本論文之研究目的在於探討大白鼠延腦鼻端網狀腹外側核中之毒蕈鹼接受器亞型於美文松中毒過程中所扮演之角色。成熟雄性 Sprague－Dawley 品系之大白鼠 (體重 240－350 克) 作為實驗動物，腹腔注射 pentobarbital (45 mg/kg) 誘導麻醉以利手術之進行。實驗全程以持續靜脈滴注 propofol (30 mg/kg/h) 維持麻醉深度之穩定。
微量注射美文松 (10 nmol) 與人工腦脊髓液於兩側延腦鼻端網狀腹外側核中，導致動脈壓頻譜之血管運動成份功率產生兩期之變化。動脈壓頻譜之血管運動成份功率於第一期表現相較於基準期明顯有增加之現象 (表示 RVLM 之活性被興奮)；於第二期之表現則較基準期低 (表示 RVLM 之活性受到抑制)。然而，微量注射美文松與毒蕈鹼第二亞型 (M2) 接受器拮抗劑 methoctramine (0.5 或 1 nmol) 或M4接受器拮抗劑 tropicamide (0.5 或 1 nmol) 可明顯地降低交感性血管運動輸出於美文松中毒過程中所引發之變化，且此抑制作用具有劑量相關性；微量注射美文松與 M1 接受器拮抗劑 pirenzepine (0.5 或 1 nmol) 或 M3 接受器拮抗劑 4-DAMP (0.5 或 1 nmol) 則無法對美文松中毒所引發之心血管變化有任何影響。另一方面，西方墨點法之結果顯示出，微量注射美文松與 methoctramine (1 nmol) 或 tropicamide (1 nmol) 於兩側延腦鼻端腹外側核中能明顯抑制神經性一氧化氮合成酶與誘導型一氧化氮合成酶於美文松中毒第一期蛋白質表現量增加之現象，此外誘導型一氧化氮合成酶於美文松中毒第二期蛋白質表現量增加的現象亦能被抑制；然而，微量注射美文松與 pirenzepine (1 nmol) 或 4-DAMP (1 nmol) 則對神經性一氧化氮合成酶與誘導型一氧化氮合成酶蛋白質表現量於美文松中毒過程中之變化無任何影響。
綜合本論文之研究結果，我們認為大白鼠延腦鼻端網狀腹外側核中之 M2 與 M4 接受器參與美文松中毒過程於心臟血管之調控。透過 M2 與 M4 接受器之活化進一歩刺激神經性一氧化氮合成酶與誘導型一氧化氮合成酶表現量增加，兩者互相制衡下於美文松中毒過程第一期產生交感神經興奮作用；此外，神經性一氧化氮合成酶並無參與第二期，因此由誘導型一氧化氮合成酶大量表現後交感神經抑制作用。

We investigated the role of muscarinic receptor subtypes at the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic neurogenic vasomotor tone, in mevinphos (Mev) intoxication. Adult Sprague-Dawley rats anesthetized by pentobarbital (45 mg/kg) and maintained by propofol (30 mg/kg/h) were used.
Co-microinjection bilaterally of Mev (10 nmol) and artificial cerebrospinal fluid (aCSF) into the RVLM resulted in an increase (Phase I) followed by a decrease (Phase II) in the power density of the vasomotor components of systemic arterial pressure spectrum, our experimental index for sympathetic vasomotor tone. These changes in sympathetic vasomotor outflow in both phases of Mev intoxication were significantly and dose-dependently reduced on co-microinjection of Mev and the M2 subtype of muscarinic receptor (M2R) antagonist methoctramine (0.5 or 1 nmol) or M4R antagonist tropicamide (0.5 or 1 nmol). On the other hand, the M1R antagonist pirenzepine (0.5 or 1 nmol) or M3R antagonist 4-DAMP (0.5 or 1 nmol) was ineffective. Western blot analysis further revealed that the increase in NOS I protein levels at the RVLM during Phase I Mev intoxication or the augmented level of NOS II during both phases were significantly blunted on co-microinjection bilaterally of Mev and methoctramine (1 nmol) or tropicamide (1 nmol) into the RVLM. Pirenzepine (1 nmol) or 4-DMAP (1 nmol) was again ineffective.
We conclude that both M2R and M4R subtypes in the RVLM may be involved in Mev intoxication. Whereas the prevalence of NOS I over NOS II at the RVLM during Phase I results in sympathoexcitation, sympathoinhibition induced by NO from NOS II in the RVLM is primarily involved in Phase II Mev intoxication.

目 錄

中文摘要………………………………………………………………1
英文摘要………………………………………………………………4
第一章 緒論與文獻回顧 ……………………………………………7
1-1 有機磷中毒之作用機轉與對心血管之影響…………………8
1-2 延腦鼻端網狀腹外側核 (RVLM) 調控心臟血管之作用……9
1-3 毒蕈鹼接受器………………………………………………10
1-3-1 毒蕈鹼接受器於中樞神經系統中之分類………………10
1-3-2 毒蕈鹼接受器於中樞神經系統之作用…………………11
1-3-3 毒蕈鹼接受器於 RVLM 中之生理作用………………12
1-4 一氧化氮 (NO)………………………………………………14
1-4-1 NO 於 RVLM 中之生理作用…………………………14
1-4-2 一氧化氮合成酶 (NOS)………………………………15
1-5 動脈壓頻譜分析………………………………………………16
1-6 大白鼠美文松中毒模式………………………………………17
第二章 研究動機與目的………………………………………………19
2-1 研究動機………………………………………………………20
2-2 研究目的………………………………………………………20
第三章 實驗材料與方法………………………………………………22
3-1 實驗動物與手術前處理………………………………………23
3-2 微量注射方式…………………………………………………23
3-3 動脈壓頻譜分析………………………………………………24
3-4 腦部組織切片…………………………………………………25
3-5 西方墨點法……………………………………………………25
3-6 統計方法………………………………………………………27
3-7 實驗藥品來源…………………………………………………27
第四章 實驗結果………………………………………………………28
4-1 大白鼠 RVLM 中不同亞型之毒蕈鹼接受器於美文松中毒過程中參與心血管調控之情形…………………………………29
4-1-1 微量注射美文松與 M1 拮抗劑於 RVLM 對心臟血管之影響……………………………………………………29
4-1-2 微量注射美文松與 M2 拮抗劑於 RVLM 對心臟血管之影響……………………………………………………30
4-1-3 微量注射美文松與 M3 拮抗劑於 RVLM 對心臟血管之影響……………………………………………………31
4-1-4 微量注射美文松與 M4 拮抗劑於 RVLM 對心臟血管之影響……………………………………………………31
4-2 大白鼠急性美文松中毒過程中 NOS 於不同亞型之毒蕈鹼接受器拮抗劑作用下之表現……………………………………33
4-2-1 大白鼠急性美文松中毒過程中 NOS 於 M1 拮抗劑作用下之表現……………………………………………33
4-2-2 大白鼠急性美文松中毒過程中 NOS 於 M2 拮抗劑作用下之表現……………………………………………33
4-2-3 大白鼠急性美文松中毒過程中 NOS 於 M3 拮抗劑作用下之表現……………………………………………34
4-2-4 大白鼠急性美文松中毒過程中 NOS 於 M4 拮抗劑作用下之表現……………………………………………35
第五章 討論……………………………………………………………36
5-1 大白鼠 RVLM 中毒蕈鹼接受器亞型於美文松中毒過程中所扮演之角色……………………………………………………37
5-2 美文松中毒過程中 NOS 於毒蕈鹼接受器拮抗劑作用下所扮演之角色………………………………………………………40
5-3 未來研究方向…………………………………………………43
第六章 結論……………………………………………………………44
參考文獻………………………………………………………………46
附圖……………………………………………………………………60

Agarwal SK, Celsema J and Calaresu FR: Inhibition of rostral VLM by baroreceptor activation is relayed through caudal VLM. Am J Physiol 58: R1271-8, 1990.

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

Amendt K, Czachurski J, Dembowsky K and Seller H: Bulbospinal projections to the intermediolateral cell column: a neuroanatomical study. J Auton Nerv Syst 1: 103-17, 1979.

Bagetta G, Massoud R, Rodinó, Federici G and Nisticó, G: Systemic administration of lithium chloride and tacrine increases nitric oxide synthase activity in the hippocampus. Eur J Pharmacol 237: 61-4, 1993.

Bataillard A, Sannajust F, Yoccoz D, Blanchet G, Sentenac-Roumanou H and Sassard J: Cardiovascular consequences of organophosphorus poisoning and of antidotes in conscious unrestrained rats. Pharm & Toxicol 67: 27-35, 1990.

Bickford ME, Gunluck AE, Guido W and Sherman SM: Evidence that cholinergic axons from the parabrachial region of the brainstem are the exclusive source of nitric oxide in the lateral geniculate nucleus of the cat. J Comp Neurol 334: 410-30, 1993.

Birdsall NJM, Curtis CAM, Eveleigh CP, Hulme EC, Pedder EK, Poyner D and Wheatley M: Muscarinic receptor subtypes and the selectivity of agonists and antagonists. Pharmacology 37: 22-31, 1988.

Borda T, Genaro A, Sterin-Borda L and Cremaschi G: Involvement of endogenous nitric oxide signalling system in brain muscarinic acetylcholine receptor activation. J Neural Transm 105: 193-204, 1998.
Bredt DS: Molecular characterization of nitric oxide synthase. In Vincent SR (ed): Nitric oxide in the nervous system. San Diego: Academic Press, pp 1–19, 1995.

Brezenoff HE and Caputi AP: Intracerebroventricular injection of hemicholium-3 lowers blood pressure in conscious spontaneously hypertensive rats but not in normotensive rats. Life Sci 26: 1037-45, 1980.

Brezenoff HE and Giuliano R: Cardiovascular control by cholinergic mechanisms in the central nervous system. Annu Rev Pharmacol Toxicol 22: 341-81, 1982.

Brezenoff HE and Rusin J: Brain acetylcholine mediates the hypertensive response to physostigmine in the rat. Eur J Pharmacol 29: 262-6, 1974.

Brown DA, Forward A and Narsh S: Antagonist discrimination between ganglionic and ileal muscarinic receptors. Br J Pharmacol 71: 362-4, 1980.

Brown DL and Guyenet PC: Electrophysiological study of cardiovascular neurons in the rostral ventrolateral medulla in rats. Circ Res 56: 359-69,1985.

Brown DL and Guyenet PG: Cardiovascular neurons of brainstem with projections to spinal cord. Am J Physiol 247: R1009-R1016, 1984.

Buccafusco JJ, Lapp CA, Aronstam RS , Hays AC and Shuster LC: Role of prostanoids in the regulation of central cholinergic receptor sensitivity. J Pharmacol Exp Ther 266: 314-22, 1993.

Buccafusco JJ, Terry JR, AV and Shuster LC: Spinal NMDA receptor: nitric oxide mediation of the expression of morphine withdrawal symptoms in the rat. Brain Res 679: 189-99, 1995.

Calaresu FR and Yardley CP: Medulla basal sympathetic tone. Annu Rev Physiol 50: 511-24, 1988.

Carrive P, Bandler R and Dampney RA: Anatomical evidence that hypertension associated with the defense reaction in the cat is mediated by a direct projection from a restricted portion of the midbrain periaqueductal gray to the subretrofacial nucleus of the medulla. Brain Res 460: 339-45, 1988.

Castoldi AF, Manzo L and Costa LG: Cyclic GMP formation induced by muscarinic receptors is mediated by nitric oxide synthesis in rat cortical primary cultures. Brain Res 610:57-61, 1993.

Castoldi AF, Manzo L, Costa LG: Cyclic GMP formation induced by muscarinic receptors is mediated by nitric oxide synthesis in rat cortical primary cultures. Brain Res 610:57–61, 1993.

Caulfield MP and Brown DA: Pharmacology of the putative M4 muscarinic receptor mediating Ca-current inhibition in neuroblastomam × gioma hybrid (NG108-15) cells. Br J Pharmacol 104: 39-45, 1991.

Caulfield MP: Muscarinic receptors-characterization, coupling and function. Pharmacol Ther 58: 319-79, 1993.

Chan JYH, Wang LL, Wu KLH and Chan SHH: Reduced functional expression and molecular synthesis of inducible nitric oxide synthase in rostral ventrolateral medulla of spontaneously hypertension rats. Circulation 104: 1676-81, 2001a.

Chan JYH, Wang SH and Chan SHH: Differential roles of iNOS and nNOS at rostral ventrolateral medulla during experimental endotoxemia in the rat. Shock 15: 65-72, 2001b.

Chan RKW, Chan YS and Wong TM: Cardiovascular responses to electrical stimulation of the ventrolateral medulla of the spontaneously hypertensive rat. Brain Res 522: 99-106, 1990.

Chan SHH, Wang LL and Chan JYH: Differential engagements of glutamate and GABA receptors in cardiovascular actions of endogenous nNOS or iNOS at rostral ventrolateral medulla of the rat. Br J Pharmacol 138: 584-93, 2003.

Chan SHH, Wang LL, Wang SH and Chan JYH: Differential cardiovascular responses to blockade of nNOS or iNOS in rostral ventrolateral medulla of the rat. Br J Pharmacol 133: 606-14, 2001c.

Chang AY, Chan JY and Chan SHH: Differential distribution of nitric oxide synthase isoforms in the rostral ventrolateral medulla. J Biomed Sci 10: 285-91, 2003.

Chang AYW, Chan JYH, Kao FJ, Huang CM and Chan SHH: Engagement of inducible nitric oxide synthase at the rostral ventrolateral medulla during mevinphos intoxication in the rat. J Biomed Sci 8: 475-83, 2001.

Ciriello J, Caverson CM and Polosa C: Function of the ventrolateral medulla in the control of the circulation. Brain Res Rev 11: 359-91, 1986.

Coram WM and Brezenoff HE: The antihypertensive effect of a selective central muscarinic cholinergic antagonist: N- (4-diethylamino-2-butynyl)-succinimide. Drug Dev Res 3: 503-16, 1983.

Dampney RAL, Goodchild AK, Robertson LG and Montgomery W: Role of ventrolateral medulla in vasomotor regulation: a correlative anatomical and physiological study. Brain Res 249: 223-35, 1982.

Dampney RAL: Brain stem mechanism in the control of arterial pressure. Clin Exp Hyperten 3: 379-91, 1981.

Deguchi T: Endogenous activating factor for guanylate cyclase in synaptosomal-solute fraction of rat brain. J Biol Chem 252: 7617-9, 1977.
Dinerman JL, Lowenstein CJ and Snyder SH: Molecular mechanisms of nitric oxide regulation. Circ Res 73: 217-22, 1993.

Dörje F, Wess J, Lambrecht G, Tacke R, Mutschler E and Brann MR: antagonist binding profiles of five cloned human muscarinic receptor subtypes. J Pharmacol Exp Ther 256: 723-33, 1991.

Eglen RM, Reddy H and Watson N: Selective inactivation of muscarinic receptor subtypes. Int J Biochem 26: 1357-68, 1994.

Ernsberger P, Arango V and Reis DJ: A high density of muscarinic receptors in the rostral ventroalteral medulla of the rat is revealed by correction for autoradiographic efficiency. Neurosci Lett 85: 179-86, 1988.

Feigenbaum P, El-Fakahany EE: Regulation of muscarinic cholinergic receptor density in neuroblastoma cells by brief exposure antagonist﹔possible involvement in desensitization of receptor function. J Pharmacol Exp Ther 233: 139-40, 1985.

Gattu M, Pauly J, Urbanawiz S and Buccafusco J: Autoradiographic comparison of muscarinic m1 and m2 binding sites in the CNS of spontaneously hypertensive and normotensive rats. Brain Res 771: 173-83, 1997.

Giuliano R, Ruggiero DA, Morrison S, Ernsberger P and Reis DJ: Cholinergic regulation of arterial pressure by the c1 area of the rostral ventrolateral medulla. J Neurosci 9: 923-42, 1989.

Granata AR, Ruggiero DA, Park DH, John TH and Reis DJ: Brain steam area with c1 epinephrine neurons mediates baroreflex vasodepressor responses. Am J Physiol 248: H1200-H1208, 1985.

Haddad EB and Rousell J: Regulation of the expression and function of the M2 muscarinic receptor. Trends Pharmacol 19: 322-7, 1998.

Hammer R and GiachettiA: Muscarinic receptor subtypes: M1 and M2 biochemical and functional characterization. Life Sci 31: 2991-9, 1982.

Hammer R, Berrie CP, Birdsall NJM, Burgen ASV and Hulme EC: Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature 283: 90-92, 1980.

Han X, Kobzik L, Serverson D and Shimoni Y: Characteristics of nitric oxide-mediated cholinergic modulation of calcium current in rabbit sinoatrial node. J Physiol 509: 741-54, 1998.

Herring N, Danson EJF and Paterson DJ: Cholinergic control of heart rate by nitric oxide is site specific. News Physiol Sci 17: 202-6, 2002.

Hirooka Y, Polson JW and Dampney RAL: Pressor and sympathoexcitatory effects of nitric oxide in the rostral ventroalteral medulla. J Hypertens 14: 1317-24, 1996.

Hosey MM: Diversity of structure, signaling and regulation within the family of muscarinic cholinergic receptors. FASEB J 6: 845-52, 1993.

Hosey MM: Diversity of structure, signaling and regulation within the family of muscarinic cholinergic receptor. FASEB J 6: 845-52, 1992.

Howe PRC, Kohn DM, Minson JB, Stead BH and Chalmers JP: Evidence for bulbospinal seretonergic pressor pathway in the rat brain. Brain Res 270: 29-36, 1983.

Hulme EC, Birdsall NJM and Buckley NJ: muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol 30: 633-73, 1990.

James MK and Frank JG: Role of rostral ventrolateral medulla in centrally mediated pressor response. Am J Physiol 267: H1549-H1556, 1994.

Krnjevic K: Chemical nature of synaptic transmission inertebrates. Physiol Rev 54: 418-540, 1974.

Krstic MK and Djurkovic D: Cardiovascular response to intracerebroventricular administration of acetylcholine in rats. Neuropharmacology 17: 341-7, 1978.

Krukoff TL: Central actions of nitric oxide in regulation of autonomic function. Brain Res Rev 30: 52-65, 1999.

Kubo T, Taguchi K, Sawai N, Ozaki S and Hagiwara Y: Cholinergic mechanism responsible for blood pressure regulation on sympathoexcitatory neurons in the rostral ventrolateral medulla of the the rat. Brain Res Bull 42:199-204, 1997.

Kuo TBJ and Chan SHH: Continuous, on-line, real-time spectral analysis of systemic arterial pressure signals. Am J Physiol 264: H2208-H2213, 1993.

Kuo TBJ, Yang CCH and Chan SHH: Selective activation of vasomotor component SAP spectrum by nucleus reticularis ventrolateralis in rats. Am J Physiol 272: H485-H492, 1997.

Kuo TBJ, Yang CCH and Chan SHH: Transfer function analysis of ventilatory influence on systemic arterial pressure in the rat. Am J Physiol 271: H2108-H2115, 1996.

Lai WS, El-Fakahany EE: Phorbol ester induced inhibition of cyclic GMP formation mediated by muscarinic receptors in murine neuroblastoma cells. J Pharmacol Exp Ther 241: 366-373, 1987.

Lazareno S and Roberts F: Functional and binding studies with muscarinic M2-subtype selective antagonists. Br J Pharmacol 98: 309-17, 1989.

Lazareno S, Buckley NJ and Roberts F: Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart and NG 108-15 cells. Molec Pharmacol 38: 805-15, 1990.

Lenox RH, Kant GJ, Meyerhoff JL: Regional sensitivity of cyclic AmP and cyclic GMP in rat brain to central cholinergic stimulation. Life Sci 26:2201–2209, 1980.

Liles WC, Hunter DD, Meier KE and Nathanson NM: Activation of protein kinase C induces rapid internalization and subsequent degradation of muscarinic acetylcholine receptors in neuroblastoma cells. J Biol Chem 26 1: 5307-13, 1986.

Main AR: Affinity and phosphorylation constants for the inhibition of esterase by organophosphates. Science 144: 992-3, 1964.

Malliana A, Pagani M, Lombardi F and Ceruyyi S: Cadiovascular neural regulation explored in the frequency domain. Circulation 84: 482-92, 1991.

Martins-Pinge MC, Baraldi-Passy I and Lopes OU: Excitatory effects of nitric oxide within the rostral ventrolateral medulla of freely moving rats. Hypertension 30: 704-7, 1997.

Maxwell DM, Leenz DE, Groff WA, Kaminskis A and Froelich HL: The effect of blood flow and detoxification on in vivo cholinesterase inhibition by soman in rats. Toxicol Appl Parmacol 88: 66-76, 1987.

Mitchelson F: Muscarinic receptor differentiation. Pharmacol Ther 37: 357-423, 1988.

Moncada S and Higgs EA: The L-arginine-nitric oxide pathway. N Engl J Med 30: 2002-12, 1993.

Moro V, Badaut J, Springhetti V, Edvinsson L and Seylaz J: Regional study of the co-localization of neuronal nitric oxide synthase with muscarinic receptors in the rat cerebral cortex. Neuroscience 69: 797-805, 1995.

Nachmansohn D and Feld EA: Studies on cholinesterase: IV. on the mechanism of di-isopropyl fluorophosphate action in vivo. J Biol Chem 171: 715-24, 1947.

Nattie EE and Li AH: Ventral medulla sites of muscarinic receptor subtypes involved in cardiorespiratory control. J Appl Physiol 69: 33-41, 1990.

Palmer RMJ, Rees DD, Ashton DS and Moncada S: L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun 153: 1251-6, 1988.

Paxinos G and Watson C: The Rat Brain: in Steroetaxic Coordinates. Academic Press, Sydney, Australia, 1998.

Price RHJR, Mayer B and Beitz AJ: Nitric oxide synthase neurons in rat brain express more NMDA receptor mRNA than non-NOS neurons. Neuroreport 4: 807-10, 1993.

Punnen S, Willette RN, Krieger AJ and Sapru HN: Medullary pressor area: Site of action of intravenous physostigmine. Brain Res 382: 178-84, 1986.

Rees DD, Palmer RMJ and Moncada S: Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci 86: 3375-8, 1989.

Rettori V, Gimeno M, Lyson, K and Mccann SM: Nitric oxide mediates norepinephrine- induced prostaglandin E2 release from the hypothalamus. Proc Natl Acad Sci USA 891: 1543-6, 1992.

Rupreht J: the central muscarinic transmission during anaesthesia and recovery--the central anticholinergic syndrome. [Review] [20 Refs] Anaesthesiol Reanim 16: 250-8, 1991.

Sandmann J and Wurtman RJ: Stimulation of phospholipase D activity in human neurobalstoma (LA-N-2) cells by activation of muscarinic acetylcholine receptors or by phorbl esters: relationship to phosphoinositide turnover. J Nuerochem 56: 1312-9, 1991.

Shapoval LN, Sagach VF and Pobegailo LS: Nitric oxide influences ventrolateral medullary mechanisms of vasomotor control in the cat. Neurosci Lett 132: 47-50, 1991.

Shih TM: Time course effects of soman on acetylcholine and choline levels in six discrete areas of the rat brain. Psychopharmacology 78: 170-5, 1982.

Sundaram K, Krieger AJ and Sapru HN: M2 muscarinic receptors mediate pressor responses to cholinergic agonists in the ventrolateral medulla pressor area. Brain Res 449: 141-9, 1988a.

Sundaram KA and Sapru H: Cholinergic nerve terminals in the ventrolateral medullar pressor area: pharmacological evidence. J Auton Nerv Syst 22: 221-8, 1988b.

Takahashi H, Kojima T, Ikeda T, Tsuda S and Shirasu Y: Differences in the mode of lethality produced through intravenous and oral administration of organophosphorus insecticides in rats. Fundam Appl Toxicol 16: 459-68, 1991.

Takeshi I, Timothy JM and Ahmmed A: Role of nitric oxide in the ventrolateral medulla on cardiovascular responses and Glutamate neurotransmission during mechanical and thermal stimuli. Pharmacol Res 47: 59–68, 2003.

Takeshi I, Yukio H, Timothy JM and Ahmmed A: Glutamate neurotransmission and nitric oxide interaction within the ventrolateral medulla during cardiovascular responses to muscle contraction. Brain Res 874: 107–15, 2000.

Triedmam JK and Saul JP: Blood pressure modulation by central venous pressure and respiration buffering effects of the heart rate reflexes. Circulation 89: 169-79, 1994.

Verberne AJM and Guyenet PG: Midbrain central gray influence on medullary sympathoexcitatory neurons and the baroreflex in rats. Am J Physiol 263: R24-R33, 1992.

Wakade AR and Wakade TD: Contribution of nicotinic and muscarinic receptors in the secretion of catecholamines evoked by endogenous acetylcholine. Neuroscience 10: 973-8, 1983.

Watson M, Yamamura HI and Roeske WR: A unique regulatory profile and regional distribution of [3H]-pirenzepine in the rat provide evidence for distinct M1 and M2 muscarinic receptor subtypes. Life Sci 32: 3001-11, 1983.

Wess J: Mutational analysis of muscarinic acethylcholine receptors: structure basis of ligand/receptor/G-protein interactions. Life Sci 53: 1447-63, 1993.

Willette RN, Barcas PP, Krieger AJ and Sapru HN: Endogenous GABAergic mechanism in the medulla and the regulation of blood pressure in the rat. J Pharmacol Exp Ther 226: 893-9, 1983a.

Willette RN, Barcas PP, Krieger AJ and Sapru HN: Vasopressor and depressor areas in the rat medulla identification by microinjection of L-glutamate. Neuropharmacology 22: 1071-9, 1983b.

Willette RN, Punnen S, Krieger AJ and Sapru HN: Cardiovascular control by cholinergic mechanisms in the rostral ventrolateral medulla. J Pharmacol Exp Ther 231: 457-63, 1984.
Yang CCH, Kuo TBJ and Chan SHH: Auto- and cross-spectral analysis of cardiovascular fluctuation during pentobarbital anesthesia in the rat. Am J Physiol 270: H575-H582, 1996.

Yang CH, Shyr MH, Kuo TBJ, Tan PCC and Chan SHH: 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: 1567-74, 1995a.

Yang MW, Kuo TBJ, Lin SM, Chan KH and Chan SHH: Continuous , on-line, real-time spectral analysis of SAP signals during cardiopulmonary bypass. Am J Physiol 268: H2329-H2335, 1995b.

Yen DHT, Yen JC, Len WB, Wang LM, Lee CH and Chan SHH: Spectral changes in systemic arterial pressure signals during acute mevinphos intoxication in the rat. Shock 15: 35-41, 2001.

Yien HW, Hseu SS, Lee LC, Kuo TBJ, Lee TY and Chan SHH: Spectral analysis of systemic arterila pressure and heart rate signals as a prognostic tool for the prediction of patient outcome in the intensive care unit. Crit Care Med 25: 258-66, 1997.

Zagon A and Smith AD: Monosynaptic projrctions from the rostral ventrolateral medulla oblongata to identified sympahetic preganglionic neurons. Neuroscience 54: 729-34, 1993.

Zanzinger J, Czachurski and Seller H: Inhibition of basal and reflex-mediated sympathetic activity in the RVLM by nitric oxide. Am J Physiol 268: R958-R962, 1995.

Zanzinger J, Czachurski J and Seller H: Neuronal nitric oxide reduces sympathetic excitability by modulation of central glutamate effects in pigs. Circ Res 80: 565-71, 1997.

Zanzinger J: Role of nitric oxide in the neural control of cardiovascular function. Cardiovasc Res 43: 639-49, 1999.

Zhuo M, Meller ST and Gebhart GF: Endogenous nitric oxide is required for tonic cholinergic inhibition of spinal mechanical transmission. Pain 54: 71-8, 1993.