Molecular and Cellular Biochemistry

, Volume 289, Issue 1–2, pp 21–29 | Cite as

Effects of carbenoxolone on heart rhythm, contractility and intracellular calcium in streptozotocin-induced diabetic rat



Cardiac dysfunction is a frequently reported complication of clinical and experimental diabetes mellitus. Streptozotocin (STZ) – induced diabetes in rat is associated with a variety of cardiac defects including disturbances to heart rhythm and prolonged time-course of cardiac muscle contraction and/or relaxation. The effects of carbenoxolone (CBX), a selective gap junction inhibitor, on heart rhythm and contractility in STZ-induced diabetic rat have been investigated. Heart rate was significantly (P < 0.05) reduced in Langendorff perfused spontaneously beating diabetic rat heart (171±12 BPM) compared to age-matched controls (229± 9 BPM) and further reduced by 10−5 M CBX in diabetic (20%) and in control (17%) hearts. Action potential durations (APDs), recorded on the epicardial surface of the left ventricle, were prolonged in paced (6 Hz) diabetic compared to control hearts. Perfusion of hearts with CBX caused further prolongation of APDs and to a greater extent in control compared to diabetic heart. Percentage prolongation at 70% from the peak of the action potential amplitude after CBX was 18% in diabetic compared to 48% in control heart. CBX had no significant effect on resting cell length or amplitude of ventricular myocyte shortening in diabetic or control rats. However, resting fura-2 ratio (indicator for intracellular Ca2+ concentration) and amplitude of the Ca2+ transient were significantly (P < 0.05) reduced by CBX in diabetic rats but not in controls. In conclusion the larger effects of CBX on APD in control ventricle and the normalizing effects of CBX on intracellular Ca2+ in ventricular myocytes from diabetic rat suggest that there may be alterations in gap junction electrophysiology in STZ-induced diabetic rat heart.

Key words

streptozotocin-induced diabetes heart muscle gap junction contractility 


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  1. 1.
    Dhalla NS, Pierce GN, Innes IR, Beamish RE: Pathogenesis of cardiac dysfunction in diabetes mellitus. Can J Cardiol 1: 263–281, 1985PubMedGoogle Scholar
  2. 2.
    Ren J, Davidoff AJ: Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes. Am J Physiol 41: H148–H158, 1997Google Scholar
  3. 3.
    Choi KM, Zhong Y, Hoit BD, Grupp IL, Hahn H, Dilly KW et al.: Defective intracellular Ca(2+) signaling contributes to cardiomyopathy in Type 1 diabetic rats. Am J Physiol 283: H1398–H1408, 2002PubMedGoogle Scholar
  4. 4.
    Howarth FC, Jacobson M, Naseer O, Adeghate E: Short-term effects of streptozotocin-induced diabetes on the electrocardiogram, physical activity and body temperature in rats. Exp Physiol 90: 237–245, 2005CrossRefPubMedGoogle Scholar
  5. 5.
    Fazan R, Jr., Ballejo G, Salgado MC, Moraes MF, Salgado HC: Heart rate variability and baroreceptor function in chronic diabetic rats. Hypertension 30: 632–635, 1997PubMedGoogle Scholar
  6. 6.
    Lo GP, Careddu A, Magni G, Quagliata T, Pacifici L, Carminati P: Autonomic neuropathy in streptozotocin diabetic rats: effect of acetyl-L-carnitine. Diabetes Res Clin Pract 56: 173–180, 2002CrossRefPubMedGoogle Scholar
  7. 7.
    Hicks KK, Seifen E, Stimers JR, Kennedy RH: Effects of streptozotocin-induced diabetes on heart rate, blood pressure and cardiac autonomic nervous control. J Auton Nerv Syst 69: 21–30, 1998CrossRefPubMedGoogle Scholar
  8. 8.
    Li XS, Tanz RD, Chang KS: Effect of age and methacholine on the rate and coronary flow of isolated hearts of diabetic rats. Br J Pharmacol 97: 1209–1217, 1989PubMedGoogle Scholar
  9. 9.
    Hicks KK, Seifen E, Stimers JR, Kennedy RH: Diabetes with and without ketoacidosis on right atrial pacemaker rate and autonomic responsiveness. Am J Physiol 273: H1888–H1893, 1997PubMedGoogle Scholar
  10. 10.
    De Angelis KL, Oliveira AR, Dall'Ago P, Peixoto LR, Gadonski G, Lacchini S et al.: Effects of exercise training on autonomic and myocardial dysfunction in streptozotocin-diabetic rats. Braz J Med Biol Res 33: 635–641, 2000PubMedGoogle Scholar
  11. 11.
    Nemeth J, Szilvassy Z, Oroszi G, Porszasz R, Jakab B, Szolcsanyi J: Impaired capsaicin-induced decrease in heart rate and coronary flow in isolated heart of diabetic rats. Acta Physiol Hung 88: 207–218, 2001CrossRefPubMedGoogle Scholar
  12. 12.
    Kofo-Abayomi A, Lucas PD: A comparison between atria from control and streptozotocin-diabetic rats: the effects of dietary myoinositol. Br J Pharmacol 93: 3–8, 1988PubMedGoogle Scholar
  13. 13.
    Koelz HR: Protective drugs in the treatment of gastroduodenal ulcer disease. Scand J Gastroenterol Suppl 125:156–164, 1986Google Scholar
  14. 14.
    Campisi D, Cataldo MG, Paterna S, Bivona A, Barbarino C: Cytoprotective therapy of gastric ulcers: a controlled clinical evaluation of triletide versus carbenoxolone. Pharmatherapeutica 4: 166–170, 1985PubMedGoogle Scholar
  15. 15.
    Murthy K, Harrington JT, Siegel RD: Profound hypokalemia in diabetic ketoacidosis: a therapeutic challenge. Endocr Pract 11: 331–334, 2005PubMedGoogle Scholar
  16. 16.
    Heller SR, Robinson RT: Hypoglycaemia and associated hypokalaemia in diabetes: mechanisms, clinical implications and prevention. Diabetes Obes Metab 2: 75–82, 2000CrossRefPubMedGoogle Scholar
  17. 17.
    Shimoni Y, Firek L, Severson D, Giles W: Short-term diabetes alters K+ currents in rat ventricular myocytes. Circ Res 74: 620–628, 1994PubMedGoogle Scholar
  18. 18.
    Jourdon P, Feuvray D: Calcium and potassium currents in ventricular myocytes isolated from diabetic rats. J Physiol 470: 411–429, 1993PubMedGoogle Scholar
  19. 19.
    Magyar J, Rusznak Z, Szentesi P, Szucs G, Kovacs L: Action potentials and potassium currents in rat ventricular muscle during experimental diabetes. J Mol Cell Cardiol 24: 841–853, 1992CrossRefPubMedGoogle Scholar
  20. 20.
    Shimoni Y: Inhibition of the formation or action of angiotensin II reverses attenuated K+ currents in type 1 and type 2 diabetes. J Physiol 537: 83–92, 2001CrossRefPubMedGoogle Scholar
  21. 21.
    Bracken NK, Woodall AJ, Howarth FC, Singh J: Voltage-dependence of contraction in streptozotocin-induced diabetic myocytes. Mol Cell Biochem 261: 235–243, 2004CrossRefPubMedGoogle Scholar
  22. 22.
    de Groot JR, Veenstra T, Verkerk AO, Wilders R, Smits JP, Wilms-Schopman FJ et al.: Conduction slowing by the gap junctional uncoupler carbenoxolone. Cardiovasc Res 60: 288–297, 2003CrossRefPubMedGoogle Scholar
  23. 23.
    Howarth FC, Qureshi MA, White E: Effects of hyperosmotic shrinking on ventricular myocyte shortening and intracellular Ca(2+) in streptozotocin-induced diabetic rats. Pflügers Arch 444: 446–451, 2002CrossRefPubMedGoogle Scholar
  24. 24.
    van Kempen MJ, ten V, I, Wessels A, Oosthoek PW, Gros D, Jongsma HJ et al.: Differential connexin distribution accommodates cardiac function in different species. Microsc Res Tech 31: 420–436, 1995CrossRefPubMedGoogle Scholar
  25. 25.
    Darrow BJ, Laing JG, Lampe PD, Saffitz JE, Beyer EC: Expression of multiple connexins in cultured neonatal rat ventricular myocytes. Circ Res 76: 381–387, 1995PubMedGoogle Scholar
  26. 26.
    Gros D, Jarry-Guichard T, ten V, I, de Maziere A, van Kempen MJ, Davoust J et al.: Restricted distribution of connexin 40, a gap junctional protein, in mammalian heart. Circ Res 74: 839–851, 1994PubMedGoogle Scholar
  27. 27.
    de Maziere A, Analbers L, Jongsma HJ, Gros D: Immunoelectron microscopic visualization of the gap junction protein connexin 40 in the mammalian heart. Eur J Morphol 31: 51–54, 1993PubMedGoogle Scholar
  28. 28.
    Coppen SR, Dupont E, Rothery S, Severs NJ: Connexin45 expression is preferentially associated with the ventricular conduction system in mouse and rat heart. Circ Res 82: 232–243, 1998PubMedGoogle Scholar
  29. 29.
    Gourdie RG, Severs NJ, Green CR, Rothery S, Germroth P, Thompson RP: The spatial distribution and relative abundance of gap-junctional connexin40 and connexin43 correlate to functional properties of components of the cardiac atrioventricular conduction system. J Cell Sci 105: 985–991, 1993PubMedGoogle Scholar
  30. 30.
    van Kempen MJ, Fromaget C, Gros D, Moorman AF, Lamers WH: Spatial distribution of connexin43, the major cardiac gap junction protein, in the developing and adult rat heart. Circ Res 68: 1638–1651, 1991PubMedGoogle Scholar
  31. 31.
    Lerner DL, Yamada KA, Schuessler RB, Saffitz JE: Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in C×43-deficient mice. Circulation 101: 547–552, 2000PubMedGoogle Scholar
  32. 32.
    Gutstein DE, Morley GE, Tamaddon H, Vaidya D, Schneider MD, Chen J et al.: Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res 88: 333–339, 2001PubMedGoogle Scholar
  33. 33.
    Rodman JR, Harris MB, Rudkin AH, St John WM, Leiter JC: Gap junction blockade does not alter eupnea or gasping in the juvenile rat. Respir Physiol Neurobiol 2005 (EPUB ahead of print)Google Scholar
  34. 34.
    Whalley BJ, Postlethwaite M, Constant! A: Further characterization of muscarinic agonist-induced epileptiform bursting activity in immature rat piriform cortex, in vitro. Neuroscience 134: 549–566, 2005Google Scholar
  35. 35.
    Hosseinzadeh H, Asl MN, Parvardeh S, Tagi Mansouri SM: The effects of carbenoxolone on spatial learning in the Morris water maze task in rats. Med Sci Monit 11: BR88-BR94, 2005Google Scholar
  36. 36.
    Sharifullina E, Ostroumov K, Nistri A: Metabotropic glutamate receptor activity induces a novel oscillatory pattern in neonatal rat hypoglossal motoneurones. J Physiol 563: 139–159, 2005CrossRefPubMedGoogle Scholar
  37. 37.
    Pacher P, Ungvari Z, Nanasi PP, Kecskemeti V: Electrophysiological changes in rat ventricular and atrial myocardium at different stages of experimental diabetes. Acta Physiol Scand 166: 7–13, 1999CrossRefPubMedGoogle Scholar
  38. 38.
    Shimoni Y, Ewart HS, Severson D: Type I and II models of diabetes produce different modifications of K+ currents in rat heart: role of insulin. J Physiol 507: 485–496, 1998CrossRefPubMedGoogle Scholar
  39. 39.
    Shigematsu S, Maruyama T, Kiyosue T, Arita M: Rate-dependent prolongation of action potential duration in single ventricular myocytes obtained from hearts of rats with streptozotocin – induced chronic diabetes sustained for 30–32 weeks. Heart Vessels 9: 300–306, 1994CrossRefPubMedGoogle Scholar
  40. 40.
    Nobe S, Aomine M, Arita M, Ito S, Takaki R: Chronic diabetes mellitus prolongs action potential duration of rat ventricular muscles: circumstantial evidence for impaired Ca2+ channel. Cardiovasc Res 24: 381–389, 1990PubMedCrossRefGoogle Scholar
  41. 41.
    Pandit SV, Giles WR, Demir SS: A mathematical model of the electrophysiological alterations in rat ventricular myocytes in type-I diabetes. Biophys J 84: 832–841, 2003PubMedCrossRefGoogle Scholar
  42. 42.
    Conrath CE, Opthof T: Ventricular repolarization: An overview of (patho)physiology, sympathetic effects and genetic aspects. Prog Biophys Mol Biol 2005 (EPUB ahead of print)Google Scholar
  43. 43.
    Goodenough DA, Goliger JA, Paul DL: Connexins, connexons, and intercellular communication. Annu Rev Biochem 65: 475–502, 1996CrossRefPubMedGoogle Scholar
  44. 44.
    Crow JM, Atkinson MM, Johnson RG: Micromolar levels of intracellular calcium reduce gap junctional permeability in lens cultures. Invest Ophthalmol Vis Sci 35: 3332–3341, 1994PubMedGoogle Scholar
  45. 45.
    Lagadic-Gossmann D, Buckler KJ, Le Prigent K, Feuvray D: Altered Ca2+ handling in ventricular myocytes isolated from diabetic rats. Am J Physiol 270: H1529–H1537, 1996PubMedGoogle Scholar
  46. 46.
    Noda N, Hayashi H, Satoh H, Terada H, Hirano M, Kobayashi A et al.: Ca2+ transients and cell shortening in diabetic rat ventricular myocytes. Jpn Circ J 57: 449–457, 1993PubMedGoogle Scholar
  47. 47.
    Yu Z, Quamme GA, Mcneill JH: Depressed [Ca2+]i responses to isoproterenol and cAMP in isolated cardiomyocytes from experimental diabetic rats. Am J Physiol 266: H2334–H2342, 1994PubMedGoogle Scholar
  48. 48.
    Norby FL, Aberle NS, Kajstura J, Anversa P, Ren J: Transgenic overexpression of insulin-like growth factor I prevents streptozotocin-induced cardiac contractile dysfunction and beta-adrenergic response in ventricular myocytes. J Endocrinol 180: 175–182, 2004CrossRefPubMedGoogle Scholar
  49. 49.
    Ha T, Kotsanas G, Wendt I: Intracellular Ca2+ and adrenergic responsiveness of cardiac myocytes in streptozotocin-induced diabetes. Clin Exp Pharmacol Physiol 26: 347–353, 1999CrossRefPubMedGoogle Scholar
  50. 50.
    John S, Cesario D, Weiss JN: Gap junctional hemichannels in the heart. Acta Physiol Scand 179: 23–31, 2003CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Department of Physiology, Faculty of Medicine & Health SciencesUnited Arab Emirates UniversityAl AinU.A.E.

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