[$Ca^{2+}-induced$ $Ca^{2+}$ Release from Sarcoplasmic Reticulum Negatively Regulates Myocytic ANP Release in Beating Rabbit Atria

  • Li, Dan (Department of Physiology, Institute for Medical Sciences, Institute for Basic Sciences, Jeonbug National University Medical School) ;
  • Quan, He Xiu (Department of Physiology, Institute for Medical Sciences, Institute for Basic Sciences, Jeonbug National University Medical School) ;
  • Wen, Jin-Fu (Department of Physiology, Institute for Medical Sciences, Institute for Basic Sciences, Jeonbug National University Medical School) ;
  • Jin, Jing-Yu (Department of Physiology, Institute for Medical Sciences, Institute for Basic Sciences, Jeonbug National University Medical School) ;
  • Park, Sung-Hun (Department of Physiology, Institute for Medical Sciences, Institute for Basic Sciences, Jeonbug National University Medical School) ;
  • Kim, Sun-Young (Department of Physiology, Institute for Medical Sciences, Institute for Basic Sciences, Jeonbug National University Medical School) ;
  • Kim, Sung-Zoo (Department of Physiology, Institute for Medical Sciences, Institute for Basic Sciences, Jeonbug National University Medical School) ;
  • Cho, Kyung-Woo (Department of Physiology, Institute for Medical Sciences, Institute for Basic Sciences, Jeonbug National University Medical School)
  • Published : 2005.04.21


It is not clear whether $Ca^{2+}-induced$ $Ca^{2+}$ release from the sarcoplasmic reticulum (SR) is involved in the regulation of atrial natriuretic peptide (ANP) release. Previously, we have shown that nifedipine increased ANP release, indicating that $Ca^{2+}$ entry via voltage-gated L-type $Ca^{2+}$ channel activation decreases ANP release. The purpose of the present study was two-fold: to define the role of SR $Ca^{2+}$ release in the regulation of ANP release and whether $Ca^{2+}$ entry via L-type $Ca^{2+}$ channel is prerequisite for the SR-related effect on ANP release. Experiments were performed in perfused beating rabbit atria. Ryanodine, an inhibitor of SR $Ca^{2+}$ release, increased atrial myocytic ANP release ($8.69{\pm}3.05$, $19.55{\pm}1.09$, $27.31{\pm}3.51$, and $18.91{\pm}4.76$% for 1, 2, 3, and $6{\mu}M$ ryanodine, respectively; all P<0.01) with concomitant decrease in atrial stroke volume and pulse pressure in a dose-dependent manner. In the presence of thapsigargin, an inhibitor of SR $Ca^{2+}$ pump, ryanodine-induced increase in ANP release was not observed. Thapsigargin attenuated ryanodine-induced decrease in atrial dynamic changes. Blockade of L-type $Ca^{2+}$ channel with nifedipine abolished ryanodine-induced increase in ANP release ($0.69{\pm}5.58$% vs. $27.31{\pm}3.51$%; P<0.001). In the presence of thapsigargin and ryanodine, nifedipine increased ANP release and decreased atrial dynamics. These data suggest that $Ca^{2+}$-induced $Ca^{2+}$ release from the SR is inversely involved in the regulation of atrial myocytic ANP release.


  1. Cui X, Wen JF, Jin H, Li D, Jin JY, Kim SH, Kim SZ, Lee HS, Cho KW. Subtype-specific roles of cAMP phosphodiesterases in regulation of atrial natriuretic peptide release. Eur J Pharmacol 451: 295-302, 2002 https://doi.org/10.1016/S0014-2999(02)02294-X
  2. Delgado C, Artiles A, Gomez AM, Vassort G. Frequency-dependent increase in cardiac $Ca^{2+}$ current is due to reduced $Ca^{2+}$ release by the sarcoplasmic reticulum. J Mol Cell Cardiol 31: 1783-1793, 1999 https://doi.org/10.1006/jmcc.1999.1023
  3. Doubell AF, Thibault G. Calcium is involved in both positive and negative modulation of the secretory system for ANP. Am J Physiol 266: H1854-H1863, 1994
  4. Hueser J, Lipsius SL, Blatter LA. Calcium gradients during excitation-contraction coupling in cat atrial myocytes. J Physiol 494: 641-651, 1996 https://doi.org/10.1113/jphysiol.1996.sp021521
  5. Hunton DL, Zou LY, Pang Y, Marchase RB. Adult rat cardiomyocytes exhibit capacitative calcium entry. Am J Physiol Heart Circ Physiol 286: H1124-H1132, 2004 https://doi.org/10.1152/ajpheart.00162.2003
  6. Ito T, Toki Y, Siegel N, Gierse JK, Needleman P. Manipulation of stretch-induced atriopeptin prohormone release and processing in the perfused rat heart. Proc Natl Acad Sci USA 85: 8365-8369, 1988 https://doi.org/10.1073/pnas.85.21.8365
  7. Lee SJ, Kim SZ, Cui X, Kim SH, Lee KS, Chung YJ, Cho KW. C-type natriuretic peptide inhibits ANP secretion and atrial dynamics in perfused atria: NPR-B-cGMP signaling. Am J Physiol Heart Circ Physiol 278: H208-H221, 2000 https://doi.org/10.1152/ajpheart.2000.278.1.H208
  8. Ruskoaho H, Vuolteenaho O, Leppaluoto J. Phorbol esters enhance stretch-induced atrial natriuretic peptide secretion. Endocrinology 127: 2445-2455, 1990 https://doi.org/10.1210/endo-127-5-2445
  9. Schiebinger RJ. Calcium, its role in isoproterenol-stimulated atrial natriuretic peptide secretion by superfused rat atria. Circ Res 65: 600-606, 1989 https://doi.org/10.1161/01.RES.65.3.600
  10. Schiebinger RJ, Li Y, Cragoe EJ Jr. Calcium dependency of frequency-stimulated atrial natriuretic peptide secretion. Hypertension 23: 710-716, 1994 https://doi.org/10.1161/01.HYP.23.6.710
  11. Taskinen P, Ruskoaho H. Stretch-induced increase in atrial natriuretic peptide secretion is blocked by thapsigargin. Eur J Pharmacol 308: 295-300, 1996 https://doi.org/10.1016/0014-2999(96)00328-7
  12. Yamasaki Y, Furuya Y, Araki K, Matsuura K, Kobayashi M, Ogata T. Ultra-high-resolution scanning electron microscopy of the sarcoplasmic reticulum of the rat atrial myocardial cells. Anat Rec 248: 70-75, 1997 https://doi.org/10.1002/(SICI)1097-0185(199705)248:1<70::AID-AR8>3.0.CO;2-J
  13. Kockskaemper J, Sheehan KA, Bare DJ, Lipsius SL, Mignery GA, Blatter LA. Activation and propagation of $Ca^{2+}$ release during excitation-contraction coupling in atrial myocytes. Biophys J 81: 2590-2605, 2001 https://doi.org/10.1016/S0006-3495(01)75903-6
  14. Pang Y, Hunton DL, Bounelis P, Marchase RB. Hyperglycemia inhibits capacitative calcium entry and hypertrophy in neonatal cardiomyocytes. Diabetes 51: 3461-3467, 2002 https://doi.org/10.2337/diabetes.51.12.3461
  15. Ruskoaho H, Toth M, Ganten D, Unger Th, Lang RE. The phorbol ester induced atrial natriuretic peptide secretion is stimulated by forskolin and BAY K 8644 and inhibited by 8-bromo-cyclic GMP. Biochem Biophys Res Commun 139: 266-274, 1986 https://doi.org/10.1016/S0006-291X(86)80108-5
  16. Bers DM. Calcium fluxes involved in control of cardiac myocyte contraction. Circ Res 87: 275-281, 2000 https://doi.org/10.1161/01.RES.87.4.275
  17. Sheehan KA, Blatter LA. Regulation of junctional and non-junctional sarcoplasmic reticulum calcium release in excitation-contraction coupling in cat atrial myocytes. J Physiol 546: 119-135, 2003 https://doi.org/10.1113/jphysiol.2002.026963
  18. McNutt NS, Fawcett DW. The ultrastructure of the cat myocardium. II. Atrial muscle. J Cell Biol 42: 46-67, 1969 https://doi.org/10.1083/jcb.42.1.46
  19. Cleemann L, Morad M. Role of $Ca^{2+}$ channel in cardiac excitationcontraction coupling in the rat: evidence from $Ca^{2+}$ transients and contraction. J Physiol 432: 283-312, 1991 https://doi.org/10.1113/jphysiol.1991.sp018385
  20. Kim SH, Cho KW, Chang SH, Kim SZ, Chae SW. Glibenclamide suppresses stretch-activated ANP secretion: involvements of $K^+_{ATP}$ channel and L-type $Ca^{2+}$ channel modulation. Pflugers Arch 434:362-372, 1997 https://doi.org/10.1007/s004240050409
  21. Church DJ, Rebsamen MC, Morabito D, Van der Bent V, Vallotton MB, Lang U. Role of cell contractions in cAMP-induced cardiomyocyte atrial natriuretic peptide release. Am J Physiol Heart Circ Physiol 278: H117-H125, 2000 https://doi.org/10.1152/ajpheart.2000.278.1.H117
  22. Hunton DL, Lucchesi PA, Pang Y, Cheng X, DellItalia LJ, Marchase RB. Capacitative calcium entry contributes to nuclear factor of activated T-cells nuclear translocation and hypertrophy in cardiomyocytes. J Biol Chem 277: 14266-14273, 2002 https://doi.org/10.1074/jbc.M107167200
  23. Cho KW, Lee SJ, Wen JF, Kim SH, Seul KH, Lee HS. Mechanical control of extracellular space in rabbit atria: an intimate modulator of the translocation of extracellular fluid and released atrial natriuretic peptide. Exp Physiol 87: 185-194, 2002 https://doi.org/10.1113/eph8702302
  24. Iida H, Page E. Determinants of atrial natriuretic peptide secretion in cultured atrial myocytes. Am J Physiol 256: C608-C613, 1989 https://doi.org/10.1152/ajpcell.1989.256.3.C608
  25. Laine M, Weckstrom M, Vuolteenaho O, Arjamaa O. Effect of ryanodine on atrial natriuretic peptide secretion by contracting and quiescent rat atrium. Pflugers Arch 426: 276-283, 1994. https://doi.org/10.1007/BF00374782
  26. Lipp P, Pott L, Callewaert G, Carmeliet E. Simultaneous recording of Indo-1 fluorescence and $Na^+/Ca^{2+}$ exchange currents reveals two components of $Ca^{2+}$-release from sarcoplasmic reticulum of cardiac atrial myocytes. FEBS Lett 275: 181-184, 1990 https://doi.org/10.1016/0014-5793(90)81467-3
  27. McDonough PM, Stella SL, Glembotski CC. Involvement of cytoplasmic calcium and protein kinases in the regulation of atrial natriuretic factor secretion by contraction rate and endothelin. J Biol Chem 269: 9466-9472, 1994
  28. Cho KW, Kim SH, Kim CH, Seul KH. Mechanical basis of atrial natriuretic peptide secretion in beating atria: atrial stroke volume and ECF translocation. Am J Physiol Regul Integr Comp Physiol 268: R1129-R1136, 1995 https://doi.org/10.1152/ajpregu.1995.268.5.R1129
  29. Bers DM, Lederer WJ, Berlin JR. Intracellular $Ca^{2+}$ transients in rat cardiac myocytes: role of Na-Ca exchange in excitationcontraction coupling. Am J Physiol 258: C944-C954, 1990 https://doi.org/10.1152/ajpcell.1990.258.5.C944
  30. Lewis Carl S, Felix K, Caswell AH, Brandt NR, Ball WJ Jr, Vaghy PL, Meissner G, Ferguson DG. Immunolocalization of sarcolemmal dihydropyridine receptor and sarcoplasmic reticular triadin and ryanodine receptor in rabbit ventricle and atrium. J Cell Biol 129: 673-682, 1995 https://doi.org/10.1083/jcb.129.3.673
  31. Nario K, Satoh H. Cardiac mechanical and electrophysiologic modulations of guinea-pig by caffeine and thapsigargin. Gen Pharmac 27: 1227-1235, 1996 https://doi.org/10.1016/0306-3623(95)02138-8
  32. Page E, Goings GE, Power B, Upshaw-Earley J. Basal and stretchaugmented natriuretic peptide secretion by quiescent rat atria. Am J Physiol 259: C801-C818, 1990 https://doi.org/10.1152/ajpcell.1990.259.5.C801
  33. Deng Y, Lang R. The influence of calcium on ANF release in the isolated rat atrium. Can J Physiol Pharmacol 70: 1057-1060, 1992 https://doi.org/10.1139/y92-145
  34. Dietz JR. Release of natriuretic factor from rat heart-lung preparation by atrial distension. Am J Physiol 247: R1093-R1096, 1984
  35. Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 245: C1-C14, 1983 https://doi.org/10.1152/ajpcell.1983.245.1.C1
  36. Kuroski-De Bold ML, De Bold AJ. Stretch-secretion coupling in atrial cardiocytes. Dissociation between atrial natriuretic factor and mechanical activity. Hypertension 18 (suppl III): III169-III178, 1991 https://doi.org/10.1161/01.HYP.18.5_Suppl.III169
  37. Wen JF, Cui X, Jin JY, Kim SM, Kim SZ, Kim SH, Lee HS, Cho KW. High and low gain switches for regulation of cAMP efflux concentration. Distinct roles for particulate GC- and soluble GC-cGMP-PDE3 signaling in rabbit atria. Circ Res 94: 936-943, 2004 https://doi.org/10.1161/01.RES.0000123826.70125.4D
  38. Woo SH, Cleemann L, Morad M. Spatiotemporal characteristics of junctional and nonjunctional focal $Ca^{2+}$ release in rat atrial myocytes. Circ Res 92: e1-e11, 2003 https://doi.org/10.1161/01.RES.0000052925.89426.09
  39. Overend CL, ONeill SC, Eisner DA. The effect of tetracaine on stimulated contractions, sarcoplasmic reticulum $Ca^{2+}$ content and membrane current in isolated rat ventricular myocytes. J Physiol 507: 759-769, 1998. https://doi.org/10.1111/j.1469-7793.1998.759bs.x
  40. Saito Y, Nakao K, Morii N, Sugawara A, Shiono S, Yamada T, Itoh H, Sakamoto M, Kurahashi K, Fujiwara M, Imura H. BAY K 8644, a voltage sensitive calcium channel agonist, facilitates secretion of atrial natriuretic peptide from isolated perfused rat hearts. Biochem Biophys Res Commun 138: 1170-1176, 1986 https://doi.org/10.1016/S0006-291X(86)80405-3
  41. Bassani JWM, Bassani RA, Bers DM. Twitch-dependent SR Ca accumulation and release in rabbit ventricular myocytes. Am J Physiol 265: C533-C540, 1993 https://doi.org/10.1152/ajpcell.1993.265.2.C533
  42. Katoh S, Toyama J, Aoyama M, Miyamoto N, Seo H, Matsui N, Kodama I, Yamada K. Mechanisms of atrial natriuretic peptide (ANP) secretion in rat hearts perfused in vitro- $Ca^{2+}$-dependent signal transduction for ANP release by mechanical stretch. Jpn Circ J 54: 1283-1294, 1990 https://doi.org/10.1253/jcj.54.10_1283
  43. Lang RE, Thoelken H, Ganten D, Luft FC, Ruskoaho H, Unger T. Atrial natriuretic factor: a circulating hormone stimulated by volume loading. Nature 314: 264-266, 1985. https://doi.org/10.1038/314264a0
  44. Wen JF, Cui X, Ahn JS, Kim SH, Seul KH, Kim SZ, Park YK, Lee HS, Cho KW. Distinct roles for L- and T-type $Ca^{2+}$ channels in regulation of atrial ANP release. Am J Physiol Heart Circ Physiol 279: H2879-H2888, 2000 https://doi.org/10.1152/ajpheart.2000.279.6.H2879
  45. De Bold ML, De Bold AJ. Effect of manipulations of $Ca^{2+}$ environment on atrial natriuretic factor release. Am J Physiol 256: H1588-H1594, 1989