Reduction of Superior Mesenteric Hemodynamic Responsiveness to [Sar^1, Thr^8]-Angiotensin Ⅱ and Bradykinin, But Not Sodium Nitroprusside, in the Presence of Homocysteine Infusion

10.4077/CJP.2010.AMH065

Chia-Hung Yen；Yunn-Hwa Ma；Huang-Ping Yu；Ying-Tung Lau

hyperhomocysteine ； superior mesentery ； endothelium-dependent relaxation

The Chinese Journal of Physiology

53卷1期（2010 / 02 / 28）

45 - 51

英文

Hyperhomocsteinemia (HHcy) has been shown to be an independent risk factor for cardiovascu1ar diseases, superior mesenteric thrombosis and inflammatory bowel disease. Superior mesenteric artery (SMA) supplies the intestine and reduced SMA blood f1ow results in intestinal ischemia. Although in vitro studies have shown that endothelium-dependent vasorelaxation of SMA is reduced in the presence of homocysteine incubation, it is not confirmed with in vivo studies. In this work, we evaluated responsiveness of SMA to endothelium-dependent or -independent vasodilators and a vasoconstrictor in the absence and presence of acute HHcy in vivo to clarify effect of HHcy on superior mesenteric vascular function. Sodium nitroprusside (SNP), bradykinin (BK), and [Sar 1, Thr 8] angiotensin Ⅱ [Sar 1, Thr 8] -ANG Ⅱ) were intravenously administrated in sequence in male Sprague-Dawley rats with or without D, L-homocysteine infusion (6 mg/kg/min) through femoral vein. Agonists-induced changes in carotid artery blood pressure, superior mesenteric blood flow and vascular resistance were measured in the present studs. We found that acute HHcy infusion had little effects on SNP-induced hemodynamic changes; however, BK-induced changes in blood pressure, blood flow and vascular resistance were significantly reduced in the presence of HHcy infusion. Additionally, HHcy also markedly decreased [Sar 1, Thr 8] -ANG Ⅱ-induced superior mesenteric hemodynamic changes. These results demonstrated that responsiveness of SMA to vasoconstrictor, endothelium-dependent, but not endothelium-independent vasodilator, was inhibited in the presence of Hcy infusion. This HHcy-associated vascular hyporesponsiveness to vasoconstrictors and endothelium-dependent vasodilators may partially contribute to circulators dysfunctions.

1. Tsen, C. M.,Hsieh, C. C.,Yen, C. H.,Lau, Y. T.(2003).Homocysteine altered ROS generation and NO accumulation in endothelial cells.Chinese J. Physiol.,46,129-136.
   連結：
2. Alexander, T.,Rajnish, R.,Balakrishnan, R.,Shallam, J. F.(2005).Hyperhomocysteinemia presenting as superior mesenteric artery thrombosis.Indian J. Gastroenterol.,24,78-79.
3. Charkoudian, N.,Joyner, M. J.,Barnes, S. A.,Johnson, C. P.,Eisenach, J. H.,Dietz, N. M.,Wallin, B. G.(2006).Relationship between muscle sympathetic nerve activity and systemic hemodynamics during nitric oxide synthase inhibition in humans.Am. J. Physiol.,291,H1378-H1383.
4. Chen, C.,Conklin, B. S.,Ren, Z.,Zhong, D. S.(2002).Homocysteine decreases endothelium-dependent vasorelaxation in porcine arteries.J. Surg. Res.,102,22-30.
5. Chowienczyk, P. J.,Cockcroft, J. R.,Ritter, J. M.(1994).Blood flow responses to intra-arterial acetylcholine in man: effects of basal flow and conduit vessel length.Clin. Sci.,87,45-51.
6. Cody, R. J.,Tarazi, R. C.,Fouad, F. M.,Bravo, E. L.(1980).Hemodynamics of a new angiotensin antagonist, [Sar1, Thr8] AII, in hypertensive man.Circulation,61,338-344.
7. Danese, S.,Sgambato, A.,Papa, A.,Scaldaferri, F.,Pola, R.,Sans, M.,Lovecchio, M.,Gasbarrini, G.,Cittadini, A.,Gasbarrini, A.(2005).Homocysteine triggers mucosal microvascular activation in inflammatory bowel disease.Am. J. Gastroenterol.,100,886-895.
8. de P Rodrigues, S. F.,dos Santos, R. A.,Silva-Antonialli, M. M.,Scavone, C.,Nigro, D.,Carvalho, M. H.,de Cassia Tostes, R.,Fortes, Z. B.(2006).Differential effect of losartan in female and male spontaneously hypertensive rats.Life Sci.,78,2280-2285.
9. De Vriese, A. S.,Blom, H. J.,Heil, S. G.,Mortier, S.,Kluijtmans, L. A.,van de Voorde, J.,Lameire, N. H.(2004).Endothelium-derived hyperpolarizing factor-mediated renal vasodilatory response is impaired during acute and chronic hyperhomocysteinemia.Circulation,109,2331-2336.
10. Drzewoski, J.,Gasiorowska, A.,Malecka-Panas, E.,Bald, E.,Czupryniak, L.(2006).Plasma total homocysteine in the active stage of ulcerative colitis.J. Gastroenterol. Hepatol.,21,739-743.
11. Eikelboom, J. W.,Lonn, E.,Genest, J.,Hankey, G.,Yusuf, S.(1999).Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence.Ann. Intern. Med.,131,363-375.
12. Erdmann, K.,Grosser, N.,Schroder, H.(2005).L-methionine reduces oxidant stress in endothelial cells: role of heme oxygenase-1, ferritin, and nitric oxide.AAPS J.,7,E195-E200.
13. Fu, W. Y.,Dudman, N. P.,Perry, M. A.,Wang, X. L.(2002).Homocysteine attenuates hemodynamic responses to nitric oxide in vivo.Atherosclerosis,161,169-176.
14. Gosink, E. C.,Forsberg, E. J.(1993).Effects of ATP and bradykinin on endothelial cell Ca2+ homeostasis and formation of cGMP and prostacyclin.Am. J. Physiol.,265,C1620-C1629.
15. Gradman, W. S.,Daniel, J.,Miller, B.,Haji-Aghaii, M.(2001).Homocysteine-associated acute mesenteric artery occlusion treated with thrombectomy and bowel resection.Ann. Vasc. Surg.,15,247-250.
16. Green, D. J.,Bilsborough, W.,Naylor, L. H.,Reed, C.,Wright, J.,O''Driscoll, G.,Walsh, J. H.(2005).Comparison of forearm blood flow responses to incremental handgrip and cycle ergometer exercise: relative contribution of nitric oxide.J. Physiol.,562,617-628.
17. Hanratty, C. G.,McGrath, L. T.,McAuley, D. F.,Young, I. S.,Johnston, G. D.(2001).The effects of oral methionine and homocysteine on endothelial function.Heart,85,326-330.
18. Hart, S. R.,Mangoni, A. A.,Swift, C. G.,Jackson, S. H.(2006).Lack of significant effects of methionine loading on endothelial function in elderly volunteers.Heart Lung Circ.,15,358-361.
19. Hata, T.,Ogihara, T.,Nakamaru, M.,Gotoh, S.,Masuo, K.,Saeki, S.,Kumagai, A.,Kumahara, Y.(1982).Effect of three angiotensin II antagonists, [Sar1,Thr8]-, [Sar1,Ile8]- and [Sar1,Ala8] angiotensin II on blood pressure and endocrine factors in normal subjects.Eur. J. Clin. Pharmacol.,23,7-10.
20. Heil, S. G.,De Vriese, A. S.,Kluijtmans, L. A.,Mortier, S.,Den Heijer, M.,Blom, H. J.(2004).The role of hyperhomocysteinemia in nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilatation.Cell. Mol. Biol.,50,911-916.
21. Herrmann, W.(2006).Significance of hyperhomocysteinemia.Clin. Lab.,52,367-374.
22. Honda, H.,Moroe, H.,Fujii, H.,Arai, K.,Notoya, Y.,Kogo, H.(2001).Short term hypercholesterolemia alters NG-nitro-L-arginine- and indomethacin-resistant endothelium-dependent relaxation by acetylcholine in rabbit renal artery.Jpn. J. Pharmacol.,85,203-206.
23. Kanaide, H.,Ichiki, T.,Nishimura, J.,Hirano, K.(2003).Cellular mechanism of vasoconstriction induced by angiotensin II: it remains to be determined.Circ. Res.,93,1015-1017.
24. Kanani, P. M.,Sinkey, C. A.,Browning, R. L.,Allaman, M.,Knapp, H. R.,Haynes, W. G.(1999).Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans.Circulation,100,1161-1168.
25. Lee, H. Y.,Chae, I. H.,Kim, H. S.,Park, Y. B.,Choi, Y. S.,Lee, Y. W.,Park, S. J.,Cha, Y. J.(2002).Differential effects of homocysteine on porcine endothelial and vascular smooth muscle cells.J. Cardiovasc. Pharmacol.,39,643-651.
26. Lentz, S. R.(2005).Mechanisms of homocysteine-induced atherothrombosis.J. Thromb. Haemost.,3,1646-1654.
27. Lin, S. L.,Lee, Y. M.,Chang, H. Y.,Cheng, Y. W.,Yen, M. H.(2005).Effects of naltrexone on lipopolysaccharide-induced sepsis in rats.J. Biomed. Sci.,12,431-440.
28. Luksha, L.,Nisell, H.,Kublickiene, K.(2004).The mechanism of EDHF-mediated responses in subcutaneous small arteries from healthy pregnant women.Am. J. Physiol,286,R1102-R1109.
29. Mancuso, D. J.,Han, X.,Jenkins, C. M.,Lehman, J. J.,Sambandam, N.,Sims, H. F.,Yang, J.,Yan, W.,Yang, K.,Green, K.,Abendschein, D. R.,Saffitz, J. E.,Gross, R. W.(2007).Dramatic accumulation of triglycerides and precipitation of cardiac hemodynamic dysfunction during brief caloric restriction in transgenic myocardium expressing human calcium-independent phospholipase A2γ.J. Biol. Chem.,282,9216-9227.
30. Morgenstern, I.,Raijmakers, M. T.,Peters, W. H.,Hoensch, H.,Kirch, W.(2003).Homocysteine, cysteine, and glutathione in human colonic mucosa: elevated levels of homocysteine in patients with inflammatory bowel disease.Dig. Dis. Sci.,48,2083-2090.
31. Pan, H. L.,Deal, D. D.,Xu, Z.,Chen, S. R.(2001).Differential resoponses of regional sympathetic activity and blood flow to visceral afferent stimulation.Am. J. Physiol.,280,1781-1789.
32. Papa, A.,Danese, S.,Urgesi, R.,Grillo, A.,Guglielmo, S.,Roberto, I.,Bonizzi, M.,Guidi, L.,De Vitis, I.,Santoliquido, A.,Fedeli, G.,Gasbarrini, G.,Gasbarrini, A.(2006).Early atherosclerosis in patients with inflammatory bowel disease.Eur. Rev. Med. Pharmacol. Sci.,10,7-11.
33. Parekh, N.,Dobrowolski, L.,Zou, A. P.,Steinhausen, M.(1996).Nitric oxide modulates angiotensin II- and norepinephrine-dependent vasoconstriction in rat kidney.Am. J. Physiol.,270,R630-R635.
34. Pizcueta, P.,Pique, J. M.,Fernandez, M.,Bosch, J.,Rodes, J.,Whittle, B. J.,Moncada, S.(1992).Modulation of the hyperdynamic circulation of cirrhotic rats by nitric oxide inhibition.Gastroenterology,103,1909-1915.
35. Polak, K.,Schmetterer, L.,Luksch, A.,Gruber, S.,Polska, E.,Peternell, V.,Bayerle-Eder, M.,Wolzt, M.,Krebs, M.,Roden, M.(2001).Free fatty acids/triglycerides increase ocular and subcutaneous blood flow.Am. J. Physiol.,280,R56-R61.
36. Pruefer, D.,Scalia, R.,Lefer, A. M.(1999).Homocysteine provokes leukocyte-endothelium interaction by downregulation of nitric oxide.Gen. Pharmacol.,33,487-498.
37. Pullamsetti, S. S.,Maring, D.,Ghofrani, H. A.,Mayer, K.,Weissmann, N.,Rosengarten, B.,Lehner, M.,Schudt, C.,Boer, R.,Grimminger, F.,Seeger, W.,Schermuly, R. T.(2006).Effect of nitric oxide synthase (NOS) inhibition on macro- and microcirculation in a model of rat endotoxic shock.Thromb. Haemost.,95,720-727.
38. Quere, I.,Hillaire-Buys, D.,Brunschwig, C.,Chapal, J.,Janbon, C.,Blayac, J. P.,Petit, P.,Loubatieres-Mariani, M. M.(1997).Effects of homocysteine on acetylcholine- and adenosine-induced vasodilatation of pancreatic vascular bed in rats.Br. J. Pharmacol.,122,351-357.
39. Ross, R.(1993).The pathogenesis of atherosclerosis: a perspective for the 1990s.Nature,362,801-809.
40. Selhub, J.(1999).Homocysteine metabolism.Annu. Rev. Nutr.,19,217-246.
41. Stern, J. M.,Saver, J. L.,Boldy, R. M.,DeGregorio, F.(1998).Homocysteine associated hypercoagulability and disseminated thrombosis-a case report.Angiology,49,765-769.
42. Tasatargil, A.,Sadan, G.,Karasu, E.(2007).Homocysteine-induced changes in vascular reactivity of guinea-pig pulmonary arteries: role of the oxidative stress and poly (ADP-ribose) polymerase activation.Pulm. Pharmacol. Ther.,20,265-272.
43. Thomas, G. R.,Thiemermann, C.,Walder, C.,Vane, J. R.(1988).The effects of endothelium-dependent vasodilators on cardiac output and their distribution in the anaesthetized rat: a comparison with sodium nitroprusside.Br. J. Pharmacol.,95,986-992.
44. van Guldener, C.,Stehouwer, C. D.(2000).Hyperhomocysteinemia, vascular pathology, and endothelial dysfunction.Semin. Thromb. Hemost.,26,281-289.
45. Wirth, K. J.,Linz, W.,Wiemer, G.,Scholkens, B. A.(1996).Differences in acetylcholine- and bradykinin-induced vasorelaxation of the mesenteric vascular bed in spontaneously hypertensive rats of different ages.N.-S. Arch. Pharmacol.,354,38-43.
46. Yen, C. H.,Lau, Y. T.(2002).Vascular responses in male and female hypertensive rats with hyperhomocysteinemia.Hypertension,40,322-328.
47. Zhang, B. Q.,Hu, S. J.,Qiu, L. H.,Zhu, J. H.,Xie, X. J.,Sun, J.,Zhu, Z. H.,Xia, Q.,Bian, K.(2007).Effects of Astragalus membranaceus and its main components on the acute phase endothelial dysfunction induced by homocysteine.Vascul. Pharmacol.,46,278-285.