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Exp Clin Endocrinol Diabetes 2015; 123(07): 394-397
DOI: 10.1055/s-0035-1548928
Article
© Georg Thieme Verlag KG Stuttgart · New York

Na+/Ca2+ Exchanger Inhibitor Restores Endothelium-dependent Relaxation in Diabetic Rat Aorta

X.-F. Li   *
1   Department of Endocrinology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
,
T.-T. Wan   *
1   Department of Endocrinology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
,
Y.-M. Sun
1   Department of Endocrinology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
,
Y. Su
1   Department of Endocrinology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
› Author Affiliations
Further Information

Publication History

received 28 July 2014
first decision 28 March 2015

accepted 01 April 2015

Publication Date:
21 April 2015 (online)

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Abstract

The aims of this study were to examine the effects of KB-R7943, an inhibitor of Na+/Ca2+ exchanger, on the endothelium-dependent relaxation (EDR) in diabetic rat aorta. Both acetylcholine (ACh)-induced EDR and sodium nitroprusside (SNP)-induced endothelium-independent relaxation (EIR) were measured in aortic rings of nondiabetic and streptozotocin-diabetic rats. Diabetes mellitus was induced by single injection of streptozotocin (60 mg/kg). The treated rats received 0.01 or 0.1 mg/kg/day of KB-R7943 for 8 weeks. ACh-induced relaxation was impaired in diabetic compared to control rings and the vasodilatation to SNP was unaffected. Treatment with KB-R7943 markedly enhanced relaxation to ACh in diabetic but not in control rings. KB-R7943 significantly increased superoxide dismutase (SOD) activity and the nitric oxide (NO) release. These results suggest that KB-R7943 can restore impaired EDR in aortic rings of diabetic rats, which may be related to scavenging oxygen free radicals and enhancing NO production.

Key words

endothelium-dependent relaxation - diabetic rat - Na+/Ca2+ exchanger - superoxide dismutase - nitric oxide

* Xiu-fen Li and Ting-ting Wan contributed equally to this study.


 

  • References

  • 1 Su Y, Liu XM, Sun YM et al. Na+/Ca2+ exchanger inhibitor ameliorates impaired endothelium-dependent Na+ relaxation induced by high glucose in rat aorta. Clin Exp Pharmacol Physiol 2008; 35: 1265-1270
    CrossrefPubMedSearch in Google Scholar
  • 2 Li J, Jin HB, Sun YM et al. KB-R7943 inhibits high glucose-induced endothelial ICAM-1 expression and monocyte-endothelial adhesion. Biochem Biophys Res Commun 2010; 392: 516-519
    CrossrefPubMedSearch in Google Scholar
  • 3 Liu D, Cui KZ, Sun YM et al. Protective effects of the sodium/calcium exchanger inhibitor on endothelial dysfunction induced by high glucose. Experimental and Clinical Endocrinology & Diabete 2015; 123: 7-10
    PubMedSearch in Google Scholar
  • 4 Zhu J, Mori T, Huang T et al. Effect of high-salt diet on NO release and superoxide production in rat aorta. Am J Physiol Heart Circ Physiol 2004; 286: H575- H583
    CrossrefPubMedSearch in Google Scholar
  • 5 Hacker A, Muller S, Meyer W et al. The nitric oxide donor pentaerythritol tetranitrate can preserve endothelial function in established atherosclerosis. Br J Pharmacol 2001; 132: 1707-1714
    CrossrefPubMedSearch in Google Scholar
  • 6 Li Y, Woo V, Bose R. Platelet hyperactivity and abnormal Ca (2+) homeostasis in diabetes mellitus. Am J Physiol Heart Circ Physiol 2001; 280: H1480- H1489
    PubMedSearch in Google Scholar
  • 7 Telejko B, Tomasiak M, Stelmach H et al. Platelet sodium-proton exchanger and phospholipid-dependent procoagulant activity in patients with type 2 diabetes. Metabolism 2003; 52: 102-106
    CrossrefPubMedSearch in Google Scholar
  • 8 Hattori Y, Matsuda N, Kimura J et al. Diminished function and expression of the cardiac Na+-Ca2+ exchanger in diabetic rats: implication in Ca2+ overload. J Physiol 2000; 527: 85-94
    CrossrefPubMedSearch in Google Scholar
  • 9 Kashihara H, Shi ZQ, Yu JZ et al. Effects of diabetes and hypertension on myocardial Na+-Ca2+ exchange. Can J Physiol Pharmacol 2000; 78: 12-19
    CrossrefPubMedSearch in Google Scholar
  • 10 Poburko D, Liao CH, Lemos VS et al. Transient receptor potential channel 6-mediated, localized cytosolic [Na+] transients drive Na+/Ca2+ exchanger-mediated Ca2+ entry in purinergically stimulated aorta smooth muscle cells. Circ Res 2007; 101: 1030-1038
    CrossrefPubMedSearch in Google Scholar
  • 11 Santo-Domingo J, Vay L, Hernandez-Sanmiguel E et al. The plasma membrane Na+/Ca2+ exchange inhibitor KB-R7943 is also a potent inhibitor of the mitochondrial Ca2+ uniporter. Br J Pharmacol 2007; 151: 647-654
    CrossrefPubMedSearch in Google Scholar
  • 12 An J, Rhodes SS, Jiang MT et al. Anesthetic preconditioning enhances Ca2+ handling and mechanical and metabolic function elicited by Na+-Ca2+ exchange inhibition in isolated hearts. Anesthesiology 2006; 105: 541-549
    CrossrefPubMedSearch in Google Scholar
  • 13 Schneider JC, EIKebir D, Chereau C et al. Involvement of Na(+)/Ca(2+) exchanger in endothelial NO production and endothelium-dependent relaxation. Am J Physiol Heart Circ Physiol 2002; 283: H837-H844
    CrossrefPubMedSearch in Google Scholar
  • 14 Rinaldi GJ. Blood pressure fall and increased relaxation of aortic smooth muscle in diabetic rats. Diabetes Metab 2005; 31: 487-495
    CrossrefPubMedSearch in Google Scholar
  • 15 Schaffer SW, Ballard-Croft C, Boerth S et al. Mechanisms underlying depressed Na+/Ca2+ exchanger activity in the diabetic heart. Cardiovasc Res 1997; 34: 129-136
    CrossrefPubMedSearch in Google Scholar
  • 16 Forte L, Cimmino G, Loffredo F et al. C-reactive protein is released in the coronary circulation and causes endothelial dysfunction in patients with acute coronary syndromes. Int J Cardiol 2011; 152: 7-12
    CrossrefPubMedSearch in Google Scholar
  • 17 Fidan E, Onder Ersoz H, Yilmaz M et al. The effects of rosiglitazone and metformin on inflammation and endothelial dysfunction in patients with type 2 diabetes mellitus. Acta Diabetol 2011; 48: 297-302
    CrossrefPubMedSearch in Google Scholar
  • 18 Dang L, Seale JP, Qu X. High glucose-induced human umbilical vein endothelial cell hyperpermeability is dependent on protein kinase C activation and independent of the Ca2+-nitric oxide signalling pathway. Clin Exp Pharmacol Physiol 2005; 32: 771-776
    CrossrefPubMedSearch in Google Scholar
  • 19 Ogura J, Mitamura M, Someya A et al. Mesaconitine-induced relaxation in rat aorta: role of Na+/Ca2+ exchangers in endothelial cells. Eur J Pharmacol 2004; 484: 139-146
    PubMedSearch in Google Scholar
  • 20 Kim MY, Seol GH, Liang GH et al. Na+-K+ pump activation inhibits endothelium-dependent relaxation by activating the forward mode of Na+/Ca2+ exchanger in mouse aorta. Am J Physiol Heart Circ Physiol 2005; 289: H2020-H2029
    CrossrefPubMedSearch in Google Scholar