Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibition of L-type Ca2+ current by ginsenoside Rd in rat ventricular myocytes

  • Lu, Cheng (Department of Otorhinolaryngology, Beijing Friendship Hospital Affiliated to Capital Medical University) ;
  • Sun, Zhijun (Department of Cardiology, Beijing Friendship Hospital Affiliated to Capital Medical University) ;
  • Wang, Line (Department of Otorhinolaryngology, Beijing Friendship Hospital Affiliated to Capital Medical University)
  • Received : 2014.05.14
  • Accepted : 2014.11.02
  • Published : 2015.04.15
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Ginsenoside Rd (GSRd), one of the most abundant ingredients of Panax ginseng, protects the heart via multiple mechanisms including the inhibition of $Ca^{2+}$ influx.We intended to explore the effects of GSRd on L-type $Ca^{2+}$ current ($I_{Ca,L}$) and define the mechanism of the suppression of $I_{Ca,L}$ by GSRd. Methods: Perforated-patch recording and whole-cell voltage clamp techniques were applied in isolated rat ventricular myocytes. Results: (1) GSRd reduced $I_{Ca,L}$ peak amplitude in a concentration-dependent manner [half-maximal inhibitory concentration $(IC_{50})=32.4{\pm}7.1{\mu}mol/L$] and up-shifted the current-voltage (I-V) curve. (2) GSRd ($30{\mu}mol/L$) significantly changed the steady-state activation curve of $I_{Ca,L}$ ($V_{0.5}:-19.12{\pm}0.68$ vs. $-6.26{\pm}0.38mV$; n = 5, p < 0.05) and slowed down the recovery of $I_{Ca,L}$ from inactivation [the time content (${\zeta}$) from 91 ms to 136 ms, n = 5, p < 0.01]. (3) A more significant inhibitive effect of GSRd ($100{\mu}mol/L$) was identified in perforated-patch recording when compared with whole-cell recording [$65.7{\pm}3.2%$ (n = 10) vs. $31.4{\pm}5.2%$ (n = 5), p < 0.01]. (4) Pertussis toxin ($G_i$ protein inhibitor) completely abolished the $I_{Ca,L}$ inhibition induced by GSRd. There was a significant difference in inhibition potency between the two cyclic adenosine monophosphate elevating agents (isoprenaline and forskolin) prestimulation [$55{\pm}7.8%$ (n = 5) vs. $17.2{\pm}3.5%$ (n = 5), p < 0.01]. (5) 1H-[1,2,4]Oxadiazolo[4,3-a]-quinoxalin-1-one (a guanylate cyclase inhibitor) and N-acetyl-$\small{L}$-cysteine (a nitric oxide scavenger) partly recovered the $I_{Ca,L}$ inhibition induced by GSRd. (6) Phorbol-12-myristate-13-acetate (a protein kinase C activator) and GF109203X (a protein kinase C inhibitor) did not contribute to the inhibition of GSRd. Conclusion: These findings suggest that GSRd could inhibit $I_{Ca,L}$ through pertussis toxin-sensitive G protein ($G_i$) and a nitric oxide-cyclic guanosine monophosphate-dependent mechanism.

Keywords

References

  1. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-93. https://doi.org/10.1016/S0006-2952(99)00212-9
  2. Chen X, Gillis CN, Moalli R. Vascular effects of ginsenosides in vitro. Br J Pharmacol 1984;82:485-91. https://doi.org/10.1111/j.1476-5381.1984.tb10784.x
  3. Chen X. Cardiovascular protection by ginsenosides and their nitric oxide releasing action. Clin Exp Pharmacol Physiol 1996;23:728-32. https://doi.org/10.1111/j.1440-1681.1996.tb01767.x
  4. Kim MK, Lee JW, Lee KY, Yang DC. Microbial conversion of major ginsenoside Rb(1) to pharmaceutically active minor ginsenoside Rd. J Microbiol 2005;43: 456-62.
  5. Ye R, Zhao G, Liu X. Ginsenoside Rd for acute ischemic stroke: translating from bench to bedside. Expert Rev Neurother 2013;13:603-13. https://doi.org/10.1586/ern.13.51
  6. Wang Y, Li X, Wang X, Lau W, Wang Y, Xing Y, Zhang X, Ma X, Gao F. Ginsenoside Rd attenuates myocardial ischemia/reperfusion injury via Akt/GSK- 3${\beta}$ signaling and inhibition of the mitochondria-dependent apoptotic pathway. PLoS One 2013;8:e70956. https://doi.org/10.1371/journal.pone.0070956
  7. Guan YY, Zhou JG, Zhang Z, Wang GL, Cai BX, Hong L, Qiu QY, He H. Ginsenoside- Rd from Panax notoginseng blocks $Ca^{2+}$ influx through receptor- and store-operated $Ca^{2+}$ channels in vascular smooth muscle cells. Eur J Pharmacol 2006;548:129-36. https://doi.org/10.1016/j.ejphar.2006.08.001
  8. Meng HX, Wang B, Liu JX. Effect of salvianolic acid B and tetrahydropalmatine on the L-type calcium channel of rat ventricular myocytes. Zhongguo Zhong Xi Yi Jie He Za Zhi 2011;31:1514-7.
  9. Meng HX, Wang B, Liu JX. Recording L-type calcium channel current by perforated patch clamp and effect of dehydrocorydaline on L-type calcium channel. Chin Pharmacol Bull 2011;27:1051-4.
  10. Zhang ZS, Cheng HJ, Onishi K, Ohte N, Wannenburg T, Cheng CP. Enhanced inhibition of L-type $Ca^{2+}$ current by beta3-adrenergic stimulation in failing rat heart. J Pharmacol Exp Ther 2005;315:1203-11. https://doi.org/10.1124/jpet.105.089672
  11. Kashihara T, Nakada T, Shimojo H, Horiuchi-Hirose M, Gomi S, Shibazaki T, Sheng X, Hirose M, Hongo M, Yamada M. Chronic receptor-mediated activation of $G_{i/o}$ proteins alters basal t-tubular and sarcolemmal L-type $Ca^{2+}$ channel activity through phosphatases in heart failure. Am J Physiol Heart Circ Physiol 2012;302:1645-54. https://doi.org/10.1152/ajpheart.00589.2011
  12. Zhu W, Zeng X, Zheng M, Xiao RP. The enigma of beta2-adrenergic receptor Gi signaling in the heart: the good, the bad, and the ugly. Circ Res 2005;97:507-9. https://doi.org/10.1161/01.RES.0000184615.56822.bd
  13. Li HY, Bian JS, Kwan YW, Wong TM. Enhanced responses to 17beta-estradiol in rat hearts treated with isoproterenol: involvement of a cyclic AMPdependent pathway. J Pharmacol Exp Ther 2000;293:592-8.
  14. Skeberdis VA, Jurevicius J, Fischmeister AR. Beta-2 adrenergic activation of Ltype $Ca^{2+}$ current in cardiac myocytes. J Pharmacol Exp Ther 1997;283:452-61.
  15. Bai CX, Sunami A, Namiki T, Sawanobori T, Furukawa T. Electrophysiological effects of ginseng and ginsenoside Re in guinea pig ventricular myocytes. Eur J Pharmacol 2003;476:35-44. https://doi.org/10.1016/S0014-2999(03)02174-5
  16. Zhang HY, Liao P, Wang JJ, Yu de J, Soong TW. Alternative splicing modulates diltiazem sensitivity of cardiac and vascular smooth muscle Ca(v)1.2 calcium channels. Br J Pharmacol 2010;160:1631-40. https://doi.org/10.1111/j.1476-5381.2010.00798.x
  17. Liao P, Zhang HY, Soong TW. Alternative splicing of voltage-gated calcium channels: from molecular biology to disease. Pflugers Arch 2009;458:481-7. https://doi.org/10.1007/s00424-009-0635-5
  18. Liao P, Yong TF, Liang MC, Yue DT, Soong TW. Splicing for alternative structures of Cav1.2 $Ca^{2+}$ channels in cardiac and smooth muscles. Cardiovasc Res 2005;68:197-203. https://doi.org/10.1016/j.cardiores.2005.06.024
  19. Zahradnik I, Minarovic I, Zahradníkova A. Inhibition of the cardiac L-type calcium channel current by antidepressant drugs. J Pharmacol Exp Ther 2008;324:977-84.
  20. Treinys R, Jurevicius J. L-type $Ca^{2+}$ channels in the heart: structure and regulation. Medicina (Kaunas) 2008;44:491-9. https://doi.org/10.3390/medicina44070064
  21. Nah SY, McCleskey EW. Ginseng root extract inhibits calcium channels in rat sensory neurons through a similar path, but different receptor, as mu-type opioids. J Ethnopharmacol 1994;42:45-51. https://doi.org/10.1016/0378-8741(94)90022-1
  22. Nah SY, Park HJ, McCleskey EW. A trace component of ginseng that inhibits $Ca^{2+}$ channels through a pertussis toxin-sensitive G protein. Proc Natl Acad Sci U S A 1995;92:8739-43. https://doi.org/10.1073/pnas.92.19.8739
  23. Jo SH, Leblais V, Wang PH, Crow MT, Xiao RP. Phosphatidylinositol 3-kinase functionally compartmentalizes the concurrent G(s) signaling during beta2- adrenergic stimulation. Circ Res 2002;91:46-53. https://doi.org/10.1161/01.RES.0000024115.67561.54
  24. Dedkova EN, Wang YG, Blatter LA, Lipsius SL. Nitric oxide signaling by selective beta(2)-adrenoceptor stimulation prevents ACh-induced inhibition of beta(2)- stimulated Ca(2+) current in cat atrial myocytes. Circ Res 2005;97:566-73. https://doi.org/10.1161/01.RES.0000181160.31851.05
  25. Lu Z, Jiang YP, Xu XH, Ballou LM, Cohen IS, Lin RZ. Decreased L-type $Ca^{2+}$ current in cardiac myocytes of type 1 diabetic Akita mice due to reduced phosphatidylinositol 3-kinase signaling. Diabetes 2007;56:2780-9. https://doi.org/10.2337/db06-1629
  26. He JQ, Balijepalli RC, Haworth RA, Kamp TJ. Crosstalk of beta-adrenergic receptor subtypes through $G_{i}$ blunts beta-adrenergic stimulation of L-type $Ca^{2+}$ channels in canine heart failure. J Physiol 2002;542:711-23. https://doi.org/10.1113/jphysiol.2002.023341
  27. Gallo MP, Malan D, Bedendi I, Biasin C, Alloatti G, Levi RC. Regulation of cardiac calcium current by NO and cGMP-modulating agents. Pflugers Arch 2001;441:621-8. https://doi.org/10.1007/s004240000475
  28. Ziolo MT, Lewandowski SJ, Smith JM, Romano FD, Wahler GM. Inhibition of cyclic GMP hydrolysis with zaprinast reduces basal and cyclic AMP-elevated L-type calcium current in guinea-pig ventricular myocytes. Br J Pharmacol 2003;138:986-94. https://doi.org/10.1038/sj.bjp.0705112
  29. Hartzell HC, Fischmeister R. Opposite effects of cyclic GMP and cyclic AMP on Ca current in single heart cells. Nature 1986;323:273-5. https://doi.org/10.1038/323273a0
  30. Rose RA, Giles WR. Natriuretic peptide C receptor signalling in the heart and vasculature. J Physiol 2008;586:353-66. https://doi.org/10.1113/jphysiol.2007.144253
  31. Kurokawa H, Murray PA, Damron DS. Propofol attenuates beta- adrenoreceptor- mediated signal transduction via a protein kinase C-dependent pathway in cardiomyocytes. Anesthesiology 2002;96:688-98. https://doi.org/10.1097/00000542-200203000-00027
  32. Weiss S, Doan T, Bernstein KE, Dascal N. Modulation of cardiac $Ca^{2+}$ channel by Gq-activating neurotransmitters reconstituted in Xenopus oocytes. J Biol Chem 2004;279:12503-10. https://doi.org/10.1074/jbc.M310196200
  33. Satin J. The long and short of PKC modulation of the L-type calcium channel. Channels (Austin) 2013;7:57-8. https://doi.org/10.4161/chan.24147
  34. Tamura T, Cui X, Sakaguchi N, Akashi M. Ginsenoside Rd prevents and rescues rat intestinal epithelial cells from irradiation-induced apoptosis. Food Chem Toxicol 2008;46:3080-90. https://doi.org/10.1016/j.fct.2008.06.011

Cited by

  1. YiQiFuMai Powder Injection Attenuates Coronary Artery Ligation-Induced Heart Failure Through Improving Mitochondrial Function via Regulating ROS Generation and CaMKII Signaling Pathways vol.10, pp.None, 2015, https://doi.org/10.3389/fphar.2019.00381
  2. The Advances on the Protective Effects of Ginsenosides on Myocardial Ischemia and Ischemia-Reperfusion Injury vol.20, pp.16, 2020, https://doi.org/10.2174/1389557520666200619115444