O óxido nitrico como neurotransmissor no sistema nervoso entérico: fisiopatologia e implicações no íleo adinâmico

Flora Filho, Rowilson; Zilberstein, Bruno

doi:10.1590/S0100-69911998000500010

Resumos

Nesta revisão do sistema nervoso entérico, enfatiza-se o mecanismo da inibição não-adrenérgica e não-colinérgica na contratilidade do sistema digestório. Introduz-se a síntese e metabolismo do óxido nítrico com apresentação das sintases do óxido nítrico. Atualiza-se mostrando o óxido nítrico como neurotransmissor do mecanismo inibitório não-adrenérgico e não-colinérgico, demonstrando sua atividade na musculatura lisa gastrointestinal e possível mecanismo intracelular através da cGMP. Após atualização do mecanismo do peristaltismo e do complexo motor migratório, faz-se uma descrição do íleo adinâmico. Por fim, todo raciocínio apresentado condensa-se na fisiopatologia do íleo adinâmico.

Óxido nítroco; Íleo adinâmico; Íleo paralítico; Sintases do óxido nítrico; Complexo motor migratório; Peristaltismo; Sistema nervoso entérico; Neurotransmissores

The non-adrenergic and non-cholinergic (NANC) inhibition has an important role in the intrinsic control of enteric nervous system (ENS). The ENS is poor in the upper digestive tract (esophagus and stomach) and totally present in the intestine. Starling and Bayliss experiments demonstrated the intrinsic activity of ENS in 1899. Since then there are searching for neurotransmitters of NANC like VIP (Vasoactive Intestinal Polypeptide) and ATP (Adenosine Triphosphate). Recent works demonstrate nitric oxide as a neurotransmitter of NANC. The nitric oxide (NO) is a gaseous molecule produced from L- arginine, with less than ten seconds half-life. The enzymes involved in the synthesis of NO are the NO synthases (NOS): neuronal NOS or isoform I, inducible NOS or isoform II, and endothelial NOS or isoform III. The isoform I and III are constitutive, and the isoform 11 is inducible. The mechanisms involved in the induction of isoform III are TNFα (Tumor Necrosis Factora), IL-Iβ (Interleukin I-β), and bacteria lypopolyssacarides stimulus. The intestinal smooth muscle motility is mediated by NANC and one example of this is the migratory motor complex (MMC). The MMC can be modified by infusion of NO-like drugs and this modification is reversed by infusion of L-NAME (L-arginine analog) in experimental trials with animals. The NO causes relaxation and inhibition of peristalsis in the small intestine. The adynamic ileum is a very common situation for surgeons. In the adynamic ileum is observed the dysfunction of MMC. The adynamic ileum induced by infusion of endotoxins is reverted by use of NOS inhibitors.

Nitric oxide; Nitric oxide synthesis; Nitric oxide synthases; Adynamic ileus; Paralitic ileus; Migratory Motor Complex; Peristaltism; Enteric nervous system; Neurotransmitters

ARTIGO DE REVISÃO

O óxido nitrico como neurotransmissor no sistema nervoso entérico: fisiopatologia e implicações no íleo adinâmico

Nitric oxide as neurotransmitter of nervous system: implications and pathophysiology of adinamic ileus

Rowilson Flora Filho, TCBC-MG^I; Bruno Zilberstein, TCBC.SP^II

^IGraduado em Gastroenterologia - Hospital das Clínicas da Faculdade de Medicina da USP

^IIProfessor Assistente do Departamento de Gastroenterologia do Hospital das Clínicas da Faculdade de Medicina da USP

^{Endereço para correspondência} Endereço para correspondência: Dr. Rowilson Flora Filho Rua Dr. Mário Mourão, 5437701-019 - Poços de Caldas-MG

RESUMO

Nesta revisão do sistema nervoso entérico, enfatiza-se o mecanismo da inibição não-adrenérgica e não-colinérgica na contratilidade do sistema digestório. Introduz-se a síntese e metabolismo do óxido nítrico com apresentação das sintases do óxido nítrico. Atualiza-se mostrando o óxido nítrico como neurotransmissor do mecanismo inibitório não-adrenérgico e não-colinérgico, demonstrando sua atividade na musculatura lisa gastrointestinal e possível mecanismo intracelular através da cGMP. Após atualização do mecanismo do peristaltismo e do complexo motor migratório, faz-se uma descrição do íleo adinâmico. Por fim, todo raciocínio apresentado condensa-se na fisiopatologia do íleo adinâmico.

Unitermos: Óxido nítroco; Íleo adinâmico; Íleo paralítico; Sintases do óxido nítrico; Complexo motor migratório; Peristaltismo; Sistema nervoso entérico; Neurotransmissores.

ABSTRACT

The non-adrenergic and non-cholinergic (NANC) inhibition has an important role in the intrinsic control of enteric nervous system (ENS). The ENS is poor in the upper digestive tract (esophagus and stomach) and totally present in the intestine. Starling and Bayliss experiments demonstrated the intrinsic activity of ENS in 1899. Since then there are searching for neurotransmitters of NANC like VIP (Vasoactive Intestinal Polypeptide) and ATP (Adenosine Triphosphate). Recent works demonstrate nitric oxide as a neurotransmitter of NANC. The nitric oxide (NO) is a gaseous molecule produced from L- arginine, with less than ten seconds half-life. The enzymes involved in the synthesis of NO are the NO synthases (NOS): neuronal NOS or isoform I, inducible NOS or isoform II, and endothelial NOS or isoform III. The isoform I and III are constitutive, and the isoform 11 is inducible. The mechanisms involved in the induction of isoform III are TNFα (Tumor Necrosis Factora), IL-Iβ (Interleukin I-β), and bacteria lypopolyssacarides stimulus. The intestinal smooth muscle motility is mediated by NANC and one example of this is the migratory motor complex (MMC). The MMC can be modified by infusion of NO-like drugs and this modification is reversed by infusion of L-NAME (L-arginine analog) in experimental trials with animals. The NO causes relaxation and inhibition of peristalsis in the small intestine. The adynamic ileum is a very common situation for surgeons. In the adynamic ileum is observed the dysfunction of MMC. The adynamic ileum induced by infusion of endotoxins is reverted by use of NOS inhibitors.

Key words: Nitric oxide; Nitric oxide synthesis; Nitric oxide synthases; Adynamic ileus; Paralitic ileus; Migratory Motor Complex; Peristaltism; Enteric nervous system; Neurotransmitters.

Texto completo disponível apenas em PDF.

Full text available only in PDF format.

Recebido em 14/11/97

Aceito para publicação em 16/7/98

Trabalho realizado no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - USP.

1. Green LC, Tannenbaum SR, Goldmann P. Nitrate synthesis in the germfree and conventional rat. Science 1981; 212: 56-58.
2. Flora-Filho R, Zylberstein B. Óxido nítrico: o simples mensageiro percorrendo a complexidade. Metabolismo, síntese e funçőes. Rev Ass Med Bras 1997 (Em impressăo).
3. Smout AJPM, Akkermans LMA. Fisiologia y Patologia de la Motilidad Gastrointestinal. Hampshire, United Kingdom: Wrightson Biochemical Publishing Ltd. 1992.
4. Bayliss WM, Starling EH. The movement and innervation of the small intestine. J Phys (London) 1899; 24: 99-143.
5. Hoyle CHV, Bumstock G. Neuromuscular transmission in gastrointestinal tract. In: Handbook of Physiology: The Gastrointestinal System. Motility and Circulation. Bethseda, USA: American Physiology Society, 1989, pp.435-464.
6. Burnstock G, Satchell DG, Smythe A. A comparison of the excitatory and inhibitory effects of non-adrenergic, non-cholinergic nerve stimulation and exogenously applied ATP on a variety of smooth muscle preparations from different vertebrate species. Brit J Pharm 1972;46:234-242.
7. Biancani P, Walch JH, Behar J. Vasoactive intestinal polypeptide: a neurotransrnitter for lower esophageal sphincter relaxation. J Clin Invest 1984;73:963-967.
8. Behar J, Guenard V, Walsh JF,et al. VIP and acetylcholine: neurotransmitters in esophageal circular smooth muscle. American J Phys 1989;257:G380-G385.
9. De Beurme FA, Lefebvre RA. Vasoactive intestinal polypeptide as possible mediator of relaxation in the rat gastric fundus. Brit J Pharm 1988;40:711-715.
10. Furchgott RF, Cherry PD, Zawadzki JV, et al. Endothelial cells as mediators of vasodilation of arteries. J Cardiovasc Pharm 1984; 53:557-573.
11. Ignarro LJ, Buga GM, Wood KS, et al. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 1987;84:9265-9269.
12. Marletta MA, Yoon PS, Iyengar R, et al. Macrophague oxidation of L-arginine to nitrite and nitrate: Nitric oxide is an intermediate. Biochem 1988;27:8706-8711.
13. Snyder SH, Bredt DS. Biological role of nitric oxide. Science Am 1992;266:68-77.
14. Konturek SK, Konturek PC. Role of nitric oxid in the digestive system. Digestion 1995;56:1-13.
15. Wang Y, Mardsen PA. Nitric oxide synthases: Biochemical and molecular regulation. Cur Opinion Nephr Hypert 1995;4: 12-22.
16. Schmidt HHHW, Pollock JS, Nakana M, et al. Purification of a soluble isoform of guanylyl cyclase-activating-factor synthase. Proc Natl Acad Sci USA 1991;88:365-369.
17. Stuehr DJ, Cho HJ, Kwon NS, et al. Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein. Proc Natl Acad Sci USA 1991; 88:7773-7777.
18. Geller DA, Lowenstein CJ, Shapiro RA, et al. Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci USA 1993;90:3.491-3.495.
19. Pollock JS, Förstermann U, Mitchell JA, et al. Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and natived bovine aortic endothelial cells. Proc Natl Acad Sci USA 1991;88:10.480-10.484.
20. Nathan C, Xie QW. Regulation of biosynthesis of nitric oxide. J Biol Chem 1994;26:13.725-13.728.
21. Schmidt HHHW, Walter U. NO at work. Cell 994;78:919-925.
22. Bult H, Boeckxstaens GE, Pelckmans PA, et al. Nitric oxide as a inhibitory non-adrenergic non-cholinergic neurotransmitter. Nature 1990;345:346-347.
23. Boeckxstaens GE, Pelckmans PA, Bult H, et al. Release of nitric oxide upon stimulation of non-adrenergic non-cholinergic nerves in the rat gastric fundus. J Pharm Exp Therap 1991;256:441-447.
24. Meyer GW, Gerhardt DC, Castell DO. Human esophageal response to rapid swallowing: Muscle refractory period or neural inhibition? American J Physiol 1981;241:GI329-GI366.
25. Tottrup A, Svane D, Forman A. Nitric oxide mediating NANC inhibition in opossum lower esophageal sphincter. American J Phys 1991; 260:G385-G389.
26. Yamato S, Spechler SJ, GoyaI RK. Role of nitric oxide in esophageal peristalsis in the opossum. Gastroenterology 1992;103:197-204.
27. Preiksaitis HG, Tremblay L, Diamant NE. Nitric oxide mediates inhibitory nerve effects in human esophagus and lower esophageal sphincter. Digest Dis Sci 1994;39: 770-775.
28. Hamada N, Hutson WR, Nakada K, et al. Intestinal neuromuscular function after preservation and transplantation. J Surg Res 1996; 63:460-466.
29. Sarna SK, Otterson MF, Ryan RP, et al. Nitric oxide regulates migrating motor complexes cycling and its postprandial disruption. American J Phys 1993;265:G749-G766.
30. Rodriguez-Membrilla A, Martinez V, Jimenez M, et al. Is nitric oxide the final mediator regulating the migrating myoelectric complex cycle? American J Phys 1995;268:G207-G214.
31. Grous M, Joslyn AF, Thompson W, et al. Change in intracellular cyclic nucleotide content accompanies relaxation of the isolated canine internal anal sphincter. J Gastroint Motil 1991; 3:46-52.
32. Ozaki H, Blondfield DP, Hori M, et al. Spontaneus release of nitric oxide inhibits electrical Ca²⁺ and mechanical transients in canine gastric smooth muscle. J Phys (London) 1991;445:231-247.
33. Watson EG, Kostka P, Oaniel EE. Effects of endotoxin and time on the induction of nitric oxide synthase in the canine ileum. Gastroenterology 1993;104:Al066.
34. Wirthlin DJ, Cullen JJ, Spates ST, et al. Gastrointestinal transit during endotoxemia: Role of nitric oxide. J Surg Reserc 1996; 60:307-311.
35. Cullen JJ, Caropreso DK, Hemann LL, et al. Pathophysiology of adynamic ileum. Digest Dis Sci 1997;42:731-37.
36. Zilberstein B, Cecconello I. Choque séptico. In: Infecçăo em Cirurgia do Aparelho Digestivo. Săo Paulo: Robe, 1994.
37. Drapier JC, Weizesbin J, Hibbs JB. Interferon g and tumor necrosis factor induce the L-arginine cytotoxic effects or mechanism in murine macrophages. European J Immun 1988;18:1.587-1.592.
38. Oswald IP, Eltoum I, Wynn TA, et al. Endothelial cells are activated by cytokine treatment to kill an intravascular parasite, Schistosoma mansoni. Proc Nat Acad Sci USA 1994;91: 999-1003.
39. Gazzinelli RT, Oswald IP, Hieny S, et al. The microbicidal activity of interferon-gamma-treated macrophages against Trypanossoma cruzi involves an L-arginine-dependent, nitrogen oxide-mediated mechanism inhibitable by interleukin-10 and transforming growth factor-beta. European J Immun 1992;22:2.501-2.506.

Endereço para correspondência:

Dr. Rowilson Flora Filho

Rua Dr. Mário Mourão, 5437701-019 - Poços de Caldas-MG

Datas de Publicação

Publicação nesta coleção
17 Maio 2010
Data do Fascículo
Out 1998

Histórico

Aceito
16 Jul 1998
Recebido
14 Nov 1997

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Green LC, Tannenbaum SR, Goldmann P. Nitrate synthesis in the germfree and conventional rat. Science 1981; 212: 56-58.

[2] 2. Flora-Filho R, Zylberstein B. Óxido nítrico: o simples mensageiro percorrendo a complexidade. Metabolismo, síntese e funçőes. Rev Ass Med Bras 1997 (Em impressăo).

[3] 3. Smout AJPM, Akkermans LMA. Fisiologia y Patologia de la Motilidad Gastrointestinal. Hampshire, United Kingdom: Wrightson Biochemical Publishing Ltd. 1992.

[4] 4. Bayliss WM, Starling EH. The movement and innervation of the small intestine. J Phys (London) 1899; 24: 99-143.

[5] 5. Hoyle CHV, Bumstock G. Neuromuscular transmission in gastrointestinal tract. In: Handbook of Physiology: The Gastrointestinal System. Motility and Circulation. Bethseda, USA: American Physiology Society, 1989, pp.435-464.

[6] 6. Burnstock G, Satchell DG, Smythe A. A comparison of the excitatory and inhibitory effects of non-adrenergic, non-cholinergic nerve stimulation and exogenously applied ATP on a variety of smooth muscle preparations from different vertebrate species. Brit J Pharm 1972;46:234-242.

[7] 7. Biancani P, Walch JH, Behar J. Vasoactive intestinal polypeptide: a neurotransrnitter for lower esophageal sphincter relaxation. J Clin Invest 1984;73:963-967.

[8] 8. Behar J, Guenard V, Walsh JF,et al. VIP and acetylcholine: neurotransmitters in esophageal circular smooth muscle. American J Phys 1989;257:G380-G385.

[9] 9. De Beurme FA, Lefebvre RA. Vasoactive intestinal polypeptide as possible mediator of relaxation in the rat gastric fundus. Brit J Pharm 1988;40:711-715.

[10] 10. Furchgott RF, Cherry PD, Zawadzki JV, et al. Endothelial cells as mediators of vasodilation of arteries. J Cardiovasc Pharm 1984; 53:557-573.

[11] 11. Ignarro LJ, Buga GM, Wood KS, et al. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 1987;84:9265-9269.

[12] 12. Marletta MA, Yoon PS, Iyengar R, et al. Macrophague oxidation of L-arginine to nitrite and nitrate: Nitric oxide is an intermediate. Biochem 1988;27:8706-8711.

[13] 13. Snyder SH, Bredt DS. Biological role of nitric oxide. Science Am 1992;266:68-77.

[14] 14. Konturek SK, Konturek PC. Role of nitric oxid in the digestive system. Digestion 1995;56:1-13.

[15] 15. Wang Y, Mardsen PA. Nitric oxide synthases: Biochemical and molecular regulation. Cur Opinion Nephr Hypert 1995;4: 12-22.

[16] 16. Schmidt HHHW, Pollock JS, Nakana M, et al. Purification of a soluble isoform of guanylyl cyclase-activating-factor synthase. Proc Natl Acad Sci USA 1991;88:365-369.

[17] 17. Stuehr DJ, Cho HJ, Kwon NS, et al. Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein. Proc Natl Acad Sci USA 1991; 88:7773-7777.

[18] 18. Geller DA, Lowenstein CJ, Shapiro RA, et al. Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci USA 1993;90:3.491-3.495.

[19] 19. Pollock JS, Förstermann U, Mitchell JA, et al. Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and natived bovine aortic endothelial cells. Proc Natl Acad Sci USA 1991;88:10.480-10.484.

[20] 20. Nathan C, Xie QW. Regulation of biosynthesis of nitric oxide. J Biol Chem 1994;26:13.725-13.728.

[21] 21. Schmidt HHHW, Walter U. NO at work. Cell 994;78:919-925.

[22] 22. Bult H, Boeckxstaens GE, Pelckmans PA, et al. Nitric oxide as a inhibitory non-adrenergic non-cholinergic neurotransmitter. Nature 1990;345:346-347.

[23] 23. Boeckxstaens GE, Pelckmans PA, Bult H, et al. Release of nitric oxide upon stimulation of non-adrenergic non-cholinergic nerves in the rat gastric fundus. J Pharm Exp Therap 1991;256:441-447.

[24] 24. Meyer GW, Gerhardt DC, Castell DO. Human esophageal response to rapid swallowing: Muscle refractory period or neural inhibition? American J Physiol 1981;241:GI329-GI366.

[25] 25. Tottrup A, Svane D, Forman A. Nitric oxide mediating NANC inhibition in opossum lower esophageal sphincter. American J Phys 1991; 260:G385-G389.

[26] 26. Yamato S, Spechler SJ, GoyaI RK. Role of nitric oxide in esophageal peristalsis in the opossum. Gastroenterology 1992;103:197-204.

[27] 27. Preiksaitis HG, Tremblay L, Diamant NE. Nitric oxide mediates inhibitory nerve effects in human esophagus and lower esophageal sphincter. Digest Dis Sci 1994;39: 770-775.

[28] 28. Hamada N, Hutson WR, Nakada K, et al. Intestinal neuromuscular function after preservation and transplantation. J Surg Res 1996; 63:460-466.

[29] 29. Sarna SK, Otterson MF, Ryan RP, et al. Nitric oxide regulates migrating motor complexes cycling and its postprandial disruption. American J Phys 1993;265:G749-G766.

[30] 30. Rodriguez-Membrilla A, Martinez V, Jimenez M, et al. Is nitric oxide the final mediator regulating the migrating myoelectric complex cycle? American J Phys 1995;268:G207-G214.

[31] 31. Grous M, Joslyn AF, Thompson W, et al. Change in intracellular cyclic nucleotide content accompanies relaxation of the isolated canine internal anal sphincter. J Gastroint Motil 1991; 3:46-52.

[32] 32. Ozaki H, Blondfield DP, Hori M, et al. Spontaneus release of nitric oxide inhibits electrical Ca²⁺ and mechanical transients in canine gastric smooth muscle. J Phys (London) 1991;445:231-247.

[33] 33. Watson EG, Kostka P, Oaniel EE. Effects of endotoxin and time on the induction of nitric oxide synthase in the canine ileum. Gastroenterology 1993;104:Al066.

[34] 34. Wirthlin DJ, Cullen JJ, Spates ST, et al. Gastrointestinal transit during endotoxemia: Role of nitric oxide. J Surg Reserc 1996; 60:307-311.

[35] 35. Cullen JJ, Caropreso DK, Hemann LL, et al. Pathophysiology of adynamic ileum. Digest Dis Sci 1997;42:731-37.

[36] 36. Zilberstein B, Cecconello I. Choque séptico. In: Infecçăo em Cirurgia do Aparelho Digestivo. Săo Paulo: Robe, 1994.

[37] 37. Drapier JC, Weizesbin J, Hibbs JB. Interferon g and tumor necrosis factor induce the L-arginine cytotoxic effects or mechanism in murine macrophages. European J Immun 1988;18:1.587-1.592.

[38] 38. Oswald IP, Eltoum I, Wynn TA, et al. Endothelial cells are activated by cytokine treatment to kill an intravascular parasite, Schistosoma mansoni. Proc Nat Acad Sci USA 1994;91: 999-1003.

[39] 39. Gazzinelli RT, Oswald IP, Hieny S, et al. The microbicidal activity of interferon-gamma-treated macrophages against Trypanossoma cruzi involves an L-arginine-dependent, nitrogen oxide-mediated mechanism inhibitable by interleukin-10 and transforming growth factor-beta. European J Immun 1992;22:2.501-2.506.

Brasil

Brasil

O óxido nitrico como neurotransmissor no sistema nervoso entérico: fisiopatologia e implicações no íleo adinâmico

Nitric oxide as neurotransmitter of nervous system: implications and pathophysiology of adinamic ileus

Resumos

Endereço para correspondência:

Datas de Publicação

Histórico