本研究之主要目的在探討：(1)大白鼠延腦網狀腹外側核中內生性血管張力素在內毒素引發敗血性低血壓過程中所扮演的角色；(2)是由哪一種接受器亞型參與此調控過程。本研究以成熟、雄性之Sprague-Dawley種系大白鼠為材料，由靜脈持續滴注Propofol (30 mg/kg/h) 維持麻醉狀態，並以pancuronium (2 mg/kg/h) 使其肌肉癱瘓，同時外接動物呼吸器來取代其主動呼吸；接著利用在靜脈注射LPS (15或30 mg/kg) 的方法來誘發敗血性低血壓的產生。在敗血性低血壓過程中，觀察動脈壓的變化發現，動脈壓首先會急速降低，接著經過短暫的回升後再度下降；除此之外，根據動脈壓頻譜中的極低頻 (0-0.25 Hz) 以及低頻 (0.25-0.8 Hz) 成分功率密度的變化，可將LPS誘導的敗血性低血壓整個過程區分為三個時期：第一期 (Phase Ⅰ)，功率密度略低於誘導前；第二期 (Phase Ⅱ)，功率密度較誘導前增加；第三期 (Phase Ⅲ)，功率密度逐漸減弱至消失。而在靜脈注射LPS之前，分別先在兩側延腦網狀腹外側核中直接以微量注射方式分別給予具專一性， non-peptide之第Ⅰ型血管張力素接受器 (AT1 receptor) 拮抗劑， losartan (1.6 nmol)，或是第Ⅱ型血管張力素接受器 (AT2 receptor) 拮抗劑， PD-123319 (1.6 nmol)，比較不同之前處理對於由不同劑量LPS所誘導的敗血性低血壓是否產生影響。結果發現，在靜脈注射15 mg/kg LPS情況下， losartan以及PD-123319之前處理雖然不會影響大白鼠之動脈壓以及心跳速率的變化，卻會使得動脈壓頻譜中極低頻成分的功率密度變化受到抑制；而在靜脈注射30 mg/kg LPS情況下，此兩組前處理均會使動脈壓第二次下降更為急遽，同時縮短敗血性低血壓整個過程的存活時間，且其主要是減短第二期以及第三期之分期時間；除了造成血壓的變動之外，其對於動脈壓頻譜中極低頻成分的功率密度變化亦會產生興奮的作用，使極低頻的功率密度大量表現。因此我們的結論是：(1) 在內毒素誘發的敗血性低血壓過程中，位於大白鼠延腦網狀腹外側核的內生性血管張力素可能與維持血壓的調控機制有關；(2) 而第Ⅰ型以及第Ⅱ型血管張力素接受器則分別藉由對動脈壓頻譜中極低頻成分功率密度變化的調控參與在此過程中。

In this study, we investigated the role of angiotensinergic neurotransmission at nucleus reticularis ventrolateralis (NRVL), and the subtype of angiotensin receptors involved, during experimental endotoxemia induced by E. coli lipopolysaccharide (LPS). In adult male Sprague-Dawley rats maintained under propofol anesthesia (30 mg/kg/h), paralyzed with pancuronium (2 mg/kg/h) and mechanically ventilated (85-95 stroke/min, 2.5-3 ml/stroke), intravenous administration of LPS (15 or 30 mg/kg) induced an immediate hypotension, followed by a rebound increase and a secondary decrease in systemic arterial pressure (SAP). LPS also reduced the power density of the very low-frequency (0-0.25 Hz) and low-frequency (0.25-0.8 Hz) components of SAP signals (Phase Ⅰ), which represented the sympathetic vasomotor tone, followed by an increase (Phase Ⅱ) and a secondary decrease (Phase Ⅲ). Pretreatment with microinjection of the selective non-peptide AT1 receptor antagonist, losartan (1.6 nmol), or the selective non-peptide AT2 receptor antagonist, PD-123319 (1.6 nmol), into the bilateral NRVL significantly reduced the survival time after the induction of acute experimental endotoxemia. Both pretreatments shortened the duration of Phase Ⅱ and Phase Ⅲ in acute endotoxemia, accelerated the secondary hypotension, and excited the power density of the very low-frequency. We conclude that endogenous angiotensin Ⅱ at the NRVL may play a crucial role in the maintenance of SAP during acute experimental endotoxemia, possibly via an action on both AT1 and AT2 subtype receptors on the very low-frequency component of SAP spectrum.

目 錄 1

中文摘要 2

英文摘要 5

第一章 文獻回顧 7

第二章 研究目的 20

第三章 實驗材料與方法 22

第四章 研究結果 27

第五章 討論 33

第六章 結論 39

參考文獻 41

附錄(圖表) 54

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., Gordon, D., Madwed, J. B., Sindman, N. C., Shannon, D. C. and Cohen, R. J. (1985) Hemodynamic regulation: investigation by spectral analysis. Am. J. Physiol. 249: H867-H875.

Alenander, R. S. (1946) Tonic and reflex functions of medullary sympathetic cardiovascular centers. J. Neurophysiol. 9: 205-217.

Allen, A. M., Dampney, R. A. L. and Mendelsohn, F. A. O. (1988) Angiotensin receptor binding and pressor effects in the cat subretrofacial nucleus. Am. J. Physiol. 255: H1011-H1017.

Allen, A. M., Moeller, I., Jenkins, T. A., Zhuo, J., Aldred, G. P., Chai, S. Y. and Mendelsohn, F. A. O. (1998) Angiotensin receptor in the nervous system. Brain Res. Bull. 47: 17-28.

Amendt, K., Czachurski, J., Demboesky, K. and Seller, H. (1979) Bulbospinal projections to the intermediaolateral cell column: a neuroanatomical study. J. Auto. Nerv. Syst. 1: 103-117.

Araújo Almeida, N. A., Antunes, V. R., Abrão Saad, W. and de Arruda Camargo, L. A. (1999) Effects of the alpha antagonists and agonists injected into the lateral hypothalamus on the water and sodium intake induced by angiotensinⅡinjection into the subfornical organ. Brain Res. Bull. 48: 521-525.

Bickerton, R. K. and Buckley, J. P. (1961) Evidence for a central mechanism in angiotensin induced hypertension. Proc. Soc. Exp. Biol. Med. 106: 834-836.

Bone, R. C. (1991) Sepsis, the sepsis syndrome, multi-organ failure: a plea for comparable definitions. Ann. Intern. Med. 114: 332-333.

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

Brown, D. L. and Guyenet, P. G. (1984) Cardiovascular neurons of brain stem with projections to spinal cord. Am. J. Physiol. 247: R1009-R1016.

Calaresu, F. R. and Yardley, C. P. (1988) Medullary basal sympathetic tone. Ann. Rev. Physiol. 50: 511-524.

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

Cerutti, C., Barrès, C. and Paultre, C. (1994) Baroreflex modulation of blood pressure and heart rate variabilities in rats: assessment by spectral analysis. Am. J. Physiol. 266: H1993-H2000.

Chan, R. K. W., Chan, Y. S. and Wong, T. M. (1994) Effects of [Sar1, Ile8]-angiotensinⅡon rostral ventrolateral medulla neurons and blood pressure in spontaneously hypertensive rats. Neuroscience 63: 367-377.

Chan, R. K. W., Chan, Y. S. and Wong, T. M. (1996) Effects of angiotensinⅡon the spontaneous activity of rostral ventrolateral medullary cardiovascular neurons and blood pressure in the spontaneously hypertensive rats. J. Biomed. Sci. 3: 191-202.

Chan, R. K. W., Chan, Y. S. and Wong, T. M. (1991) Responses of cardiovascular neurons in the rostral ventrolateral medulla of the normotensive Wistar Kyoto and spontaneously hypertensive rats to iontophoretic application of angiotensinⅡ. Brain Res. 556: 145-150.

Chan, J. Y. H., Wang, S. H. and 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.

Chandler, L. J., Kopnisky, K., Richards, E., Crews, F. T. and Sumners, C. (1995) AngiotensinⅡdecreases inducible nitric oxide synthase expression in rat astroglial cultures. Am. J. Physiol. 268: C700-C707.

Chen, F. W. (1999) The role of endogenous angiotensins and nucleus reticularis ventrolateralis in the modulation of sympathetic vasomotor tone in the rat. Master thesis.

Chiu, A. D., Herblin, W. F., McCall, D. E., Ardecky, R. J., Carini, D. J., Duncia, J. V., Pease, L. J., Wong, P. C., Wexler, R. R., Johnson, A. L. and Timmermans, P. B. M. W. M. (1989) Identification of angiotensinⅡreceptor subtypes. Biochem. Biophys. Res. Commun. 165: 196-203.

Dampney, R. A. L. and Moon, E. A. (1980) Role of ventrolateral medulla in vasomotor response to cerebral ischemia. Am. J. Physiol. 239: H349-H358.

Dampney, R. A. L., Goodchild, A. K., Robertson, L. G. and Montgomery, W. (1982) Role of ventrolateral medulla in vasomotor regulation: a correlative anatomical and physiological study. Brain Res. 249: 223-235.

DeBoer, R. W., Karemaker, J. M. and Strackee, J. (1987) Hemodynamic fluctuations and baroreflex sensitivity in humans: a beat-to-beat model. Am. J. Physiol. 253: H680-H689.

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

Fischer-Ferraro, C., Nahmod, V. E., Goldstein, D. J. and Finkielman, S. (1971) Angiotensin and renin in rat and dog brain. J. Exp. Med. 133: 353-361.

Fontes, M. A. P., Silva, L. C. S., Campagnole-Santos, M. J., Khosla, M. C., Guertzensten, P. G. and 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.

Gantan, D., Marquez-Julio, A., Granger, P., Hayduk, K., Karsunky, K. P., Boucher, R. and Genest, J. (1971) Renin in dog brain. Am. J. Physiol. 221: 1733-1737.

Ganten, D. and Speck, G. (1978) The brain-renin angiotensin system: a model for the synthesis of peptides in the brain. Biochem. Pharmacol. 27: 2379-2389.

Gardiner, S. M., Kemp, P. A., March, J. E. and Bennett, T. (1996) Temporal differences between the involvement of angiotensinⅡand endothelin in the cardiovascular responses to endotoxaemia in conscious rats. Br. J. Pharmacol. 119: 1619-1627.

Granata, A. R., Kumada, M. and Reis, D. J. (1985a) Sympathoinhibition by A1-noradrenergic neurons is mediated by neurons in the C1 area of the rostral medulla. J. Auto. Nerv. Syst. 14: 387-395.

Granata, A. R., Ruggiero, D. A., Park, D. H., Joh, T. H. and Reis, D. J. (1985b) Brain stem area with C1 epinephrine neurons mediates baro-reflex vasodepressor response. Am. J. Physiol. 248: H547-H567.

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

Guyton, A. C. and Harris, J. W. (1951) Pressoreceptor-autonomic oscillation: a probable cause of vasomotor waves. Am. J. Physiol. 165: 158-166.

Haselton, J. R. and Guyenet, P. G. (1989) Electrophysiological characterization of putative C1 adrenergic neurons in the rat. Neuroscience 30: 199-214.

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

Hein, L., Barsh, G. S., Pratt, R. E., Dzau, D. J. and Kobilka, B. K. (1995) Behavioral and cardiovascular effects of disrupting the angiotensinⅡtype-2 receptor gene in mice. Nature 377: 744-747.

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

Hirooka, Y., Potts, P. D. and Dampney, R. A. L. (1997) Role of angiotensinⅡreceptor 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.

Hökfelt, T., Fuxe, K., Goldstein, M. and Johansson, O. (1974) Immunohistochemical evidence for the existence of adrenaline neurons in rat brain. Brain Res. 66: 235-251.

Ichiki, T., Labosky, P. A., Shiota, C., Okuyama, S., Imagawa, Y., Fogo, A., Niimura, F., Ichikawa, I., Hogan, B. L. M. and Inagami, T. (1995) Effects on blood pressure and exploratory behavior of mice lacking angiotensin Ⅱtype-2 receptor. Nature 377: 748-750.

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

Ito, S. and Sved, A. F. (1996) Blackade of angiotensin receptors in rat rostral ventrolateral medulla removes exvitatory vasomotor tone. Am. J. Physiol. 270: R1317-R1323.

Ito, S. and Sved, A. F. (1997) Tonic glutamate-mediated control of rostral ventrolateral medulla and sympathetic vasomotor tone. Am. J. Physiol. 273: R487-R494.

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

Kambayashi, Y., Bardhan, S., Takahashi, K., Tsuzuki, S., Inui, H., Hamakubo, T. and Inagami, T. (1993) Molecular cloning of a novel angiotensinⅡreceptor isoform involved in phosphotyrosine phosphatase inhibition. J. Biol. Chem. 268: 24543-24546.

Kilbourn, R. G., Jubran, A., Gross, S. S., Griffith, O. W., Levi, R., Adams, J. and Lodato, R. F. (1990) Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem. Biophys. Res. Comm. 172: 1132-1138.

Kopnisky, K. L., Sumner, C. S. and Chandler, L. J. (1997) Cytokine- and endotoxin- induced nitric oxide synthase in rat astroglial cultures: differential modulation by angiotensinⅡ. J. Neurochem. 68: 935-944.

Kopnisky, K. L. and Sumner, C. S. (2000) Angiotensin II-induced decrease in expression of inducible nitric oxide synthase in rat astroglial cultures: role of protein kinase C. J. Neurochem. 74: 613-20.

Kuo, T. B. J. and 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. and Chan, S. H. H. (1997a) Selective activation of vasomotor component of 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. and Chan, S. H. H. (1997b) Diminished vasomotor component of systemic arterial pressure signals and baroreflex in brain death. Am. J. Physiol. 273: H1291-H1298.

Lee, T. -Y., Fu, M. -J., Kuo, T. B. J., Lui, P. -W. and Chan, S. H. H. (1994) Power spectral analysis of electromyographic and systemic arterial pressure signals during fentanyl-induced muscular rigidity in the rat. Brit. J. Anaesth. 72: 328-334.

Li, Y. -W., Polson, J. W. and Dampney, R. A. L. (1992) AngiotensinⅡ excites vasomotor neurons but not respiratory neurons in the rostral and caudal ventrolateral medulla. Brain Res. 577: 161-164.

Lin, K. S., Chan, S. H. H. and 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.

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

Malliani, A., Pagani, M., Lombardi, F. and Cerutti, S. (1991) Cardiovascular neural regulation explored in the frequency domain. Circulation 84: 482-492.

Morrison, S. F., Callaway, J., Milner, T. A. and Reis, D. J. (1991) Rostral ventrolateral medulla: a source of the glutamatergic innervation of the sympathetic intermediolateral nucleus. Brain Res. 562: 126-135.

Mozes, T., Ben-Efraim, S. and Bonta, I. L. (1992) Lethal and non-lethal course of endotoxic shock is determined by interactions between tumor necrosis factor, platelet activating factor and eicosanoids. Pathol. Biol. 40: 807-12.

Muratani, H., Averill, D. B. and Ferrario, C. M. (1991) Effect of angiotensinⅡin ventrolateral medulla of spontaneously hypertensive rats. Am. J. Physiol. 260: R977-R984.

Muratani, H., Ferrario, C. M. and Averill, D. B. (1993) Ventrolateral medulla in spontaneously hypertensive rats: role of angiotensinⅡ. Am. J. Physiol. 264: R388-R395.

Murphy, T. J., Alexander, R. W., Griendling, K. K., Runge, M. S. and Bernstein, K. E. (1991) Isolation of a cDNA encoding the vascular type-1 angiotensinⅡreceptor. Nature 351: 233-235.

Paxinos, G. and Watson, C. (1998) The rat brain in stereotaxic coordinates, Academic Press, Sydney, Australia.

Phillips, M. I. (1987) Functions of angiotensin in the central nervous system. Ann. Rev. Physiol. 49: 413-435.

Phillips, M. I., Weyhenmeyer, J., Felix, D., Ganten, D. and Hohhman, W. E. (1979) Evidence for an endogenous brain-renin angiotensin system. Fed. Proc. 38: 2260-2266.

Preiss, G. and Polosa, C. (1974) Patterns of sympathetic neuron activity associated with Mayer waves. Am. J. Physiol. 226: 724-730.

Rasetti, C. and Vicaut, E. (1995) Short exposure to endotoxin increases the constriction induced by angiotensinⅡin rat aorta. J. Appl. Physiol. 79 (6): 2094-2100.

Reid, I. A. (1992) Interaction between ANGⅡ, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am. J. Physiol. 262: E763-E778.

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

Reis, D. J., Morrison, S. and Ruggiero, D. A. (1988) The C1 area of the brain stem in tonic and reflex control of blood pressure. Hypertension 11: I8-I13.

Robbe, H. W. J., Mulder, L. J. M., Rüddel, M., Langewitz, W. A., Veldman, J. B. P. and Mulder, G. (1987) Assessment of barereceptor reflex sensitivity by means of spectral analysis. Hypertension 10: 538-543.

Ross, C. A., Ruggiero, D. A., Joh, T. H., Park, D. H. and Reis, D. J. (1984a) Rostral ventrolateral medulla: selective projections to the thoracic autonomic cell column from the region containing C1 adrenaline neurons. J. Comp. Neurol. 288: 165-185.

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

Saigusa, T., Iriki, M. and Arita, J. (1996) Brain angiotensinⅡtonically modulates sympathetic baroreflex in rabbit ventrolateral medulla. Am. J. Physiol. 271: H1015-H1021.

Sasaki, S. and Dampney, R. A. L. (1990) Tonic cardiovascular effects of angiotensinⅡin the ventrolateral medulla. Hypertension 15: 274-283.

Sasaki, S., Li, Y. -W. and Dampney, R. A. L. (1993) Comparison of the pressor effects of angiotensinⅡandⅢin the rostral ventrolateral medulla. Brain Res. 600: 335-338.

Schelman, W. R., Kurth, J. L., Berdeaux, R. L., Norby, S. -W. and Weyhenmeyer, J. A. (1997) AngiotensinⅡtype-2 (AT2) receptor-mediated inhibition of NMDA receptor signalling in neuronal cells. Mol. Brain Res. 48: 197-250.

Schreihofer, A. M. and Guyenet, P. G. (1997) Identification of C1 presympathetic neurons in rat rostral ventrolateral medulla by juxtacellular labeling in vivo. J. Comp. Neurol. 387: 524-536.

Schreihofer, A. M., Stornetta, R. L. and Guyenet, P. G. (2000) Regulation of sympathetic tone and arterial pressure by rostral ventrolateral medulla after depletion of C1 cells in rat. J Physiol 15: 221-36.

Shoemaker, W. C., Appel, P. L., Waxmzn, K., Schwartz, S. and Chang, P. (1982) Clincial trial of survivors’ cardiorespiratory patterns as therapeutic goals in critically ill postoperative patients. Crit. Care. Med. 10: 398-404.

Shyr, M. -H., Yang, C. -H., Kuo, T. B. J., Pan, W. H. T., Tan, P. P. C. and Chan, S. H. H. (1993) Power spectral analysis of the electro-encephalographic and hemodynamic correlates of propofol anesthesia in the rat: intravenous bolus administration. Neurosci. Lett. 153: 161-164.

Smith, R. D., Chiu, A. T., Wong, P. C., Herblin, W. F. and Timmermans, P. B. M. W. M. (1992) Pharmacology of nonpeptide angiotensinⅡreceptor antagonists. Ann. Rev. Pharmacol. Taxicol. 32: 135-165.

Stornetta, R. L., Morrison, S. F., Ruggiero, D. A. and Reis, D. J. (1989) Neurons of rostral ventrolateral medulla mediate somatic pressor reflex. Am. J. Physiol. 256: R448-R462.

Tagawa, T., Horiuchi, J., Potts, P. D. and Dampney, R. A. L. (1999) Sympathoinhibition after angiotensin receptor blockade in the rostral ventrolateral medulla is independent of glutamate and γ-aminobutyric acid receptors. J. Auto. Nerv. Syst. 77: 21-30.

Tarpey, S. B., Bennett, T., Randall, M. D. and Gardiner, S. M. (1998) Differential effects of endotoxaemia on pressor and vasoconstrictor actions of angiotensinⅡand arginine vasopressin in conscious rats. Br. J. Pharmacol. 123: 1367-1374.

Timmermans, P. B. M. W. M., Wong, P. C., Chiu, A. T. and Herblin, W. F. (1991) Nonpeptide angiotensinⅡreceptor antagonists. Trends. Pharmacol. Sci. 23: 55-62.
Timmermans, P. B. M. W. M., Wong, P. C., Chiu, A. T., Herblin, W. F., Benfield, P., Carini, D. J., Lee, R. J., Wexler, R. R., Saye, J. M. and Smith, R. D. (1993) Angiotensin Ⅱreceptors and angiotensinⅡreceptor antagonists. Pharmacol. Rev. 45: 205-251.

Toney, G. M. and Porter, J. P. (1993) Functional role of brain AT1 and AT2 receptors in the central angiotensinⅡ pressor response. Brain Res. 603: 57-63.

Widdop, R. E., Gardiner, S. M., Kemp, P. A. and Bennett, T. (1993) Central administration of PD 123319 or EXP-3174 inhibits effects of angiotensinⅡ. Am. J. Physiol. 264: H117-H125.

Willette, R. N., Punnen, S., Krieger, A. J. and Sapru, H. N. (1984) Interdependence of rostral and caudal ventrolateral medullary areas in the control of blood pressure. Brain Res. 321: 169-174.

Wong, P. C., Price, W. A., Chiu, A. T., Duncia, J. V., Carini, D. J., Wexler, R. R., Johnson, A. L. and Timmermans, P. B. M. W. M. (1990) Nonpeptide angiotensinⅡreceptor antagonists.Ⅸ.Antihypertensive activity in rats of Dup 753, an orally active antihypertensive agent. J. Pharmacol. Exp. Ther. 252: 726-732.

Wong. P. C., Tam, S. W., Herblin, W. F. and Timmermans, P. B. M. W. M. (1991) Further studies on the selectivity of DuP 753, an nonpeptide angiotensinⅡreceptor antagonist. Eur. J. Pharmacol. 196: 201-203.

Wright, J. W. and Harding, J. W. (1997) Important role for angiotensin Ⅲand Ⅳ in the brain renin-angiotensin system. Brain Res. Rev. 25: 96-124.

Wright, J. W. and Harding, J. W. (1992) Regulatory role of brain angiotensins in the control of physiological and behavioral responses. Brain Res. Rev. 17: 227-262.

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

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

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

Yasuda, S. and Lew, W. Y. W. (1999) AngiotensinⅡexacerbates lipopolysaccharide-induced contractile depression in rabbit cardiac myocytes. Am. J. Physiol. 276: H1442-H1449.

Yien, H. -W., Hseu, S. -S., Lee, L. -C., Kuo, T. B. J., Lee, T. -Y. and 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.

Zhu, D. -N. Moriguchi, A., Mikami, H., Higaki, J. and Ogihara, T. (1998) Central amino acids mediate cardiovascular response to angiotensinⅡin the rat. Brain Res. Bull. 45: 189-197.