Science China Life Sciences

, Volume 57, Issue 7, pp 681–689

Enhanced vasoconstriction to α1 adrenoceptor autoantibody in spontaneously hypertensive rats

Open Access
Research Paper

Abstract

Autoimmune activities have been implicated in the pathogenesis of hypertension. High levels of autoantibodies against the second extracellular loop of α1-adrenoceptor (α1-AR autoantibody, α1-AA) are found in patients with hypertension, and α1-AA could exert a α1-AR agonist-like vasoconstrictive effect. However, whether the vasoconstrictive effect of α1-AA is enhanced in hypertension is unknown. Using aortic rings of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, we observed the vasoconstrictive responses to α1-AA with phenylephrine (α1-AR agonist) as a positive control drug. Aortic nitrotyrosine levels were also measured by ELISA and immunohistochemistry. The results showed that the aortic constrictive responses to α1-AA and phenylephrine (both 1 nmol L−1−10 μmol L−1) were greater in SHR than in WKY rats. Endothelial denudation or L-NAME (a non-selective NOS inhibitor) (100 μmol L−1) increased α1-AA- or phenylephrine-induced vasoconstrictions both in SHR and WKY. However, selective iNOS inhibitor 1400W (10 μmol L−1) enhanced the α1-AA-induced aortic constriction in WKY, but not in SHR. The aortic nitrotyrosine level was significantly higher in SHR than WKY, as shown by both ELISA and immunohistochemistry. These results indicate that the vasoconstrictive response to α1-AA is enhanced in SHR, and this altered responsiveness is due to endothelial dysfunction and decreased NO bioavailability. The study suggests an important role of α1-AR autoimmunity in the pathogenesis and management of hypertension especially in those harboring high α1-AA levels.

Keywords

autoimmunity adrenergic receptor blood vessel endothelium protein nitration hypertension 

References

  1. 1.
    Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet, 2005, 365: 217–223PubMedCrossRefGoogle Scholar
  2. 2.
    Dzielak DJ. The immune system and hypertension. Hypertension, 1992, 19: I36–I44PubMedCrossRefGoogle Scholar
  3. 3.
    Fu ML. Do immune system changes have a role in hypertension? J Hypertens, 1995, 13: 1259–1265PubMedCrossRefGoogle Scholar
  4. 4.
    Fu ML, Herlitz H, Wallukat G, Hilme E, Hedner T, Hoebeke J, Hjalmarson A. Functional autoimmune epitope on alpha1-adrenergic receptors in patients with malignant hypertension. Lancet, 1994, 344: 1660–1663PubMedCrossRefGoogle Scholar
  5. 5.
    Luther HP, Homuth V, Wallukat G. Alpha1-adrenergic receptor antibodies in patients with primary hypertension. Hypertension, 1997, 29: 678–682PubMedCrossRefGoogle Scholar
  6. 6.
    Wenzel K, Haase H, Wallukat G, Derer W, Bartel S, Homuth V, Herse F, Hubner N, Schulz H, Janczikowski M, Lindschau C, Schroeder C, Verlohren S, Morano I, Muller DN, Luft FC, Dietz R, Dechend R, Karczewski P. Potential relevance of α1-adrenergic receptor autoantibodies in refractory hypertension. PLoS ONE, 2008, 3: e3742PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Yan L, Xu Y, Yao H, Xue W, Tian J, Ren H, Wu Y, Yang G, Ma XL, Liu H. The effects of autoantibodies against the second extracellular loop of alpha1-adrenoceptor on vasoconstriction. Basic Res Cardiol, 2009, 104: 581–589PubMedCrossRefGoogle Scholar
  8. 8.
    Ibarra M, López-Guerrero JJ, Mejía-Zepeda R, Villalobos-Molina R. Endothelium-dependent inhibition of the contractile response is decreased in aorta from aged and spontaneously hypertensive rats. Arch Med Res, 2006, 37: 334–341PubMedCrossRefGoogle Scholar
  9. 9.
    Linder L, Kiowski W, Bühler FR, Lüscher TF. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo: blunted response in essential hypertension. Circulation, 1990, 81: 1762–1767PubMedCrossRefGoogle Scholar
  10. 10.
    Panza JA, García CE, Kilcoyne CM, Quyyumi AA, Cannon RO 3rd. Impaired endothelium-dependent vasodilation in patients with essential hypertension. Evidence that nitric oxide abnormality is not localized to a single signal transduction pathway. Circulation, 1995, 91: 1732–1738Google Scholar
  11. 11.
    Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med, 1990, 323: 22–27PubMedCrossRefGoogle Scholar
  12. 12.
    Guimarães S, Moura D. Vascular adrenoceptors: an update. Pharmacol Rev, 2001, 53: 319–356PubMedGoogle Scholar
  13. 13.
    Li J, Cao YX, Liu H, Xu CB. Enhanced G-protein coupled receptors-mediated contraction and reduced endothelium-dependent relaxation in hypertension. Eur J Pharmacol, 2007, 28: 186–194CrossRefGoogle Scholar
  14. 14.
    Behrendt D, Ganz P. Endothelial function: from vascular biology to clinical applications. Am J Cardiol, 2002, 90: 40L–48LPubMedCrossRefGoogle Scholar
  15. 15.
    Lüscher TF, Boulanger CM, Yang Z, Noll G, Dohi Y. Interactions between endothelium derived relaxing and contracting factors in health and cardiovascular disease. Circulation, 1993, 87(Suppl V): 36–44Google Scholar
  16. 16.
    Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev, 1991, 43: 109–142PubMedGoogle Scholar
  17. 17.
    Bullock GR, Taylor SG, Weston AH. Influence of the vascular endothelium on agonist-induced contractions and relaxations in rat aorta. Br J Pharmacol, 1986, 89: 819–830PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Criscione L, Müller K, Forney Prescott M. Endothelial cell loss enhances the pressor response in resistance vessels. J Hypertens, 1984, 2: S441–S444Google Scholar
  19. 19.
    Eglème C, Godfraind T, Miller RC. Enhanced responsiveness of rat isolated aorta to clonidine after removal of the endothelial cell. Br J Pharmacol, 1984, 81: 16–18PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Martin W, Furchgott RF, Villani GM, Jothianandan D. Depression of contractile responses in rat aorta by spontaneously released endothelium-derived relaxing factor. J Pharmacol Exp Ther, 1986, 237: 529–538PubMedGoogle Scholar
  21. 21.
    Yamaguchi T, Rodman D, O’Brien R, McMurtry I. Modulation of pulmonary artery contraction by endothelium-derived relaxing factor. Eur J Pharmacol, 1989, 161: 259–262PubMedCrossRefGoogle Scholar
  22. 22.
    Alvarez Y, Briones AM, Hernanz R, Pérez-Girón JV, Alonso MJ, Salaices M. Role of NADPH oxidase and iNOS in vasoconstrictor responses of vessels from hypertensive and normotensive rats. Br J Pharmacol, 2008, 153: 926–935PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Félétou M, Vanhoutte PM. Endothelial dysfunction: a multifaceted disorder. Am J Physiol Heart Circ Physiol, 2006, 291: H985–H1002PubMedCrossRefGoogle Scholar
  24. 24.
    Förstermann U, Closs EI, Pollock JS, Nakane M, Schwarz P, Gath I, Kleinert H. Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension, 1994, 23: 1121–1131PubMedGoogle Scholar
  25. 25.
    Ridnour LA, Thomas DD, Mancardi D, Espey MG, Miranda KM, Paolocci N, Feelisch M, Fukuto J, Wink DA. The chemistry of nitrosative stress induced by nitric oxide and reactive nitrogen oxide species. Putting perspective on stressful biological situations. Biol Chem, 2004, 385: 1–10PubMedCrossRefGoogle Scholar
  26. 26.
    Upmacis RK, Crabtree MJ, Deeb RS, Shen H, Lane PB, Benguigui LE, Maeda N, Hajjar DP, Gross SS. Profound biopterin oxidation and protein tyrosine nitration in tissues of ApoE-null mice on an atherogenic diet: contribution of inducible nitric oxide synthase. Am J Physiol Heart Circ Physiol, 2007, 293: H2878–H2887PubMedCrossRefGoogle Scholar
  27. 27.
    Förstermann U, Li H. Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling. Br J Pharmacol, 2011, 164: 213–223PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Liu HR, Zhao RR, Zhi JM, Wu BW, Fu ML. Screening of serum autoantibodies to cardiac β1-adrenoceptors and M2-muscarinic acetylcholine receptors in 408 healthy subjects of varying ages. Autoimmunity, 1999, 29: 43–51PubMedCrossRefGoogle Scholar
  29. 29.
    Porstmann T, Kiessig ST. Enzyme immunoassay techniques-an overview. J Immunol Methods, 1992, 150: 5–21PubMedCrossRefGoogle Scholar
  30. 30.
    Tao L, Liu HR, Gao F, Qu Y, Christopher TA, Lopez BL, Ma XL. Mechanical traumatic injury without circulatory shock causes cardiomyocyte apoptosis: role of reactive nitrogen and reactive oxygen species. Am J Physiol Heart Circ Physiol, 2005, 288: H2811–H2818PubMedCrossRefGoogle Scholar
  31. 31.
    Alvarez Y, Briones AM, Balfagón G, Alonso MJ, Salaices M. Hypertension increases the participation of vasoconstrictor prostanoids from cyclooxygenase-2 in phenylephrine responses. J Hypertens, 2005, 23: 767–777PubMedCrossRefGoogle Scholar
  32. 32.
    Alvarez Y, Pérez-Girón JV, Hernanz R, Briones AM, García-Redondo A, Beltrán A, Alonso MJ, Salaices M. Losartan reduces the increased participation of COX-2 derived products in vascular responses of hypertensive rats. J Pharmacol Exp Ther, 2007, 321: 381–388PubMedCrossRefGoogle Scholar
  33. 33.
    Fu ML, Wallukat G, Hjalmarson A, Hoebeke J. Characterization of anti-peptide antibodies directed against an extracellular immunogenic epitope on the human α1-adrenergic receptor. Clin Exp Immunol, 1994, 97: 146–151PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Bkaily G, EI-Bizri N, Bui M, Sukarieh R, Jacques D, Fu ML. Modulation of intracellular Ca2+ via L-type calcium channels in heart cells by the autoantibody directed against the second extracellular loop of the alpha1-adrenoceptors. Can J Physiol Pharmacol, 2003, 81: 234–246PubMedCrossRefGoogle Scholar
  35. 35.
    Dora KA, Hinton JM, Walker SD, Garland CJ. An indirect influence of phenylephrine on the release of endothelium-derived vasodilators in rat small mesenteric artery. Br J Pharmacol, 2000, 129: 381–387PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Nishina H, Ozaki T, Hanson MA, Poston L. Mechanism of noradrenaline-induced vasorelaxation in isolated femoral arteries of the neonatal rat. Br J Pharmacol, 1999, 127: 809–812PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Mendez E, Calzada C, Ocharan E, Sierra A, Castillo C, Ramirez I, Meaney E, Meaney A, Asbun J, Miliar A, Herrera J, Ceballos G. Differential expression of alpha1-adrenergic receptor subtypes in coronary microvascular endothelial cells in culture. Eur J Pharmacol, 2006, 546: 127–133PubMedCrossRefGoogle Scholar
  38. 38.
    Briones AM, Alonso MJ, Hernanz R, Miguel M, Salaices M. Alterations of the nitric oxide pathway in cerebral arteries from spontaneously hypertensive rats. J Cardiovasc Pharmacol, 2002, 39: 378–388PubMedCrossRefGoogle Scholar
  39. 39.
    Vaziri ND, Ni Z, Oveisi F. Upregulation of renal and vascular nitric oxide synthase in young spontaneously hypertensive rats. Hypertension, 1998, 31: 1248–1254PubMedCrossRefGoogle Scholar
  40. 40.
    Rees DD, Cellek S, Palmer RM, Moncada S. Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on vascular tone: an insight into endotoxin shock. Biochem Biophys Res Commun, 1990, 173: 541–547PubMedCrossRefGoogle Scholar
  41. 41.
    Alonso MJ, Rodríguez-Martínez MA, Martínez-Orgado J, Marín J, Salaices M. The L-arginine inhibition of rat middle cerebral artery contractile responses is mediated by inducible nitric oxide synthase. J Auton Pharmacol, 1998, 18: 105–113PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2014

Authors and Affiliations

  1. 1.Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medical Sciences Peking Union Medical CollegeBeijingChina
  2. 2.Key Laboratory of Medical Electrophysiology of Ministry of EducationLuzhou Medical CollegeLuzhouChina
  3. 3.The High School Affiliated to Renmin University of ChinaBeijingChina
  4. 4.Department of Pathophysiology, School of Basic Medical SciencesCapital Medical University, the Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of EducationBeijingChina

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