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. 1997 Oct 1;100(7):1782–1788. doi: 10.1172/JCI119705

Mechanism of hypoxic K loss in rabbit ventricle.

K Shivkumar 1, N A Deutsch 1, S T Lamp 1, K Khuu 1, J I Goldhaber 1, J N Weiss 1
PMCID: PMC508363  PMID: 9312178

Abstract

Although a critical factor causing lethal ischemic ventricular arrhythmias, net cellular K loss during myocardial ischemia and hypoxia is poorly understood. We investigated whether selective activation of ATP-sensitive K (KATP) channels causes net cellular K loss by examining the effects of the KATP channel agonist cromakalim on unidirectional K efflux, total tissue K content, and action potential duration (APD) in isolated arterially perfused rabbit interventricular septa. Despite increasing unidirectional K efflux and shortening APD to a comparable degree as hypoxia, cromakalim failed to induce net tissue K loss, ruling out activation of KATP channels as the primary cause of hypoxic K loss. Next, we evaluated a novel hypothesis about the mechanism of hypoxic K loss, namely that net K loss is a passive reflection of intracellular Na gain during hypoxia or ischemia. When the major pathways promoting Na influx were inhibited, net K loss during hypoxia was almost completely eliminated. These findings show that altered Na fluxes are the primary cause of net K loss during hypoxia, and presumably also in ischemia. Given its previously defined role during hypoxia and ischemia in promoting intracellular Ca overload and reperfusion injury, this newly defined role of intracellular Na accumulation as a primary cause of cellular K loss identifies it as a central pathogenetic factor in these settings.

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Selected References

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  1. Bridge J. H., Smolley J. R., Spitzer K. W. The relationship between charge movements associated with ICa and INa-Ca in cardiac myocytes. Science. 1990 Apr 20;248(4953):376–378. doi: 10.1126/science.2158147. [DOI] [PubMed] [Google Scholar]
  2. Chopra L. C., Twort C. H., Ward J. P. Direct action of BRL 38227 and glibenclamide on intracellular calcium stores in cultured airway smooth muscle of rabbit. Br J Pharmacol. 1992 Feb;105(2):259–260. doi: 10.1111/j.1476-5381.1992.tb14242.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cook G. A. The hypoglycemic sulfonylureas glyburide and tolbutamide inhibit fatty acid oxidation by inhibiting carnitine palmitoyltransferase. J Biol Chem. 1987 Apr 15;262(11):4968–4972. [PubMed] [Google Scholar]
  4. Drewnowska K., Baumgarten C. M. Regulation of cellular volume in rabbit ventricular myocytes: bumetanide, chlorothiazide, and ouabain. Am J Physiol. 1991 Jan;260(1 Pt 1):C122–C131. doi: 10.1152/ajpcell.1991.260.1.C122. [DOI] [PubMed] [Google Scholar]
  5. Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol. 1983 Jul;245(1):C1–14. doi: 10.1152/ajpcell.1983.245.1.C1. [DOI] [PubMed] [Google Scholar]
  6. Ferrero J. M., Jr, Sáiz J., Ferrero J. M., Thakor N. V. Simulation of action potentials from metabolically impaired cardiac myocytes. Role of ATP-sensitive K+ current. Circ Res. 1996 Aug;79(2):208–221. doi: 10.1161/01.res.79.2.208. [DOI] [PubMed] [Google Scholar]
  7. Fiolet J. W., Baartscheer A., Schumacher C. A., Coronel R., ter Welle H. F. The change of the free energy of ATP hydrolysis during global ischemia and anoxia in the rat heart. Its possible role in the regulation of transsarcolemmal sodium and potassium gradients. J Mol Cell Cardiol. 1984 Nov;16(11):1023–1036. doi: 10.1016/s0022-2828(84)80015-2. [DOI] [PubMed] [Google Scholar]
  8. Janse M. J., Wit A. L. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev. 1989 Oct;69(4):1049–1169. doi: 10.1152/physrev.1989.69.4.1049. [DOI] [PubMed] [Google Scholar]
  9. Ju Y. K., Saint D. A., Gage P. W. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996 Dec 1;497(Pt 2):337–347. doi: 10.1113/jphysiol.1996.sp021772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lazdunski M., Frelin C., Vigne P. The sodium/hydrogen exchange system in cardiac cells: its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH. J Mol Cell Cardiol. 1985 Nov;17(11):1029–1042. doi: 10.1016/s0022-2828(85)80119-x. [DOI] [PubMed] [Google Scholar]
  11. Luo C. H., Rudy Y. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ Res. 1994 Jun;74(6):1071–1096. doi: 10.1161/01.res.74.6.1071. [DOI] [PubMed] [Google Scholar]
  12. Luo C. H., Rudy Y. A model of the ventricular cardiac action potential. Depolarization, repolarization, and their interaction. Circ Res. 1991 Jun;68(6):1501–1526. doi: 10.1161/01.res.68.6.1501. [DOI] [PubMed] [Google Scholar]
  13. Mitani A., Shattock M. J. Role of Na-activated K channel, Na-K-Cl cotransport, and Na-K pump in [K]e changes during ischemia in rat heart. Am J Physiol. 1992 Aug;263(2 Pt 2):H333–H340. doi: 10.1152/ajpheart.1992.263.2.H333. [DOI] [PubMed] [Google Scholar]
  14. Nichols C. G., Ripoll C., Lederer W. J. ATP-sensitive potassium channel modulation of the guinea pig ventricular action potential and contraction. Circ Res. 1991 Jan;68(1):280–287. doi: 10.1161/01.res.68.1.280. [DOI] [PubMed] [Google Scholar]
  15. Reeve H. L., Vaughan P. F., Peers C. Glibenclamide inhibits a voltage-gated K+ current in the human neuroblastoma cell line SH-SY5Y. Neurosci Lett. 1992 Jan 20;135(1):37–40. doi: 10.1016/0304-3940(92)90130-y. [DOI] [PubMed] [Google Scholar]
  16. Satoh H., Delbridge L. M., Blatter L. A., Bers D. M. Surface:volume relationship in cardiac myocytes studied with confocal microscopy and membrane capacitance measurements: species-dependence and developmental effects. Biophys J. 1996 Mar;70(3):1494–1504. doi: 10.1016/S0006-3495(96)79711-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Shine K. I., Douglas A. M., Ricchiuti N. 42K exchange during myocardial ischemia. Am J Physiol. 1977 Jun;232(6):H564–H570. doi: 10.1152/ajpheart.1977.232.6.H564. [DOI] [PubMed] [Google Scholar]
  18. Silverman H. S., Stern M. D. Ionic basis of ischaemic cardiac injury: insights from cellular studies. Cardiovasc Res. 1994 May;28(5):581–597. doi: 10.1093/cvr/28.5.581. [DOI] [PubMed] [Google Scholar]
  19. Sipido K. R., Wier W. G. Flux of Ca2+ across the sarcoplasmic reticulum of guinea-pig cardiac cells during excitation-contraction coupling. J Physiol. 1991 Apr;435:605–630. doi: 10.1113/jphysiol.1991.sp018528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Tominaga M., Horie M., Sasayama S., Okada Y. Glibenclamide, an ATP-sensitive K+ channel blocker, inhibits cardiac cAMP-activated Cl- conductance. Circ Res. 1995 Aug;77(2):417–423. doi: 10.1161/01.res.77.2.417. [DOI] [PubMed] [Google Scholar]
  21. Undrovinas A. I., Fleidervish I. A., Makielski J. C. Inward sodium current at resting potentials in single cardiac myocytes induced by the ischemic metabolite lysophosphatidylcholine. Circ Res. 1992 Nov;71(5):1231–1241. doi: 10.1161/01.res.71.5.1231. [DOI] [PubMed] [Google Scholar]
  22. Venkatesh N., Lamp S. T., Weiss J. N. Sulfonylureas, ATP-sensitive K+ channels, and cellular K+ loss during hypoxia, ischemia, and metabolic inhibition in mammalian ventricle. Circ Res. 1991 Sep;69(3):623–637. doi: 10.1161/01.res.69.3.623. [DOI] [PubMed] [Google Scholar]
  23. Venkatesh N., Stuart J. S., Lamp S. T., Alexander L. D., Weiss J. N. Activation of ATP-sensitive K+ channels by cromakalim. Effects on cellular K+ loss and cardiac function in ischemic and reperfused mammalian ventricle. Circ Res. 1992 Dec;71(6):1324–1333. doi: 10.1161/01.res.71.6.1324. [DOI] [PubMed] [Google Scholar]
  24. Watanabe I., Johnson T. A., Engle C. L., Graebner C., Jenkins M. G., Gettes L. S. Effects of verapamil and propranolol on changes in extracellular K+, pH, and local activation during graded coronary flow in the pig. Circulation. 1989 Apr;79(4):939–947. doi: 10.1161/01.cir.79.4.939. [DOI] [PubMed] [Google Scholar]
  25. Weiss J. N., Lamp S. T., Shine K. I. Cellular K+ loss and anion efflux during myocardial ischemia and metabolic inhibition. Am J Physiol. 1989 Apr;256(4 Pt 2):H1165–H1175. doi: 10.1152/ajpheart.1989.256.4.H1165. [DOI] [PubMed] [Google Scholar]
  26. Weiss J. N., Shieh R. C. Potassium loss during myocardial ischaemia and hypoxia: does lactate efflux play a role? Cardiovasc Res. 1994 Aug;28(8):1125–1132. doi: 10.1093/cvr/28.8.1125. [DOI] [PubMed] [Google Scholar]
  27. Weiss J. N., Venkatesh N., Lamp S. T. ATP-sensitive K+ channels and cellular K+ loss in hypoxic and ischaemic mammalian ventricle. J Physiol. 1992 Feb;447:649–673. doi: 10.1113/jphysiol.1992.sp019022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Weiss J., Shine K. I. Effects of heart rate on extracellular [K+] accumulation during myocardial ischemia. Am J Physiol. 1986 Jun;250(6 Pt 2):H982–H991. doi: 10.1152/ajpheart.1986.250.6.H982. [DOI] [PubMed] [Google Scholar]
  29. Weiss J., Shine K. I. Extracellular K+ accumulation during myocardial ischemia in isolated rabbit heart. Am J Physiol. 1982 Apr;242(4):H619–H628. doi: 10.1152/ajpheart.1982.242.4.H619. [DOI] [PubMed] [Google Scholar]
  30. Wilde A. A., Aksnes G. Myocardial potassium loss and cell depolarisation in ischaemia and hypoxia. Cardiovasc Res. 1995 Jan;29(1):1–15. [PubMed] [Google Scholar]
  31. Wilde A. A., Escande D., Schumacher C. A., Thuringer D., Mestre M., Fiolet J. W., Janse M. J. Potassium accumulation in the globally ischemic mammalian heart. A role for the ATP-sensitive potassium channel. Circ Res. 1990 Oct;67(4):835–843. doi: 10.1161/01.res.67.4.835. [DOI] [PubMed] [Google Scholar]
  32. Yan G. X., Chen J., Yamada K. A., Kléber A. G., Corr P. B. Contribution of shrinkage of extracellular space to extracellular K+ accumulation in myocardial ischaemia of the rabbit. J Physiol. 1996 Jan 1;490(Pt 1):215–228. doi: 10.1113/jphysiol.1996.sp021137. [DOI] [PMC free article] [PubMed] [Google Scholar]

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