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Journal of Gastrointestinal Surgery

Published in:

01-03-2009 | original article

Nitroglycerin Protects Small Intestine from Ischemia–Reperfusion Injury via NO–cGMP Pathway and Upregulation of α-CGRP

Authors: Jie Li, Mingsheng Zhang, Caihong Yang, Ying Dun, Yi Zhang, Yibin Hao

Published in: Journal of Gastrointestinal Surgery | Issue 3/2009

Abstract

Introduction

Nitroglycerin (NTG) has been reported to possess preconditioning-like (PCL) protections on heart and other tissues. Our previous studies showed that NTG has acute PCL effects on rat small intestine. The present studies were designed to study whether NTG has delayed PCL protection on rat small intestine and to explore its mechanism(s).

Methods

The intestine lesions were evaluated by histologic examination and serum lactate dehydrogenase (LDH) measurement. The effects of nitric oxide (NO), cGMP, and α-calcitonin gene-related peptide (CGRP) synthesis on the effects of NTG were analyzed.

Results

Pretreatment with NTG (0.12 mg/kg i.v.) 24 h before ischemia–reperfusion (I/R) of super mesenteric artery significantly reduced histologic lesions and serum LDH with elevated blood levels of NO and CGRP. Inhibition of guanylate cyclase by methylene blue (30 mg/kg i.p.) or specific depletion of transmitters in capsaicin-sensitive sensory nerve by capsaicin (50 mg/kg s.c.) abrogated the protection conferred by NTG. Reverse-transcription polymerase chain reaction analysis showed that NTG upregulates the expression of α-CGRP messenger RNA (mRNA), but not β-CGRP mRNA in lumbar dorsal root ganglia.

Conclusion

In conclusion, NTG prevents rat small intestine from I/R injury by delayed PCL effects 24 h after administration. The protective effects are mediated by NO–cGMP pathway and α-CGRP upregulation.

Hayward R, Lefer AM. Time course of endothelial-neutrophil interaction in splanchnic artery ischemia–reperfusion. Am J Physiol 1998;275:H2080–H2086.PubMed

Kalia N, Brown NJ, Wood RF, Hopkinson K, Fairburn B, Pockley AG. Effects of intestinal ischemia–reperfusion injury on rat peripheral blood neutrophil activation. Dig Dis Sci 2003;48:1677–1684. doi:10.1023/A:1025418322527.PubMedCrossRef

Ferencz A, Szanto Z, Borsiczky B, Kiss K, Kalmar-Nagy K, Szeberenyi J, Horvath PO, Roth E. The effects of preconditioning on the oxidative stress in small-bowel autotransplantation. Surgery 2002;132:877–884. doi:10.1067/msy.2002.129910.PubMedCrossRef

Sola A, De Oca J, Gonzalez R, Prats N, Rosello-Catafau J, Gelpi E, Jaurrieta E, Hotter G. Protective effect of ischemic preconditioning on cold preservation and reperfusion injury associated with rat intestinal transplantation. Ann Surg 2001;234:98–106. doi:10.1097/00000658-200107000-00015.PubMedCrossRef

Wu B, Ootani A, Iwakiri R, Fujise T, Tsunada S, Toda S, Fujimoto K. Ischemic preconditioning attenuates ischemia–reperfusion-induced mucosal apoptosis by inhibiting the mitochondria-dependent pathway in rat small intestine. Am J Physiol Gastrointest Liver Physiol 2004;286:G580–G587. doi:10.1152/ajpgi.00335.2003.PubMedCrossRef

Yang SP, Hao YB, Wu YX, Dun W, Shen LH, Zhang Y. Ischemic preconditioning mediated by activation of KATP channels in rat small intestine. Zhongguo Yao Li Xue Bao 1999;20:341–344.PubMed

Baxter GF, Ferdinandy P. Delayed preconditioning of myocardium: current perspectives. Basic Res Cardiol 2001;96:329–344. doi:10.1007/s003950170041.PubMedCrossRef

Bolli R. The late phase of preconditioning. Circ Res 2000;87:972–983.PubMed

Chiari PC, Pagel PS, Tanaka K, Krolikowski JG, Ludwig LM, Trillo RA Jr, Puri N, Kersten JR, Warltier DC. Intravenous emulsified halogenated anesthetics produce acute and delayed preconditioning against myocardial infarction in rabbits. Anesthesiology 2004;101:1160–1166. doi:10.1097/00000542-200411000-00016.PubMedCrossRef

10.

Salloum F, Yin C, Xi L, Kukreja RC. Sildenafil induces delayed preconditioning through inducible nitric oxide synthase-dependent pathway in mouse heart. Circ Res 2003;92:595–597. doi:10.1161/01.RES.0000066853.09821.98.PubMedCrossRef

11.

Guo Y, Stein AB, Wu WJ, Zhu X, Tan W, Li Q, Bolli R. Late preconditioning induced by NO donors, adenosine A1 receptor agonists, and delta1-opioid receptor agonists is mediated by iNOS. Am J Physiol Heart Circ Physiol 2005;289:H2251–H2257. doi:10.1152/ajpheart.00341.2005.PubMedCrossRef

12.

Jneid H, Chandra M, Alshaher M, Hornung CA, Tang XL, Leesar M, Bolli R. Delayed preconditioning-mimetic actions of nitroglycerin in patients undergoing exercise tolerance tests. Circulation 2005;111:2565–2571. doi:10.1161/CIRCULATIONAHA.104.515445.PubMedCrossRef

13.

Li YJ, Xiao ZS, Peng CF, Deng HW. Calcitonin gene-related peptide-induced preconditioning protects against ischemia–reperfusion injury in isolated rat hearts. Eur J Pharmacol 1996;311:163–167. doi:10.1016/0014-2999(96)00426-8.PubMedCrossRef

14.

Song QJ, Li YJ, Deng HW. Early and delayed cardioprotection by heat stress is mediated by calcitonin gene-related peptide. Naunyn Schmiedebergs Arch Pharmacol 1999;359:477–483. doi:10.1007/PL00005379.PubMedCrossRef

15.

He SY, Deng HW, Li YJ. Monophosphoryl lipid A-induced delayed preconditioning is mediated by calcitonin gene-related peptide. Eur J Pharmacol 2001;420:143–149. doi:10.1016/S0014-2999(01)00921-9.PubMedCrossRef

16.

Chai W, Mehrotra S, Jan Danser AH, Schoemaker RG. The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning in isolated rat hearts. Eur J Pharmacol 2006;531:246–253. doi:10.1016/j.ejphar.2005.12.039.PubMedCrossRef

17.

Bolli R, Dawn B, Tang XL, Qiu Y, Ping P, Xuan YT, Jones WK, Takano H, Guo Y, Zhang J. The nitric oxide hypothesis of late preconditioning. Basic Res Cardiol 1998;93:325–338. doi:10.1007/s003950050101.PubMedCrossRef

18.

Takano H, Tang XL, Qiu Y, Guo Y, French BA, Bolli R. Nitric oxide donors induce late preconditioning against myocardial stunning and infarction in conscious rabbits via an antioxidant-sensitive mechanism. Circ Res 1998;83:73–84.PubMed

19.

Wang G, Liem DA, Vondriska TM, Honda HM, Korge P, Pantaleon DM, Qiao X, Wang Y, Weiss JN, Ping P. Nitric oxide donors protect murine myocardium against infarction via modulation of mitochondrial permeability transition. Am J Physiol Heart Circ Physiol 2005;288:H1290–H1295. doi:10.1152/ajpheart.00796.2004.PubMedCrossRef

20.

Dun Y, Hao YB, Wu YX, Zhang Y, Zhao RR. Protective effects of nitroglycerin-induced preconditioning mediated by calcitonin gene-related peptide in rat small intestine. Eur J Pharmacol 2001;430:317–324. doi:10.1016/S0014-2999(01)01256-0.PubMedCrossRef

21.

Feng Q, Lu X, Jones DL, Shen J, Arnold JM. Increased inducible nitric oxide synthase expression contributes to myocardial dysfunction and higher mortality after myocardial infarction in mice. Circulation 2001;104:700–704. doi:10.1161/hc3201.092284.PubMedCrossRef

22.

Chiu CJ, McArdle AH, Brown R, Scott HJ, Gurd FN. Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg 1970;101:478–483.PubMed

23.

Amara SG, Arriza JL, Leff SE, Swanson LW, Evans RM, Rosenfeld MG. Expression in brain of a messenger RNA encoding a novel neuropeptide homologous to calcitonin gene-related peptide. Science 1985;229:1094–1097. doi:10.1126/science.2994212.PubMedCrossRef

24.

Leesar MA, Stoddard MF, Dawn B, Jasti VG, Masden R, Bolli R. Delayed preconditioning-mimetic action of nitroglycerin in patients undergoing coronary angioplasty. Circulation 2001;103:2935–2941.PubMed

25.

Kallner G. Release and effects of calcitonin gene-related peptide in myocardial ischaemia. Scand Cardiovasc J Suppl 1998;49:1–35. doi:10.1080/140174398427965.PubMedCrossRef

26.

Zhou ZH, Deng HW, Li YJ. Improvement of preservation with cardioplegic solution by nitroglycerin-induced delayed preconditioning is mediated by calcitonin gene-related peptide. Int J Cardiol 2001;81:211–218. doi:10.1016/S0167-5273(01)00569-1.PubMedCrossRef

27.

Li G, Chen S, Lu E, Luo W. Cardiac ischemic preconditioning improves lung preservation in valve replacement operations. Ann Thorac Surg 2001;71:631–635. doi:10.1016/S0003-4975(00)02015-4.PubMedCrossRef

28.

Lu R, Hu CP, Peng J, Deng HW, Li YJ. Role of calcitonin gene-related peptide in ischaemic preconditioning in diabetic rat hearts. Clin Exp Pharmacol Physiol 2001;28:392–396. doi:10.1046/j.1440-1681.2001.03467.x.PubMedCrossRef

29.

Li YJ, Song QJ, Xiao J. Calcitonin gene-related peptide: an endogenous mediator of preconditioning. Acta Pharmacol Sin 2000;21:865–869.PubMed

30.

Rizvi A, Tang XL, Qiu Y, Xuan YT, Takano H, Jadoon AK, Bolli R. Increased protein synthesis is necessary for the development of late preconditioning against myocardial stunning. Am J Physiol 1999;277:H874–H884.PubMed

31.

Steenbergh PH, Hoppener JW, Zandberg J, Lips CJ, Jansz HS. A second human calcitonin/CGRP gene. FEBS Lett 1985;183:403–407. doi:10.1016/0014-5793(85)80820-6.PubMedCrossRef

32.

Doi Y, Peng H, Kudo H, Hamasaki K, Fujimoto S. Expression of alpha-calcitonin gene-related peptide in the enteric nervous system of rat small intestine. Neurosci Lett 2000;285:33–36. doi:10.1016/S0304-3940(00)01018-1.PubMedCrossRef

33.

Xing L, Guo J, Wang X. Induction and expression of beta-calcitonin gene-related peptide in rat T lymphocytes and its significance. J Immunol 2000;165:4359–4366.PubMed

34.

Burak Kandilci H, Gumusel B, Wasserman A, Witriol N, Lippton H. Intermedin/adrenomedullin-2 dilates the rat pulmonary vascular bed: dependence on CGRP receptors and nitric oxide release. Peptides 2006;27:1390–1396. doi:10.1016/j.peptides.2005.10.024.PubMedCrossRef

35.

Kodani E, Xuan YT, Takano H, Shinmura K, Tang XL, Bolli R. Role of cyclic guanosine monophosphate in late preconditioning in conscious rabbits. Circulation 2002;105:3046–3052. doi:10.1161/01.CIR.0000019408.67709.B5.PubMedCrossRef

36.

Zhou ZH, Peng J, Ye F, Li NS, Deng HW, Li YJ. Delayed cardioprotection induced by nitroglycerin is mediated by alpha-calcitonin gene-related peptide. Naunyn Schmiedebergs Arch Pharmacol 2002;365:253–259. doi:10.1007/s00210-002-0537-y.PubMedCrossRef

37.

Banerjee S, Tang XL, Qiu Y, Takano H, Manchikalapudi S, Dawn B, Shirk G, Bolli R. Nitroglycerin induces late preconditioning against myocardial stunning via a PKC-dependent pathway. Am J Physiol 1999;277:H2488–H2494.PubMed

38.

Um JW, Matthews JB, Song JC, Mun EC. Role of protein kinase C in intestinal ischemic preconditioning. J Surg Res 2005;124:289–296. doi:10.1016/j.jss.2004.10.011.PubMedCrossRef

39.

Du YH, Peng J, Huang ZZ, Jiang DJ, Deng HW, Li YJ. Delayed cardioprotection afforded by nitroglycerin is mediated by alpha-CGRP via activation of inducible nitric oxide synthase. Int J Cardiol 2004;93:49–54. doi:10.1016/S0167-5273(03)00123-2.PubMedCrossRef

Title: Nitroglycerin Protects Small Intestine from Ischemia–Reperfusion Injury via NO–cGMP Pathway and Upregulation of α-CGRP
Authors: Jie Li
Mingsheng Zhang
Caihong Yang
Ying Dun
Yi Zhang
Yibin Hao
Publication date: 01-03-2009
Publisher: Springer-Verlag
Published in: Journal of Gastrointestinal Surgery / Issue 3/2009
Print ISSN: 1091-255X
Electronic ISSN: 1873-4626
DOI: https://doi.org/10.1007/s11605-008-0728-z

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Nitroglycerin Protects Small Intestine from Ischemia–Reperfusion Injury via NO–cGMP Pathway and Upregulation of α-CGRP

Abstract

Introduction

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusion

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