胃延遲性排空是病患接受幽門保留式胰十二指腸切除術的主要併發症, 多種機轉曾被提出嘗試去討論其成因，皆無法圓滿解釋, 抑制性放鬆是控制胃排空機轉之一，乃經由非乙醯膽鹼、非腎上腺神經所傳導。一氧化氮(NO)是由一氧化氮酶(NOS)所製造，是非乙醯膽鹼、非腎上腺神經的主要傳導物質之一。一氧化氮酶共有三種,在腸胃道肌肉中，一氧化氮是由位於肌肉層含神經性一氧化氮酶之神經元(nNOS-containing neurons)負責產生。在一氧化氮酶基因剔除鼠動物模型裡，發現含一氧化氮酶神經元減少會導致胃延遲性排空 但小腸蠕動並不受影響。臨床上對神經性一氧化氮酶神經元所扮演的角色並不清楚。 因此, 本文乃探討神經性一氧化氮酶神經元在幽門保留式胰十二指腸切除術造成胃延遲性排空的角色。
　　本研究之設計首先藉由本院患者分析幽門保留式胰十二指腸切除術後胃功能的改變和胃延遲性排空的相關性。並在臨床病例研究中，使用放射性同位素胃排空功能檢查及胃內食物分布型圖表現確定，遠端胃功能異常是造成胃延遲性排空的主要成因。另術後體間素治療是預防胰臟術後和剩餘胰臟相關併發症的產生，由於體間素治療會增加幽門保留式胰十二指腸切除患者產生胃延遲性排空的機會，放射性胃排空檢查顯示接受治療患者其T1/2及Tmax均顯著延長。因此，體間素引發遲性胃排空將作為爾後動物實驗之用。另外，於體外研究，我們首先建立乙醯膽鹼刺激收縮模型，以檢試一氧化氮酶神經元釋放一氧化氮去影響肌肉收縮, 證實一氧化氮乃神經傳導物質可由神經間作用直接放鬆肌肉, 不需經由cGMP作為媒介。另外, 適量的一氧化氮才能維持肌肉收縮功能。在動物實驗中，亦發現體間素會明顯減少胃竇肌肉收縮及增加胃竇肌肉中一氧化氮的產生量, 亦就是說體間素可同時減少腸胃道中蠕動素的分泌造成胃竇收縮不足及刺激一氧化氮酶神經元增加分泌一氧化氮血卻引起胃竇過度放鬆進而達到抑制胃竇區的蠕動，此支持幽門保留式胰十二指腸切除術後引發延遲性胃排空與一氧化氮酶受損有關。最後以臨床上兩個病例在幽門保留式胰十二指腸切除患者併發胃延遲性空的研究發現，在肌肉收縮功能檢查及雙重螢光染色法下,胃延遲性排空病患的胃竇及幽門肌肉收縮型態異常, 所保留遠端胃竇及幽門肌肉中抑制性一氧化氮酶神經元減少導致遠端胃功能異常，進而引起胃延遲性排空。既胃延遲性排空是和肌肉中抑制性一氧化氮酶神經元減少相關。
　　總之,一氧化氮是非乙醯膽鹼、非腎上腺素神經傳導物質主要藉由NO-cGMP-independent pathway使肌肉放鬆, 抑制腸胃道肌肉過度收縮, 以維持肌肉收縮能力, 進而使腸胃道保持正常蠕動功能。本研究之貢獻乃是 1)證實一氧化氮酶神經元在幽門保留式胰十二指腸切除術術後引發胃延遲性排空扮演重要腸胃道肌肉維持收縮功能的重要角色, 2)體間素可能經由增加一氧化氮酶神經元分泌一氧化氮而導致遠端胃功能異常，再引起接受幽門保留式胰十二指腸切除術病患產生胃延遲性排空, 3)此發現推測手術引發急性腸胃道神經傷害進而影響腸胃排空功能,可提供臨床醫師未來利用可促進周圍神經再生物質以治療功能型腸胃疾病或改善術後腸胃功能時新觀點。

　　Delayed gastric emptying is the major complication in the patients receiving pylorus-preserving pancreaticoduodenectomy (PPPD). Several mechanisms suggested to responsible for PPPD-induced delayed gastric emptying are still not clear. The inhibitory input for the relaxation of the smooth muscle anally is the main function of gastrointestinal tract, and it is mediated by non-adrenergic, non-cholinergic (NANC) pathway. Several substances have been suggested that the neurotransmitters from NANC inhibitory motor neurons, such as NO, play an important role in the nonadrenergic noncholinergic (NANC)-mediated in the gastrointestinal relaxation. NO is converted from L-arginine by nitric oxide synthase. Among three NOS isoforms, eNOS, nNOS, iNOS, the expression of nNOS-containing neurons in the gastrointestinal smooth muscle is higher than other. The exact role of nNOS-containing neurons in the gastrointestinal tract of clinical diseases is still under investigation. In the nNOS-/- mouse, the deficiency of nNOS-containing neurons result in delay gastric emptying for solids and liquids, but no influence on the motility of small bowel. Therefore, the aim of this study is to investigate the impact of nNOS-containing neurons on the development of delayed gastric emptying after receiving pylorus-preseving pancreaticoduodenectomy.
　　First of all, our clinical studies demonstrated that dysfunction of the distal stomach is the main factor for the development of delayed gastric emptying after operation using nucleotide gastric emptying test and food distribution in the retained stomach. Somatostatin (SST) prophylaxis is the adjunct therapy to prevent pancreatic stump related complications but it also increases the incidence of delayed gastric emptying in the patients receiving pylorus-preserving pancreaticoduodenectomy. During treatment, the T1/2 and Tmax of gastric emptying test are significantly prolonged. The fasting motilin level also reduced and was lower than 6pg/ml serum if the patients developed delayed gastric emptying.
　　Afterward, in vitro model was used to examine the influence of NO on the gastrointestinal smooth muscle. As a result, the activation of the nNOS-containing neurons by acetylcholine functions as an interneuron to modulate acetylcholine-induced contraction. Then, NO-induced relaxation of the gastrointestinal tract is cGMP-independent.
　　In view that exposure to SST decreases contraction of antrum muscle by promoting the release of NO from nNOS-containing neurons in vitro. Immunofluorescence studies also showed co-localization of, SST- and nNOS-containing neurons. The data confirm that modulation of the nNOS-containing neurons by SST increase the secretion of NO and influence gastric emptying. During treatment by SST, the decrease of gastrointestinal hormone, motilin, can reduce the contraction power and increase release of NO from nNOS-containing neurons can relax the antrum. Therefore, the SST prophylaxis after PPPD promotes the incidence of delayed gastric emptying.
　　Finally, standard muscle bath experiments and immunohistochemical studies demonstrate the reduction of the nNOS-containing enteric inhibitory neurons is associated with the decrease of contraction force and frequency in the pylorus and antrum muscle of the PPPD patients with delayed gastric emptying. That is to say, the surgical procedures cause the reduction of nNOS-containing neurons in the pyloric and antral muscle, which further result in the dysfunction of the distal stomach and the inability of emptying food.
　　In conclusion, nNOS-containing neurons, an inhibitory intrinsic neuron, play important role in the regulation of gastrointestinal motility. The reduction of nNOS-containing neurons in the pylorus and antrum muscle by surgery results in the dysfunction of the distal stomach and delay in gastric emptying after PPPD. SST-mediated antral relaxation increases the incidence of delayed gastric emptying after PPPD via increasing the NO production from the nNOS-containing enteric neurons and reduction of secretion of motilin. The results demonstrate that the nNOS-containing neurons play an important role in gastric emptying. The significance of this study is to identify that NO from nNOS is as an inhibitory transmitter in gastrointestinal smooth muscle and fills an important gap in understanding the physiological control of motility and it can give a new insight for clinician to use nerve growth factor to improve postoperative gastrointestinal function or to treat functional gastrointestinal diseases.

References
1. Agrawal S, Stollman NH, Rogers AI. University of Miami Division of Clinical of Pharmacology Therapeutic Rounds: Update on diagnosis and treatment of gastroparesis. Am. J. Thera. 1999; 6:97-109.
2. Allescher HD, Daniel EE. Role of NO in pyloric, antral, and duodenal motility and its interaction with other inhibitory mediators. Dig Dis Sci 1994; 39: 73S-75S.
3. Allescher HD, Daniel EE, Dent J, et al. Extrinsic and intrinsic neural control pyloric sphincter pressure in the dog. J Physiol 1988; 401:17-38.
4. Allerscher HD, Tougas G, Vergara P, et al. Nitric oxide as a putative nonadrenegic noncholinergic inhibitory transmitter in the canine pylorus in vivo. Am J Physiol. 1992; 262: G695-702.
5. Belai A, Wheeler H, Burnstock G. Innervation of the rat gastrointestinal sphincters: Changes during development and aging. Int J Devl Neuroscience 1995; 13: 81-95.
6. Bell FR, Mostaghni K. Duodenal control of gastric emptying in the milk-fed calf. J Physiol 1975; 245: 387-407.
7. Bell FR, Webber DE, Wass JA, et al. Correlation of endogenous somatostatin, gastric inhibitory polypeptide, glucagons and insulin with gastric function in conscious calf. J Endocrinol 1981; 89: 451-6.
8. Blanc-Louvry I, Ducrotte P, Pellion C, et al. Upper jejunal motility after pancreaticoduodenectomy according to the type of anastomosis, pancreaticojejunal or pancreaticogastric. J Am Coll Surg 1999; 188: 261-70.
9. Bloom SR, Mortimer DH, Thorner MO, et al. Inhibition of gastrin and gastric acid secretion by growth hormone release inhibiting hormone. Lancet 1974; ii: 1106-9.
10. Bloom SR, Mitznegg P, Bryant MG. Measurement of human plasma motilin. Scand. J. Gastroent. 1976; 11 Suppl 39: 47-52.
11. Bloom SR, Mitznegg P, Bryant MG. Measurement of human plasma motilin. Scand. J. Gastroent. 1976; 11 Suppl 39: 47-52.
12. Bolotina VM, Najibi S, Palacino JJ, et al. Nitric oxide directly activates calcium dependent potassium channels in vascular smooth muscle, Nature 368; 1994: 850-853.
13. Braasch JW, Deziel DJ, Rossi RL et al. Pyloric and gastric preserving pancreatic resection. Experience with 87 patients. Ann Surg 1986; 204: 411-418.
14. Brookes SJ. Neuronal nitric oxide in the gut. J Gastrenterol Hepatol. 1993; 8: 590-603.
15. Bult H, Boeckxstaens GE, Pelckmaus PA, et al. Nitric Oxide as an inhibitory non-adrenegric non-cholonegric neurotransmitter. Nature 1990: 345: 346-7.
16. Calver A, Collier J. Vallance P. Nitric oxide and the control of human vascular tone in health and disease. European J. Med. 1993; 2(1): 48-53.
17. Canon WB, Lieb CW. The receptive relaxation of the stomach. Am J Phhysiol 1911; 29: 267-73.
18. Camilleri M. Effects of somatostatin analogues on human gastrointestinal motility. Digestion 1996; 57 suppl 1: 90-2.
19. Chiba T, Bharucha AE, Thomforde GM, et al. Mode of rapid gastrointestinal transit in dogs: effect of muscarinic antagonists and a nitric oxide synthase inhibitor. Neurogastroenterol Motil 2002; 14: 535-41.
20. Chung SA, Rotstein O, Greenberg GR, et al. Mechanisms coordinating gastric and small intestinal MMC: role of extrinsic innervation rather than motilin. Ann J physiol 1994: 267: G800-9.
21. Cronin M, Rogul A, Myers C, et al. Pertusis toxin blocks the somatostatin inhibition of
growth hormone release and cyclic AMP accumulation. Endocrinology 1983; 113: 199-215.
22. Davis MG. Ali S. Leikauf GD. Dorn GW 2nd. Tyrosine kinase inhibition prevents deformation-stimulated vascular smooth muscle growth. Hypertension. 1994: 24(6): 706-13.
23. Debas HT, Faroog O, Grossman MI. Inhibition of gastric emptying is a physiological action of cholecystokinin. Gastroenterology. 1975; 68: 1211-7.
24. DeHaan D. Spitz J, Ayasononda V. Richter H. Gastrointestinal motility following pylorus-preserving duodenectomy in the dog. Gastroenterlogy.
25. Desai KW, Sessa WC, Vane JR. Involvement of nitric oxide in the reflex relaxation of the stomach to accomodate food or fluid. Nature 1991; 351: 477-9.
26. Dochray GJ. Neurochemial basis of reflex relaxation in gastric corpus. Dig Dis Sci 1994; 39 (12): 82S-85S.
27. Eglen RM. Muscarinic receptors and gastrointestinal tract smooth muscle function, Life. Sci. 68 (2001) 2573-2578.
28. Ehlert FJ, G.W. Sawyer, Esqueda EE. Contractile role of M2 and M3 muscarinic receptors in gastrointestinal smooth muscle. Lif Sci. 1999; 64: 387-394.
29. Fink AS, DeSouza LR, Mayer EA, Hawkins R, Longmire WP. Long-term evaluation of pylorus preservation during pancreaticoduodenectomy. World J Surg 1988; 12: 663-70.
30. Fish JC, Smith LB, William RD. Digestive function after radical pancreaticoduodenectomy. Am J Surg 1969; 117: 40-5.
31.Fish R, Cohen S. Physiological characteristics of the human pyloric sphincter. Gastroenterology 1973; 64: 67-75.
32. Fox JE, Daniel EE, Jury J, et al: The mechanism of motilin excitation of the canine small intestine. Life Sci 1984; 34: 1001-1006.
33. Friess H., Bordih, K, Ebert M, et al. Inhibition of pancreatic secretion under long-term octreotide treatment in humans. Digestion 1994; 55 (suppl 1): 10-15.
34. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288: 373-6.
35. Furness JB, Sanger GJ. Intrinsic nerve circuits of the gastrointestinal tract: identification of drug targets. Curr Opin Pharmacol 2002; 2: 612-22.
36.Garthwaite J, Charles SL, Chess-Willaims R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 1988; 343: 385-8.
37. Gillespie JS. The rat anococcygeus muscle and its response to nerve stimulation and to some drugs. Br J Pharmacol 1972; 45(3): 404-16l.
38. Glaogow I, Matter K, Krantis A. Rat gastroduodenal motility in vivo: involvement of NO and ATP in spontaneous motor activity. Am. J Physiol 1998; 38: G889-96.
39. Grace PA, Pitt HA, Longmire WP. Pylorus preserving pancreato-duodenectomy: an overview. Br J Surg 1990; 77: 968-74.
40. Grisoni E, Dusleag D, Super D. Nitric oxide synthase inhibition: The effect on rabbit pyloric muscle. J Ped Surg 1996; 31: 800-9.
41. Grider JR. Makhlouf GM. Vasoactive intestinal peptide. Transmitter of inhibitory motor eurons of the gut. Annals of the New York Academy of Sciences. 1988; 527: 369-77.
42. Gue M, Peeters T, Depoortere I, et al. Stress-induced changes in gastric emptying, postprandial motility, and plasma gut hormone levels in dogs. Gastroenterolgy 1989; 97: 1101-7.
43. Haruma K, Wiste JA, Camilleri M. Effect of octreotide on gastrointestinal pressure profiles in health and in functional and organic gastrointestinal disorders. Gut 1994; 35: 1064-9.
44. Hasler WL. The physiology of gastric motility and gastric emptying. In: Yamada T editor. Textbook of gastroenterology. 2nd ed. Philadelphia: JB Lippincott. 1995; chap 8; 181-206.
45. Hocking MP, Harrison WD, Sninsky CA. Gastric dysrhymias following pylorus-preserving pancreaticoduodenectomy. Possible mechanism for early delayed gastric emptying. Dig Dis Sci 1990; 35:1226-30
46. Holle CH, Burnstock G. Neuromuscular transmission in the gastrointestinal tract. 1989 In Handbook of Physiology. The gastrointestinal system, Vol. 1, Motility and Circulation, ed. Wood, J.D. pp. 435-464. Bethesda, MD, U.S.A.: American Physiol. Society, Waverly Press.
47. Hounghton LA, Read NW, Heddle R, et al. Relationship of the motor activity of the antrum, pylorus, and duodenum to gastric emptying of a solid-liquid mixed meal. Gastroenterology 1988; 94: 1285-91.
48. Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman MC. Targeted disruption of the neuronal nitric oxide synthase gene. Cell 1993; 75: 1273-86.
49. Huber A, Trudrung P, Storr M, et al. Protein kinase G expression in the small intestine and functional importance for smooth muscle relaxation, Am. J. Physiol. 275 (1998) G629-G637.
50. Hunt DR, McLean R. Pylorus-preserving pancreatectomy: functional results. Br J Surg 1989: 76; 173-6.
51. Ishiguchi T, Nishioka S, Takahashi T. Inhibitory neural pathway regulating gastric emptying in rats. J Auton Nerv Syst 2000; 79: 45-51.
52. Itani KMF, Coleman RE, Akwari OE, et al. Pylorus-preserving pancreaticoduodenectomy: a clinical and physiological appraisal. Ann Surg 1986; 204: 655-64.
53. Iversen HH, Wiklund NP, Olgart C, et al. Nerve stimulation-induced nitric oxide as a consequence of muscarinic M1 receptor activation. Eur J Pharmacol 1997; 331: 213-9.
54. Izzo AA, Mascolo N, Maiolino P, et al. Nitric oxide-donating compounds and cyclic GMP depress the spontaneous contractile activity of the isolated rabbit jejunum, Pharmacology 1996; 53: 109-113.
55. Kasuaya H, Nakao A, Nomoto S, et al. Postoperative delayed emptying in pylorus-preserving pancreato-duodenectomy using pancreaticogastrostomy: comparison of the reconstruction position. Hepatogastroenterol 1997; 44: 856-60.
56. Kelly KA. Gastric emptying of liquids and solids: role of proximal and distal stomach. Am J physiol 1980; 239:G71-6.
57. Kingsnorth AN, Formela LJ, Chen D, et al. Plasma gastrin and cholecystokinin response after pylorus-preserving pancreatoduodenectomy and defunctioned Roox-loop pancreaticojejunostomy. Br J Surg 1984; 81; 1356-9.
58. Knoweles RG, Palacios M, Palmer RMJ, et al. Formation of nitric oxide from L-arginine in the nervous system: A transduction mechanism for stimulation of the soluble guanylate cyclase. Proc Natl Acad Sci USA 1989; 86: 5159-5162.
59. Koh SD, Campell JD, Carl A, et al. Nitric oxide activates multiple potassium channels in canine colonic smooth muscle. J Physiol 1995; 489: 735-43.
60. Kunze WAA, Clerc N, Furness JB, et al. The soma and neuritis of primary afferent neurons in the guinea-pig intestine response differentially to deformation. J Physiol (Lond) 2000; 526: 375-85.
61. Kurita N, Wada D, Harada M, et al. Gastric function after pylorus-preserving duodenectomy in dogs. Hepatogastroenterology 1998; 45: 260-7.
62. Kozuschek W, Reith HB, Waleczek H, et al. A comparison of long term results of the standard Whipple procedure and the pylorus preserving pancreaticoduodenectomy. J Am Coll. Surg 1994; 178: 443-58.
63. Labo G, Bortolotti M, Vezzadini P, et al. Interdigestive gastroduodenal motility and serum motilin levels in patients with idiopathic delay in gastric emptying. Gastroenterology 1986; 90: 20-6.
64. Ladabaum URI, Koshy SS, Woods ML, et al. Differential symptoms and electrogastrographic effect of distal and proximal human gastric distension. Am J Physiol 1998; 275: G418-G424.
65. Lee KY, Chey WY, Tai HH, et al. Cyclic changes in plasma motilin levels and interdigestive myoelectric activity of canine antrum and duodenum. Gastroenteology. 1977; 72: 1162.
66. Lee KY, Chang TM, Chey WY. Effect of rabbit antimotilin serum on myoelectric activity and plasma motilin concentration in fasting dog. Am. J Physiol. 1983; 245: G547-53.
67. Liberski SM, Koch KL, Atnip RG, Stern RM. Ischemia gastroparesisL Resolution after revascularization. Gastroenterology 1990; 99:252-7.
68. Lin PW, Lin JC: Complication after pancreaticoduodenectomy, a prospective, randomized comparison between PPPD and Whipple's procedure. Br J Surg 1999; 86: 603-7.
69. Lindeotrön LM, Ekalad E. Origins and projections of nerve fiber in rat pyloric sphincter. Autonomic Neuroscience: Basic and Clinical 2002; 97: 73-82.
70. Lloyd KC, Maxwell V, Ohning G, et al. Intestinal fat does not inhibit gastric function through a hormonal somatostatin mechanism in dogs. Gastroenterology 1992; 103: 1221-8.
71. Londong W, Angerer M, Kutz K, et al. Diminishing efficacy of octreotide (SMS 201-995) on gastric functions of healthy subjects during one-week administration. Gastroenterology 1989; 96: 713-22.
72. Lu YX, Owyang C. Duodenal acid-induced gastric relaxation is mediated by multiple pathways. Am. J. Physiol. 1999; 276: G1501-6.
73. Lupo LG, Pannarole OC, Altomare DF, Caputi L, Dell'Erba L, Ricci P, Memeo V. Is pylorus function preserved in pylorus-preserving pancreaticoduodenectomy? Eur. J. Surg 1998; 164:127-32.
74. Mashimo H, and Goyal RK. Lessons from genetically engineered animal models. IV. Nitic oxide synthase gene knockout mice. Am. J. Physiol. 1999; 277 (gastrointest. Liver physiol. 40): G745-50.
75. Mashimo H, Kjellin A, Goyal RK. Gastric stasis in neuronal nitric oxide synthase-deficient knockout mice. Gastroenterology 2000; 119: 766-73.
76. Matsunaga H, Tanaka M, Naritomi G, et al: Effect of leucine 13-motilin (KW5139) on early gastric stasis after pylorus-preserving pancreaticoduodenectomy. Ann Surg 1998; 227: 507-12.
77. McAfee MK, Van Heerden JA, Adson MA. Is proximal pancreaticoduodenectomy with pyloric preservation superior to total pancreatectomy. Surgery 1989; 125: 347-51.
78. Miller GV, Preston SR, Woodhouse LF, er al. Somatostatin binding in human gastrointestinal tissues: effect of cations and somatostatin analogues. Gut 1993; 34: 1351-6.
79. Ohwada S, Satoh Y, Kawate S, et al. Low-dose erythromycin reduces delayed gastric emptying and improves gastric motility after Billroth I pylorus-preserving pancreaticoduodenectomy. Ann Surg 2001; 234: 668-74.
80. Okamoto E, Haruma K, Hata J, et al. Effects of octreotide, a somatostatin analogue, ongastric function evaluated by real-time ultrasonography. Aliment Pharmacol Ther 1997; 11: 177-84.
81. Mertz H, Walsh JH, Sytnik B, et al. The effect of octreotide on human gastric compliance and sensory perception. Neurogastroenterol Motil 1995; 7: 175-85.
82. Meulemans AL, Eelen J GMG, Schuurkes J AJ. NO mediates gastric relaxation after brief vagal stimulation in anesthesized dogs. Am. J. Physiol 1995; 269: G255-61.
83. Montorsi M, Zago M, Mosca F, et al. Efficacy of octreotide in the prevention of pancreatic fistula after elective pancreatic resection: A prospective controlled randomized clinical trial. Surgery 1995; 117: 26-31.
84. Mourad FH, Gorard D, Thillainayagam AV, et al. Effective treatment of diabetic diarrhoea with somatostatin analogue, octreotide. Gut 1992; 33: 1578-80.
85. Nakabayashi T, Mochiki E, Garcia M, et al. Pyloric motility after pylorus-preserving gastrectomy with or without the pyloric branch of the vagus nerve. World J Surg 2002; 26: 577-583.
86. Nakamura K, Takahashi T, Taniuchi M, et al. Nicotinic receptor mediates nitric oxide synthase expression in the rat gastric myenteric plexus. J. Clin Invest. 1998; 101:1479-89.
87. Naritomi G, Tanaka M, Matsunaga H, et al. Pancreatic head resection with and without preservation of the duodenum. Different postoperative gastric motility. Surgery 1996; 120: 831-7.
88. Ohwada S, Satoh Y, Kawate S, et al: Low-dose erythromycin reduces delayed gastric emptying and improves gastric motility after Billroth I pylorus-preserving pancreaticoduodenectomy. Ann Surg 2001; 234: 668-674.
89. Olgart C, Iversen HH, Nitric oxide-dependent relaxation induced by M1 muscarinic receptor activation in the rat small intestine, Br J Pharmacol. 1999; 127: 309-13.
90. Palmer RM. Ferrige AG. Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987; 327(6122):524-6.
91. .Peeters TL, Janseens J, Vantrappen GR. Somatostatin and the interdigestive migrating motor complex in man. Regul Peptide 1983; 5: 209-17.
92. Peeters TL, Vantrappen G, Janssens J. Fasting plasma motilin levels are related to the interdigestive motility complex. Gastroenterology 1980; 79: 716-9.
93. Piessevaux H, Tack J, Walrand S et al. Intragastric distribution of a standard meal in health and functional dyspepsia: correlation withspecific symptoms. Neurogastroenterol Motil 2003; 15: 447-55.
94. Poitras P, Lahaie RG, St-pierre S. et al. Comparative stimulation of motilin duodenal receptor by porcine or canine motilin. Gstroenterology. 1987; 92:658-62.
95. Rapits S, Schlegel W, Lehmann E, et al. Effects of somatostatin on the exocrine pancreas and the release of duodeneal hormones. Metabolism 1978; 27: 1321-8.
96. Read NW, Houghton LA. Physiology of gastric emptying and patho-physiology of gastroparesis. Gastroenterol Clin North Am 1989; 18:359-73.
97. Schwizer W, Borvicka J, Kunz P, et al. Role of cholecystokinin in the regulation of liquid gastric emptying and gastric motility in human: studies with the CCK antagonist loxiglumide. Gut 1997; 41:500-4.
98. Shafik A. Effect of duodenal distension on the pylorus sphincter and antrum and the gastric corpus: Duodenopylorus reflex. World J. Surg. 1998; 22: 1061-4.
99. Siadati M, Sarr M. Role of extrinsic innervation in release of motilin and patterns of upper gut canine motility. J gastrointest Surg. 1998; 2: 363-72.
100. Serio R, Zizzo MG, Mulè F. Nitric oxide induces muscular relaxation via cyclic GMP-dependent and –independent mechanisms in the longitudinal muscle of the mouse duodenum, Nitric oxide 2003; 8: 48-52.
101. Shan YS, Sy ED, Tung HL, et al. Reduction of intrinsic inhibitory enteric neurons in the antropyloric area in PPPD patients with delayed gastric emptying. Hepatogastroenterology 2004 (Accepted).
102. Shan YS, Hsieh YH, Sy ED, et al. Delayed Gastric Emptying After Pylorus-Preserving Pancreaticoduodenectomy: An Analysis of 63 Consecutive Patients. Formosan J Med. 2004 (in press).
103. Shan YS, Sy ED, Lin PW. Somatostatin in the prevention of pancreatic stump related morbidity following elective pancreaticoduodenectomy in high risk patients after excluded surgical factor. A prospective, randomized, double blind, controlled clinical trial. World J. Surg. 2003; 27: 709-14.
104. Shuttleworth CW, Sanders KM. Involvement of nitric oxide in neuromuscular transmission in canine proximal colon. P Soc Exp Bio Med 1996; 211: 16-23.
105. Smedh U, Kaplan JM, Bjorstrand E, et al. Dual effects of somatostatin analog octreotide on gastric emptying during and after intragastric fill. Am J Physiol 1999; 277: R1291-6.
106. Smith VC, Dhatt N, Buchan AMJ. The innervation of the human antro-pyloric region: organization and composition. Can. J. Physio. Pharmacol. 2001; 79: 905-918.
107. Soediono P, Burnstock G. Contribution of ATP and nitric oxide to NANC inhibitory transmission in rat pyloric sphincter. Br. J Pharmacol 1994; 113: 681-686.
108. Stengel PW, Cohen ML. M1 receptor-mediated nitric oxide-dependent relaxation unmasked in stomach fundus from M3 receptor knockout mice, J. Pharmacol. Exp. Therapeutics 2003; 304: 675-682.
109. Sumida K, Nimura Y, Yasui A, et al. Influence of vagal pyloric branches on gastric secretion and gastrointestinal motility in patients following a pylorus preserving pancreaticoduodenectomy. Hepatogastroenterology 1999; 46: 336-342.
110. Sy ED, Shan YS, Lin CH, et al. Immature Intrinsic Nerve Innervations of Pyloric Muscle in Idiopathic Hypertrophic Pyloric Stenosis (Equal distribution) Formosan J Med. 2004; 103: 558-61.
111. Takahashi T, Dwyang C. Mechanism of Cholecystokinin-induced relaxation of the rat stomach. J. Auton Nerv Syst. 1999; 75:123-30.
112. Takahashi T, Nakamura K, ItoH H, et al. Impaired expression of nitric oxide synthase in the gastric myenteric plexus of spontaneous diabetes rats. Gastroenterology. 1997; 113: 1535-44.
113. Takahashi T, Owyang C. Vagal control of gastric motility: participation of nitric oxide and vasoactive intestinal polypeptide in the regulation of gastric relaxation. J Physiol (London) 1995; 484: 481-92.
114. Takeda T, Yoshida J, Tanaka M, et al. Delayed gastric emptying after Billroth I pylorus-preserving pancreaticoduodenectomy. Effect of postoperative time and cisapride. Ann Surg 1999; 229: 223-9.
115. Tanaka M, Sarr M. Total duodenectomy: Effect on canine gastro-intestinal motility. J. Surg. Res. 1987:42; 483-93.
116. Tanaka M, Sarr M. Role of the duodenum in the control of canine gastrointestinal motility. Gastroenterology 1988; 94: 622-9.
117. Tanović A, Jiménez M, Fernández E. Action of NO donors and endogenous nitrergic transmitter on the longitudinal muscle of rat ileum in vitro: mechanisms involved, Life. Sci. 2001; 69: 1143-1154.
118.Thor PJ, Matyja A, Popiela T, et al. Early effects of standard and pylorus-preserving pancreaticoduodenectmy on myoelectric activity and gastric emptying. Hepatogastroenterology 1999; 46: 1963-7.
119. Tomita R, Tanjoh K, Fujisaki S, et al. The role of nitric oxide (NO) in the human pyloric sphincter. Hepatogastroenterology 1999; 46: 2999-3003.
120. Tougas G, Anvari M, Dent J, et al. Relation of pyloric motility to pyloric opening and closure in healthy subjects, Gut. 1992; 33: 466-471.
121. Traverso LW, Longmire WP Jr. Preservation of the pylorus in pancreaticoduodenectomy. Surg Genecol Obstet 1978; 146: 959-962.
122. Tulassay Z. Somatostatin and the gastrointestinal tract. Scand J Gastroenterol. 33 Suppl 1998; 228: 115-121.
123. Valdovinos MA, Thomforde GM, Camilleri M. Effect of putative carcinoid mediators on gastric and small bowel transit in rats and the role of 5-HT receptors. Aliment Pharmacol Therapy 1993; 7: 61-6.
124. Vantrappen G, Janssens J, Peeters TL, et al: Motilin and the interdigestive migrating motor complex in man. Dig Dis Sci 1979; 24: 497-500.
125. Von der Ohe M, Camilleri M, Thomforde GM, et al. Differential regional effects of octreotide on human gastrointestinal motor function. Gut 1995; 36: 743-8.
126. Ward SM, Morris G, Reese L, et al. Interstitial cells of Cajal mediate enteric inhibitory neurotransmission in the lower esophageal and pyloric sphincters. Gastroenterology 1998; 115: 314-329.
127. Warshaw AL, Torchiana DL. Delayed gastric emptying after pylorus-preserving pancreaticoduodenectomy. Surg. Gyn. Obs. 1985; 160:1-4.
128. Watson K. Carcinoma of the ampulla of Vater. Successful radical resection. Br J Surg 1944; 31: 368-373.
129. Whipple AO. Pancreaticoduodenectomy for islet carcinoma: A five-year follow up. Ann Surg 1945; 121: 847-852.
130. Wiley J, Owyang C. Somatostatin inhibits cAMP-mediated cholinergic transmission in he myenteric plexus. Am. J Physiol. 1987; 253: G607-12.
131. Williamson RCN, Bliouras FN, Cooper MJ, Davis ER. Gastric emptying and enterogastric reflux after coursevative and conventional pancreatico-duodenectomy. Surgery 1993; 114: 82-6.
132. Wu X, Somlyo AV, Somlyo AP. Cyclic GMP-dependent strimulation reverses G-protein coupled inhibition of smooth muscle myosin light chain phosphatase. Biochem. Biophys. Res. Comm. 1996; 220: 658-663.
133. Yeo CJ, Barrry MK, Sauter PK, et al. Erythromycin accelerates gastric emptying after pancreaticoduodenectomy. A prospective, randomized, placebo-controlled trial. Ann Surg 1993; 218: 229-38.
134.Yeo CJ, Bany MK, Santer PK, et al. Erythromycin accelerates gastric emptying after pancreatico-duodenectomy; A prospective, randomized, placebo-controlled Trial. Ann Surg.1993; 218: 229-38.
135. Yeo CJ, Cameron JL, Lillemore KD, et al. Does prophylactic octreotide decrease the rates of pancreatic fistula and other complications after pancreaticoduodenectomy? Ann Surg 2000; 232: 419-29.