuo, T.B.J., Tan, P.P.C., Chan, S.H.H., 1995a. Effects of propofol on nociceptive response and power spectra of electroencephalographic and systemic arterial pressure signals in the rat: correlation with plasma concentration. J. Pharmacol. Exp. Ther. 275, 1568-1574.

Yang, M.W., Kuo, T.B.J., Lin, S.M., Chan, K.H., Chan, S.H.H., 1995b. Continuous, on-line, real-time spectral analysis of SAP signals during cardiopulmonary bypass. Am. J. Physiol. 268, H2329-H2335.

Yang, C.C.H., Kuo, T.B.J., Chan, S.H.H., 1996. Auto- and cross-spectral
analysis of cardiovascular fluctuation during pentobarbital anesthesia in the rat. Am. J. Physiol. 270, H575-H582.

Yen, D.H.T., Yen, J.C., Len, W.B., Wang, L.M., Lee, C.H., Chan, S.H.H., 2001. Spectral changes in systemic arterial pressure signals during acute mevinphos intoxication in the rat. Shock 15, 35-41.

Yen, D.H.T., Yien, H.W., Wang, L.M., Lee, C.H., Chan, S.H.H., 2000. Spectral analysis of systemic arterial pressure and heart rate signals of patients with acute respiratory failure induced by severe organophosphate poisoning. Crit. Care Med. 28, 2805-2811.

Yien, H.W., Hseu, S.S., Lee, L.C., Kuo, T.B.J., Lee, T.Y., Chan, S.H.H., 1997. Spectral analysis of systemic arterial pressure and heart rate signals as a prognostic tool for the prediction of patient outcome in the intensive care unit. Crit. Care Med. 25, 258-266.

Zhao, Y., Biermann, T., Luther, C., 2003. Contribution of bradykinin and nitric oxide to AT2 receptor-mediated differentiation in PC12 W cells. J. Neurochem. 85, 759-767.

Zhu, G.Q., Gao, L., Patel, K.P., Zucker, I.H., Wang, W., 2004. ANG II in the paraventricular nucleus potentiates the cardiac sympathetic afferent reflex in rats with heart failure. J. Appl. Physiol. 97, 1746-1754.

Zhu, M., Gelband, C.H., Moore, J.M., Posner, P., Sumners, C., 1998. Angiotensin II type 2 receptor stimulation of neuronal delayed-rectifier potassium current involves phospholipase A2 and arachidonic acid. J. Neurosci. 18, 679-686.