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. 1992 Apr;89(4):1121–1127. doi: 10.1172/JCI115692

Cyclic nucleotides attenuate thrombin-evoked alterations in parameters of platelet Na/H antiport. The role of cytosolic Ca.

M Kimura 1, N Lasker 1, A Aviv 1
PMCID: PMC442968  PMID: 1313446

Abstract

In this work, we explored the role of cyclic nucleotides in modulating parameters of the Na/H antiport in human platelets. Sodium nitroprusside and iloprost, as well as cyclic nucleotide analogues, were used to raise cellular levels of cAMP and cGMP. Cyclic nucleotides reversed the thrombin-evoked alkaline shift in cytosolic pH set point and the activity of the Na/H antiport, concurrently with attenuation of thrombin-induced rise in cytosolic free Ca. No effect of cyclic nucleotides was observed in platelets not treated with thrombin, or platelets subjected to phorbol 12-myristate 13-acetate. cAMP did not reverse ionomycin-induced changes in the parameters of the Na/H antiport. Collectively, these observations indicate that cyclic nucleotides modulate the Na/H antiporter in human platelets through their effect on thrombin-evoked changes in cytosolic free Ca. Presumably, this effect holds for other agonists which stimulate phospholipase C, raise cytosolic-free Ca, and activate the Na/H antiport through protein kinase C dependent and protein kinase C-independent mechanisms.

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Selected References

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  1. Alonso M. T., Sanchez A., Garcia-Sancho J. Arachidonic acid-induced calcium influx in human platelets. Comparison with the effect of thrombin. Biochem J. 1990 Dec 1;272(2):435–443. doi: 10.1042/bj2720435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boyarsky G., Rosenthal N., Barrett E., Boron W. F. Effect of diabetes on Na(+)-H+ exchange by single isolated hepatocytes. Am J Physiol. 1991 Jan;260(1 Pt 1):C167–C175. doi: 10.1152/ajpcell.1991.260.1.C167. [DOI] [PubMed] [Google Scholar]
  3. Brickman A. S., Nyby M. D., von Hungen K., Eggena P., Tuck M. L. Calcitropic hormones, platelet calcium, and blood pressure in essential hypertension. Hypertension. 1990 Nov;16(5):515–522. doi: 10.1161/01.hyp.16.5.515. [DOI] [PubMed] [Google Scholar]
  4. Castagna M., Takai Y., Kaibuchi K., Sano K., Kikkawa U., Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem. 1982 Jul 10;257(13):7847–7851. [PubMed] [Google Scholar]
  5. Cooper R. S., Shamsi N., Katz S. Intracellular calcium and sodium in hypertensive patients. Hypertension. 1987 Mar;9(3):224–229. doi: 10.1161/01.hyp.9.3.224. [DOI] [PubMed] [Google Scholar]
  6. Erne P., Bolli P., Bürgisser E., Bühler F. R. Correlation of platelet calcium with blood pressure. Effect of antihypertensive therapy. N Engl J Med. 1984 Apr 26;310(17):1084–1088. doi: 10.1056/NEJM198404263101705. [DOI] [PubMed] [Google Scholar]
  7. Felder C. C., Campbell T., Albrecht F., Jose P. A. Dopamine inhibits Na(+)-H+ exchanger activity in renal BBMV by stimulation of adenylate cyclase. Am J Physiol. 1990 Aug;259(2 Pt 2):F297–F303. doi: 10.1152/ajprenal.1990.259.2.F297. [DOI] [PubMed] [Google Scholar]
  8. Gardner J. P., Tokudome G., Tomonari H., Aladjem M., Cragoe E., Jr, Aviv A. Refined estimation of kinetic parameters of the Na+/H+ antiport in human fibroblasts and platelets. Proc Soc Exp Biol Med. 1990 Jun;194(2):165–171. doi: 10.3181/00379727-194-43073. [DOI] [PubMed] [Google Scholar]
  9. Kahn A. M., Dolson G. M., Hise M. K., Bennett S. C., Weinman E. J. Parathyroid hormone and dibutyryl cAMP inhibit Na+/H+ exchange in renal brush border vesicles. Am J Physiol. 1985 Feb;248(2 Pt 2):F212–F218. doi: 10.1152/ajprenal.1985.248.2.F212. [DOI] [PubMed] [Google Scholar]
  10. Kahn A. M., Dolson G. M., Hise M. K., Bennett S. C., Weinman E. J. Parathyroid hormone and dibutyryl cAMP inhibit Na+/H+ exchange in renal brush border vesicles. Am J Physiol. 1985 Feb;248(2 Pt 2):F212–F218. doi: 10.1152/ajprenal.1985.248.2.F212. [DOI] [PubMed] [Google Scholar]
  11. Kase H., Iwahashi K., Nakanishi S., Matsuda Y., Yamada K., Takahashi M., Murakata C., Sato A., Kaneko M. K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. Biochem Biophys Res Commun. 1987 Jan 30;142(2):436–440. doi: 10.1016/0006-291x(87)90293-2. [DOI] [PubMed] [Google Scholar]
  12. Kawahara Y., Yamanishi J., Fukuzaki H. Inhibitory action of guanosine 3',5'-monophosphate on thrombin-induced calcium mobilization in human platelets. Thromb Res. 1984 Jan 15;33(2):203–209. doi: 10.1016/0049-3848(84)90181-6. [DOI] [PubMed] [Google Scholar]
  13. Kimura M., Gardner J. P., Aviv A. Agonist-evoked alkaline shift in the cytosolic pH set point for activation of Na+/H+ antiport in human platelets. The role of cytosolic Ca2+ and protein kinase C. J Biol Chem. 1990 Dec 5;265(34):21068–21074. [PubMed] [Google Scholar]
  14. Käser-Glanzmann R., Jakäbovä M., George J. N., Lüscher E. F. Stimulation of calcium uptake in platelet membrane vesicles by adenosine 3',5'-cyclic monophosphate and protein kinase. Biochim Biophys Acta. 1977 May 2;466(3):429–440. doi: 10.1016/0005-2736(77)90336-4. [DOI] [PubMed] [Google Scholar]
  15. Lagast H., Pozzan T., Waldvogel F. A., Lew P. D. Phorbol myristate acetate stimulates ATP-dependent calcium transport by the plasma membrane of neutrophils. J Clin Invest. 1984 Mar;73(3):878–883. doi: 10.1172/JCI111284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lanza F., Beretz A., Stierlé A., Corre G., Cazenave J. P. Cyclic nucleotide phosphodiesterase inhibitors prevent aggregation of human platelets by raising cyclic AMP and reducing cytoplasmic free calcium mobilization. Thromb Res. 1987 Mar 1;45(5):477–484. doi: 10.1016/0049-3848(87)90310-0. [DOI] [PubMed] [Google Scholar]
  17. Lechi A., Lechi C., Bonadonna G., Sinigaglia D., Corradini P., Polignano R., Arosio E., Covi G., de Togni P. Increased basal and thrombin-induced free calcium in platelets of essential hypertensive patients. Hypertension. 1987 Mar;9(3):230–235. doi: 10.1161/01.hyp.9.3.230. [DOI] [PubMed] [Google Scholar]
  18. Lerea K. M., Glomset J. A., Krebs E. G. Agents that elevate cAMP levels in platelets decrease thrombin binding. J Biol Chem. 1987 Jan 5;262(1):282–288. [PubMed] [Google Scholar]
  19. Lidbury P. S., Antunes E., de Nucci G., Vane J. R. Interactions of iloprost and sodium nitroprusside on vascular smooth muscle and platelet aggregation. Br J Pharmacol. 1989 Dec;98(4):1275–1280. doi: 10.1111/j.1476-5381.1989.tb12674.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lindner A., Kenny M., Meacham A. J. Effects of a circulating factor in patients with essential hypertension on intracellular free calcium in normal platelets. N Engl J Med. 1987 Feb 26;316(9):509–513. doi: 10.1056/NEJM198702263160904. [DOI] [PubMed] [Google Scholar]
  21. Livne A., Balfe J. W., Veitch R., Marquez-Julio A., Grinstein S., Rothstein A. Increased platelet Na+-H+ exchange rates in essential hypertension: application of a novel test. Lancet. 1987 Mar 7;1(8532):533–536. doi: 10.1016/s0140-6736(87)90176-0. [DOI] [PubMed] [Google Scholar]
  22. MacIntyre D. E., Bushfield M., Shaw A. M. Regulation of platelet cytosolic free calcium by cyclic nucleotides and protein kinase C. FEBS Lett. 1985 Sep 2;188(2):383–388. doi: 10.1016/0014-5793(85)80407-5. [DOI] [PubMed] [Google Scholar]
  23. Mazeaud M. M., Le Quan Sang K. H., Devynck M. A. Platelet cyclic AMP in essential hypertension. J Hypertens. 1989 Jun;7(6):501–506. doi: 10.1097/00004872-198906000-00010. [DOI] [PubMed] [Google Scholar]
  24. Mellion B. T., Ignarro L. J., Ohlstein E. H., Pontecorvo E. G., Hyman A. L., Kadowitz P. J. Evidence for the inhibitory role of guanosine 3', 5'-monophosphate in ADP-induced human platelet aggregation in the presence of nitric oxide and related vasodilators. Blood. 1981 May;57(5):946–955. [PubMed] [Google Scholar]
  25. Nakashima S., Tohmatsu T., Hattori H., Okano Y., Nozawa Y. Inhibitory action of cyclic GMP on secretion, polyphosphoinositide hydrolysis and calcium mobilization in thrombin-stimulated human platelets. Biochem Biophys Res Commun. 1986 Mar 28;135(3):1099–1104. doi: 10.1016/0006-291x(86)91041-7. [DOI] [PubMed] [Google Scholar]
  26. Nishizuka Y. Studies and perspectives of protein kinase C. Science. 1986 Jul 18;233(4761):305–312. doi: 10.1126/science.3014651. [DOI] [PubMed] [Google Scholar]
  27. Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature. 1984 Apr 19;308(5961):693–698. doi: 10.1038/308693a0. [DOI] [PubMed] [Google Scholar]
  28. Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature. 1984 Apr 19;308(5961):693–698. doi: 10.1038/308693a0. [DOI] [PubMed] [Google Scholar]
  29. Nishizuka Y. Turnover of inositol phospholipids and signal transduction. Science. 1984 Sep 21;225(4668):1365–1370. doi: 10.1126/science.6147898. [DOI] [PubMed] [Google Scholar]
  30. Nishizuka Y. Turnover of inositol phospholipids and signal transduction. Science. 1984 Sep 21;225(4668):1365–1370. doi: 10.1126/science.6147898. [DOI] [PubMed] [Google Scholar]
  31. Oliva D. W., Maderna P., Accomazzo M. R., Nicosia S., Tremoli E. Iloprost binding and inhibition of aggregation in platelet rich plasma. Differences between normal and type IIa hypercholesterolemic subjects. Biochem Pharmacol. 1989 Jan 1;38(1):39–45. doi: 10.1016/0006-2952(89)90146-9. [DOI] [PubMed] [Google Scholar]
  32. Pannocchia A., Hardisty R. M. Cyclic AMP inhibits platelet activation independently of its effect on cytosolic free calcium. Biochem Biophys Res Commun. 1985 Feb 28;127(1):339–345. doi: 10.1016/s0006-291x(85)80164-9. [DOI] [PubMed] [Google Scholar]
  33. Reid I. R., Civitelli R., Avioli L. V., Hruska K. A. Parathyroid hormone depresses cytosolic pH and DNA synthesis in osteoblast-like cells. Am J Physiol. 1988 Jul;255(1 Pt 1):E9–15. doi: 10.1152/ajpendo.1988.255.1.E9. [DOI] [PubMed] [Google Scholar]
  34. Reuss L., Petersen K. U. Cyclic AMP inhibits Na+/H+ exchange at the apical membrane of Necturus gallbladder epithelium. J Gen Physiol. 1985 Mar;85(3):409–429. doi: 10.1085/jgp.85.3.409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rickard J. E., Sheterline P. Evidence that phorbol ester interferes with stimulated Ca2+ redistribution by activating Ca2+ efflux in neutrophil leucocytes. Biochem J. 1985 Nov 1;231(3):623–628. doi: 10.1042/bj2310623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rink T. J., Sage S. O. Stimulated calcium efflux from fura-2-loaded human platelets. J Physiol. 1987 Dec;393:513–524. doi: 10.1113/jphysiol.1987.sp016837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Rosskopf D., Morgenstern E., Scholz W., Osswald U., Siffert W. Rapid determination of the elevated Na(+)-H+ exchange in platelets of patients with essential hypertension using an optical swelling assay. J Hypertens. 1991 Mar;9(3):231–238. [PubMed] [Google Scholar]
  38. Sage S. O., Jobson T. M., Rink T. J. Agonist-evoked changes in cytosolic pH and calcium concentration in human platelets: studies in physiological bicarbonate. J Physiol. 1990 Jan;420:31–45. doi: 10.1113/jphysiol.1990.sp017900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sage S. O., Rink T. J. Inhibition by forskolin of cytosolic calcium rise, shape change and aggregation in quin2-loaded human platelets. FEBS Lett. 1985 Aug 19;188(1):135–140. doi: 10.1016/0014-5793(85)80890-5. [DOI] [PubMed] [Google Scholar]
  40. Seregi A., Schobert A., Hertting G. The stable prostacyclin-analogue, iloprost, unlike prostanoids and leukotrienes, potently stimulates cyclic adenosine monophosphate synthesis of primary astroglial cell cultures. J Pharm Pharmacol. 1988 Jun;40(6):437–438. doi: 10.1111/j.2042-7158.1988.tb06311.x. [DOI] [PubMed] [Google Scholar]
  41. Shuntoh H., Taniyama K., Fukuzaki H., Tanaka C. Inhibition by cyclic AMP of phorbol ester-potentiated norepinephrine release from guinea pig brain cortical synaptosomes. J Neurochem. 1988 Nov;51(5):1565–1572. doi: 10.1111/j.1471-4159.1988.tb01126.x. [DOI] [PubMed] [Google Scholar]
  42. Siess W. Molecular mechanisms of platelet activation. Physiol Rev. 1989 Jan;69(1):58–178. doi: 10.1152/physrev.1989.69.1.58. [DOI] [PubMed] [Google Scholar]
  43. Siffert W., Fox G., Mückenhoff K., Scheid P. Thrombin stimulates Na+-H+ exchange across the human platelet plasma membrane. FEBS Lett. 1984 Jul 9;172(2):272–274. doi: 10.1016/0014-5793(84)81139-4. [DOI] [PubMed] [Google Scholar]
  44. Simpson A. W., Rink T. J. Elevation of pHi is not an essential step in calcium mobilisation in fura-2-loaded human platelets. FEBS Lett. 1987 Sep 28;222(1):144–148. doi: 10.1016/0014-5793(87)80208-9. [DOI] [PubMed] [Google Scholar]
  45. Stamler J., Mendelsohn M. E., Amarante P., Smick D., Andon N., Davies P. F., Cooke J. P., Loscalzo J. N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor. Circ Res. 1989 Sep;65(3):789–795. doi: 10.1161/01.res.65.3.789. [DOI] [PubMed] [Google Scholar]
  46. Sweatt J. D., Johnson S. L., Cragoe E. J., Limbird L. E. Inhibitors of Na+/H+ exchange block stimulus-provoked arachidonic acid release in human platelets. Selective effects on platelet activation by epinephrine, ADP, and lower concentrations of thrombin. J Biol Chem. 1985 Oct 25;260(24):12910–12919. [PubMed] [Google Scholar]
  47. Takai Y., Kaibuchi K., Matsubara T., Nishizuka Y. Inhibitory action of guanosine 3', 5'-monophosphate on thrombin-induced phosphatidylinositol turnover and protein phosphorylation in human platelets. Biochem Biophys Res Commun. 1981 Jul 16;101(1):61–67. doi: 10.1016/s0006-291x(81)80010-1. [DOI] [PubMed] [Google Scholar]
  48. Takaya J., Lasker N., Bamforth R., Gutkin M., Byrd L. H., Aviv A. Kinetics of Ca2(+)-ATPase activation in platelet membranes of essential hypertensives and normotensives. Am J Physiol. 1990 Jun;258(6 Pt 1):C988–C994. doi: 10.1152/ajpcell.1990.258.6.C988. [DOI] [PubMed] [Google Scholar]
  49. Tokudome G., Tomonari H., Gardner J. P., Aladjem M., Fine B. P., Lasker N., Gutkin M., Byrd L. H., Aviv A. Variations in the apparent pH set point for activation of platelet Na-H antiport. Hypertension. 1990 Aug;16(2):180–189. doi: 10.1161/01.hyp.16.2.180. [DOI] [PubMed] [Google Scholar]
  50. Valone F. H., Johnson B. Modulation of platelet-activating-factor-induced calcium influx and intracellular calcium release in platelets by phorbol esters. Biochem J. 1987 Nov 1;247(3):669–674. doi: 10.1042/bj2470669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Waldmann R., Walter U. Cyclic nucleotide elevating vasodilators inhibit platelet aggregation at an early step of the activation cascade. Eur J Pharmacol. 1989 Jan 17;159(3):317–320. doi: 10.1016/0014-2999(89)90165-9. [DOI] [PubMed] [Google Scholar]
  52. Yamanishi J., Takai Y., Kaibuchi K., Sano K., Castagna M., Nishizuka Y. Synergistic functions of phorbol ester and calcium in serotonin release from human platelets. Biochem Biophys Res Commun. 1983 Apr 29;112(2):778–786. doi: 10.1016/0006-291x(83)91529-2. [DOI] [PubMed] [Google Scholar]
  53. Zavoico G. B., Cragoe E. J., Jr, Feinstein M. B. Regulation of intracellular pH in human platelets. Effects of thrombin, A23187, and ionomycin and evidence for activation of Na+/H+ exchange and its inhibition by amiloride analogs. J Biol Chem. 1986 Oct 5;261(28):13160–13167. [PubMed] [Google Scholar]
  54. Zavoico G. B., Feinstein M. B. Cytoplasmic Ca2+ in platelets is controlled by cyclic AMP: antagonism between stimulators and inhibitors of adenylate cyclase. Biochem Biophys Res Commun. 1984 Apr 30;120(2):579–585. doi: 10.1016/0006-291x(84)91294-4. [DOI] [PubMed] [Google Scholar]

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