Skip to main content
SpringerLink
Log in

Quinine and quinidine inhibit and reveal heterogeneity of K-Cl cotransport in low K sheep erythrocytes

  • Articles
  • Published:
The Journal of Membrane Biology Aims and scope Submit manuscript

Abstract

Low K (LK) sheep red blood cells (SRBCs) serve as a model to study K-Cl cotransport which plays an important role in cellular dehydration in human erythrocytes homozygous for hemoglobin S. Cinchona bark derivatives, such as quinine (Q) and quinidine (QD), are effectively used in the treatment of malaria. In the present study, we investigated in LK SRBCs, the effect of various concentrations of Q and QD on Cl-dependent K efflux and Rb influx (K(Rb)-Cl flux), activated by either swelling in hyposmotic media, thiol alkylation with N-ethylmaleimide (NEM), or by cellular Mg (Mg i ) removal through A23187 in the presence of external chelators. K efflux or Rb influx were determined in Cl and NO3 medium and K(Rb)-Cl flux was defined as the Cl-dependent (Cl minus NO3) component. K(Rb)-Cl flux stimulated by all three interventions was inhibited by both Q and QD in a dose-dependent manner. Maximum inhibition of K(Rb)-Cl flux occurred at Q and QD concentrations ⩾1 mm. The inhibitory effect of Q was manifested in Cl, but not in NO3, whereas QD reduced K and Rb fluxes both in Cl and NO3 media. The mean 50% inhibitory concentration (IC50) of Q and QD to inhibit K(Rb)-Cl flux varied between 0.23 and 2.24 mm. From determinations of the percentages of inhibition of the different components of K and Rb fluxes, we found that SRBCs possess a Cl-dependent QD-sensitive and a Cl-dependent QD-insensitive K efflux and Rb influx. These two components vary in magnitude depending on the manipulation and directional flux, but in average they are about 50% of the total Cl-dependent flux. This study raises the possibility that, in SRBCs, the Cl-dependent K(Rb) fluxes are heterogeneous.

This work was supported by a grant from the National Institutes of Health (NIH DK5RO1 37,160).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Adragna, N.C., Lauf, P.K. 1994. Quinine and quinidine inhibit K-Cl cotransport in low K sheep erythrocytes. Biophys. J. 66:A32 (Abstr.)

    Google Scholar 

  2. Ahmad, S., Phillips, R.S., Stammer, C.H. 1992. Inhibition of pig kidney L-aromatic aminoacid decarboxylase by 2,3-methano-mtyrosines. J. Med. Chem. 35:1410–1417

    Google Scholar 

  3. Bookchin, R.M., Ortiz, O.E., Lew, V.L. 1991. Evidence for a direct reticulocyte origin of dense red cells in sickle cell anemia. J. Clin. Invest. 87:113–124

    Google Scholar 

  4. Brugnara, C., Van Ha, T., Tosteson, D.C. 1989. Role of chloride in potassium transport through a K-Cl cotransport system in human red cells. Am. J. Physiol. 256:C994-C1003

    Google Scholar 

  5. Covinsky, J.O., Conn, R.D. 1981. Quinidine. Therapeutic use and serum concentration monitoring. In: Individualizing Drug Therapy. Practical Applications of Drug Monitoring. W.J. Taylor and A.L. Finn, editors. pp. 111–132. Gross, Townsend, Frank, New York

    Google Scholar 

  6. Cowan, C.L., Cohen, R.A. 1992. Different mechanisms of relaxation of pig coronary artery to bradykinin and cromakalim are distinguished by potassium channel blockers. J. Pharmacol. Exp. Ther. 260:248–253

    Google Scholar 

  7. Cummings, T.A., Kinnamon, S.C. 1992. Apical K+ channels in Necturus taste cells. Modulation by intracellular factors and taste stimuli. J. Gen. Physiol. 99:591–613

    Google Scholar 

  8. Dahl, M.L., Nordin, C., Bertilsson, L. 1991. Enantioselective hydroxylation of nortriptyline in human liver microsomes, intestinal homogenate, and patients treated with nortriptyline. Ther. Drug Monit. 13:189–194

    Google Scholar 

  9. Deuticke, B., Grebe, R., Haest, C.W.M. 1990. Action of drugs on the erythrocyte membrane. Blood Cell. Bioch. 1:475–529

    Google Scholar 

  10. Discala, F., Belachgar, F., Planelies, G., Hulin, P., Anagnostopoulos, T. 1992. Barium-or quinine-induced depolarization activates K+, Na+ and cationic conductances in frog proximal tubular cells. J. Physiol. 448:525–537

    Google Scholar 

  11. Dunham, P.B. (1990). K,Cl cotransport in mammalian erythrocytes. In: Regulation of Potassium Transport across Biological Membranes. L. Reuss, J.M. Russel, and G. Szabo, editors, pp. 331–360. University of Texas Austin

  12. el Benna, J., Pasquier, C., Labro, M.T. 1991. Quinine uptake by human polymorphonuclear neutrophils. Antimicrob. Agents Chemother. 35:1474–1478

    Google Scholar 

  13. Ellory, J.C., Dunham, P.B. 1980. Volume-dependent passive potassium transport in LK sheep red cells. In: Membrane Transport in Erythrocytes. Alfred Benzon Symposium 14. U. Lassen, H.H. Ussing, and J.O. Wieth, editors. pp. 409–425. Munskgaard, Copenhagen

    Google Scholar 

  14. Garay, R.P., Nazaret, C., Hannaert, P.S., and Cragoe, E.J., Jr. 1988. Demonstration of a [K+,Cl]-cotransport system in human red cells by its sensitivity to [(Dihydroindenyl)oxy]alkanoic acids: regulation of cell swelling and distinction from the bumetanide-sensitive [Na+,K+,Cl−]-cotransport system. Mol. Pharmacol. 33:696–701

    Google Scholar 

  15. Gendrel, D., Kombila, M., Nardou, M., Gendrel, C., Djouba, F., Martz, M., Richard-Lenoble, D. 1992. Malaria and Hemoglobin S: Interactions in African children. Presse Med. 21:887–890

    Google Scholar 

  16. Goldstein, J.L., Fogelson, B.G., Snow, J.C., Schmidt, L.N., Mozwecz, H., Layden, T.J. 1993. Rabbit esophageal cells possess K+ channels: effect of hyposmotic stress on channel activity. Gastroenterology 104:417–426

    Google Scholar 

  17. Halsberg, A., Romanin, C., Koerber, R. 1992. Membrane potential modulates release of tumor necrosis factor in lipopolysaccharidestimulated mouse macrophages. Mol. Biol. Cell 3:451–460

    Google Scholar 

  18. Hille, B. 1992. Ionic Channels of Excitable Membranes, pp. 291–314, 390–422. Sinauer Associates, Sunderland, MA

    Google Scholar 

  19. Hughes, I.E., Ilett, K.F., Jellett L.B. 1975. The distribution of quinidine in human blood. Br. J. Clin. Pharmacol. 2:521–525

    Google Scholar 

  20. Ikehara, T., Takahashi, A., Yamaguchi, H., Hosokawa, K., Masuya, T., Miyamoto, H. 1991. Regulatory changes in the K+, Cl− and water contents of HeLa cells incubated in an isosmotic high K(+)-medium. Biochim. Biophys. Acta 1068:87–96

    Google Scholar 

  21. Kaji, D. 1986. Volume-sensitive K transport in human erythrocytes. J. Gen. Physiol. 88:719–738

    Google Scholar 

  22. Kaji, D. 1992. Effect of varying membrane potential on K-Cl cotransport in human erythrocytes. Am. J. Physiol. 264:C376-C382

    Google Scholar 

  23. Karbwang, J., Molunto, P., Bunnag, D., Harinasuta, T. 1991. Plasma quinine levels in patients with falciparum malaria when given alone or in combination with tetracycline with or without primaquine. Southeast Asian J. Trop. Med. Public Health 22:72–76

    Google Scholar 

  24. Lauf, P.K. 1983. Thiol-dependent passive K/Cl transport in sheep red cells. I. Dependence on chloride and external K+(Rb+)ions. J. Membrane Biol. 73:237–246

    Google Scholar 

  25. Lauf, P.K., 1988. Volume and anion dependency of ouabainresistant K-Rb fluxes in sheep red blood cells. Am. J. Physiol. 255:C331-C339

    Google Scholar 

  26. Lauf, P.K., Bauer, J., Adragna, N.C., Fujise, H., Zade-Oppen, A.M., Ryu, K.H., Delpire, E. 1992. Erythrocyte K-Cl cotransport: properties and regulation. Am. J. Physiol. 263:C917-C932

    Google Scholar 

  27. Lauf, P.K., Erdmann, A., Adragna, N.C. 1994. Response of K-Cl cotransport to pH and cellular magnesium in volume-clamped low K sheep erythrocytes: three equilibrium states. Am. J. Physiol. 266: C95-C103

    Google Scholar 

  28. Luchi, R., Helwig, J., Jr., Conn, H., Jr. 1963. Quinidine toxicity and its therapy: An experimental study. Am. Heart J. 65:340–348

    Google Scholar 

  29. Murakami, M., Takada, K., Muranishi, S. 1992. Further mechanistic study on intestinal absorption enhanced by unsaturated fatty acids: Reversible effect by sulfhydryl modification. Biochem. Biophys. Acta 117:83–89

    Google Scholar 

  30. Muralidharan, G., Hawes, E.M., McKay, G., Korchinski, E.D., Midha, K.K. 1991. Quinidine but not quinine inhibits in man the oxidative metabolic routes of methoxyphenamine which involve debrisoquine 4-hydroxylase. Eur. J. Clin. Pharmacol. 41:471–474

    Google Scholar 

  31. Muralidharan, G., Hawes, E.M., McKay, G., Midha, K.K. 1991. Quinine is a more potent inhibitor than quinidine in rat of the oxidative metabolic routes of methoxyphenamine which involve debrisoquine 4-hydroxylase. Xenobiotica 21:1441–1450

    Google Scholar 

  32. Ott, R.J., Hui, A.C., Wong, F.M., Hsyu, P.H., Giacomini, K.M. 1991. Interactions of quinidine and quinine and (+)-and (−)-pindolol with the organic cation/proton antiporter in renal brushborder membrane vesicles. Biochem. Pharmacol. 41:142–145

    Google Scholar 

  33. Sabchareon, A., Chongsuphajaisiddhi, T., Attanath, P., Singhasivanon, V., Acmor-Apolinar, M.M., Pojjaroen-Anant, C. 1991. Red cell plasma concentrations of combined quinine-quinidine and quinine in falciparum malaria. Ann. Trop. Paediatr. 11:315–324

    Google Scholar 

  34. Schlatter, E., Bleich, M., Hirsch, J., Markstahler, U., Frobe, U., Greger, R. 1993. Cation specificity and pharmacological properties of the Ca(2+)-dependent K+ channel of rat cortical collecting ducts. Pfluegers Arch. 422:481–491

    Google Scholar 

  35. Slater, A.F.G., Ceramil, A. 1992. Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature 355:167–169

    Google Scholar 

  36. Sugioka, Y., Suzuki, M. 1991. The chemical basis for the ferriprotoporphyrin IX-chloroquine complex induced lipid peroxidation. Biochim. Biophys. Acta 1074:19–24

    Google Scholar 

  37. Takeuchi, S., Marcus, D.C., Wangemann, P. 1992. Maxi K+ channel in apical membrane of vestibular dark cells. Am. J. Physiol. 262:C1430–1436

    Google Scholar 

  38. Wang, H., Grahame-Smith, D.G. 1992. The effects of rubidium, caesium and quinine on 5-HT-mediated behaviour in rat and mouse. 3. Quinine. Neuropharmacology 31:425–431

    Google Scholar 

  39. Warrell, D.A. 1992. Cerebral Malaria. Schweiz Med. Wochenschr. 122:879–886

    Google Scholar 

  40. Watt, G., Shanks, G.D., Edstein, M.D., Pavanand, K., Webster, H.K., Wechgritaya, S. 1991. Ciprofloxacin treatment of drugresistant falciparum malaria. J. Infect. Dis. 164:602–604

    Google Scholar 

  41. Xiao, J., Nie, L.H., Yao, S.Z. 1991. Transfer mechanism of quinine drug across the oil/water (O/W) interface. Sci. China B 34:42–53

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Pharmacology and Toxicology, and Physiology and Biophysics, Wright State University, School of Medicine, 45401-0927, Dayton, Ohio

    N. C. Adragna & P. K. Lauf

Authors
  1. N. C. Adragna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. K. Lauf
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

We thank Dr. Luo Lu from the Department of Physiology and Biophysics for helpful discussions, Mrs. Samyuktha Ramalingam for excellent technical assistance, undergraduate summer student, Salman Elmi, for assisting in the calculations, and the Word Processing Center of Wright State University School of Medicine for typing of this manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Adragna, N.C., Lauf, P.K. Quinine and quinidine inhibit and reveal heterogeneity of K-Cl cotransport in low K sheep erythrocytes. J. Membarin Biol. 142, 195–207 (1994). https://doi.org/10.1007/BF00234941

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00234941

Key words

Search

Navigation