Advertisement

Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

Effects of dipyridamole on adenosine concentration, insulin sensitivity and glucose utilisation in soleus muscle of the rat

  • 26 Accesses

  • 7 Citations

Abstract

Adenosine has been shown to modulate the sensitivity of skeletal muscle to insulin (Budohoski et al. 1984). In an attempt to further characterize the modulatory action of adenosine on insulin sensitivity inskeletal muscle we have investigated the effect of the nucleoside transport inhibitor dipyridamole in isolated incubated soleus muscle strips. At a concentration of 50 μM, dipyridamole increased the concentration of adenosine in the soleus muscle by 36% and in the incubation medium by 32%. At this concentration of dipyridamole, the basal rates (in the presence of 1 μunit of insulin/ml) of lactate formation, 2-deoxy [2,6-3H]glucose phosphorylation and glucose oxidation were decreased by 48%, 43% and 47% respectively, whilst the rate of glycogen synthesis was unaffected. Insulin-stimulated rates (in the presence of 10000 μunit of insulin/ml) of lactate formation, 2-deoxy [2,6-3H] glucose phosphorylation, glycogen synthesis and glucose oxidation were decreased by 70%, 30%, 26% and 20% respectively in the presence of 50 μM dipyridamole. Although 50 μM dipyridamole was required to exert a significant effect on medium and soleus muscle adenosine concentrations, statistically significant effects on glycolytic rate were observed at concentrations as low as 2 μM dipyridamole.

It is concluded that the results are not consistent with dipyridamole exerting an effect on skeletal muscle carbohydrate metabolism solely through elevation of the intracellular or interstial adenosine concentration, but strongly suggest that dipyridamole inhibits glucose transport and/or phosphorylation in skeletal muscle.

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

References

  1. Arch JRS, Newsholme EA (1978) The control of the metabolism and the hormonal role of adenosine. Essays Biochem 14:82–123

  2. Arend LJ, Thompson CI, Spielman WS (1985) Dipyridamole decreases glomerular filtration in the sodium-depleted dog. Circ Res 56:242–251

  3. Berne RM (1980) The role of adenosine in the regulation of coronary bloodflow. Circ Res 47:807–813

  4. Budohoski L, Challiss RAJ, McManus B, Newsholme EA (1984) Effects of analogues of adenosine and methylxanthines on insulin sensitivity in soleus muscle of the rat. FEBS Lett 167:1–4

  5. Bunger R, Soboll S (1986) Cytosolic adenylates and adenosine release in perfused working heart: comparison of whole tissue with cytosolic nonaqueous fractionation analyses. Eur J Biochem 159:203–213

  6. Challiss RAJ, Espinal J, Newsholme EA (1983) Insulin sensitivity of rates of glycolysis and glycogen synthesis in soleus, strippedsoleus, epitrochlearis and hemi-diaphragm muscles isolated from sedentary rats. Biosci Rep 3:675–679

  7. Challiss RAJ, Lozeman FJ, Leighton B, Newsholme EA (1986) Effects of the β-adrenoceptor agonist isoprenaline on insulin sensitivity in soleus muscle of the rat. Biochem J 233:377–381

  8. Crettaz M, Prentki M, Zaninetti D, Jeanrenaud B (1980) Insulin resistance in solues muscle from obese Zucker rats. Biochem J 186:525–534

  9. Degenring FH, Curnish RR, Rubio R, Berne RM (1976) Effect of dipyridamole on myocardial adenosine metabolism and coronary bloodflow in hypoxia and reactive hyperemia in the isolated perfused guinea pig heart. J Mol Cell Cardiol 8:877–888

  10. Espinal J, Challiss RAJ, Newsholme EA (1983) Effect of adenosine deaminase and an adenosine analogue on insulin sensitivity in soleus muscle of the rat. FEBS Lett 158:103–106

  11. Fuster V, Chesebro JH (1986) Role of platelets and platelet-inhibitors in aortocoronary artery-vein graft disease. Circulation 73:227–232

  12. Harker LA, Kadatz RA (1983) Mechanism of action of dipyridamole. Thromb. Res (Suppl IV) 32:39–46

  13. Harmsen E, DeJong JW, Serruys PW (1981) Hypoxanthine production by ischemic heart demonstrated by high performance liquid chromatography of blood purine nucleosides and oxypurines. Clin Chim Acta 115:73–84

  14. Harmsen E, DeTombe PP, DeJong JW (1982) Simultaneous determination of myocardial adenine nucleotides and creatine phosphate by high performance liquid chromatography. J Chromatogr 230:131–136

  15. Hirche H, Grun D, Grun G, Langohr HD, Wacher U (1974) The effect of carbocromen and dipyridamole on bloodflow of the gastrocnemius of the dog. Arzneimittelforsch 24:1762–1769

  16. Honig CR, Frierson JL (1980) Role of adenosine in exercise vasodilation in dog gracilis muscle. Am J Physiol 238:H703-H715

  17. Jarvis SM, Young JD, Wu J-SR, Belt JA, Paterson ARP (1986) Photoaffinity labelling of the human erythrocyte glucose transporter with 8-azidoadenosine. J Biol Chem 261:11077–11085

  18. Klabunde RE (1983) Effects of dipyridamole on post-ischemic vasodilation and extracellular adenosine. Am J Physiol 244:H273-H280

  19. Klabunde RE (1986) Conditions for dipyridamole potentiation of skeletal muscle active hyperemia. Am J Physiol 250:H62-H67

  20. Knabb RM, Gidday JM, Ely SW, Rubio R, Berne RM (1984) Effects of dipyridamole on myocardial adenosine and active hyperemia. Am J Physiol 247:H804-H810

  21. Kolassa N, Pfleger K (1975) Adenosine uptake by erythrocytes of man, rat and guinea pig and its inhibition by hexobendine and dipyridamole. Biochem Pharmacol 24:154–156

  22. Kolassa N, Pfleger K, Rummel W (1970) Specificity of adenosine uptake into the heart and inhibition by dipyridamole. Eur J Pharmacol 9:265–268

  23. Kubler W, Spieckermann PG, Bretschneider HJ (1970) Influence of dipyridamole (persantine) on myocardial adenosine metabolism. J Mol Cell Cardiol 1:23–28

  24. Lang G, Michal G (1974) D-glucose 6-phosphate andd-fructose 6-phosphate. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Academic Press, New York London, pp 1238–1242

  25. Leighton B, Budohoski L, Lozeman FJ, Challiss RAJ, Newsholme EA (1985) The effect of prostaglandin E1, E2, F and indomethacin on the sensitivity of glycolysis and glycogen synthesis to insulin in stripped soleus muscles of the rat. Biochem J 277:337–340

  26. Lozeman FJ, Leighton B, Challiss RAJ, Owen SA, Newsholme EA (1986) The effect of adenosine deaminase on insulin sensitivity in the extensor digitorum longus muscle of the rat. Biochem Soc Trans 14:328–329

  27. Magnusson RP, Portis AR, McCarty RE (1976) Quantitative, analytical separation of adenine nucleotides by column chromatography on polyethyleneimine-coated cellulose. Anal Biochem 72:653–657

  28. Mahoney C, Wolfram KM, Cocchetto DM, Cocchetto DM, Bjornsson TD (1982) Dipyridamole kinetics. Clin Pharmacol Ther 31:330–338

  29. Maghji P, Holmquist CA, Newby AC (1985) Adenosine formation and release from neonatal-rat heart cells in culture. Biochem J 229:799–805

  30. Muira M, Tominaga S, Hashimoto K (1967) Potentiation of reactive hyperemia in the coronary and femoral circulation by the selective use of dipyridamole. Arzneimittelforsch 17:976–979

  31. Nesher R, Karl IE, Kipnis DM (1985) Dissociation of effects of insulin and contraction on glucose transport in rat epitrochlearis muscle. Am J Physiol 249:C226-C232

  32. Newby AC (1984) Adenosine and the concept of ‘retaliatory metabolites’. Trends Biochem Science 9:42–44

  33. Newby AC (1986) How does dipyridamole elevate extracellular adenosine concentration? Biochem J 237:845–851

  34. Newsholme EA, Crabtree B (1979) Theoretical principles in the approaches to control of metabolic pathways and their application to glycolysis in muscle. J Mol Cell Cardiol 11:839–856

  35. Pedersen AK (1979) Specific detemination of dipyridamole in serum by high performance liquid chromatography. J Chromatogr 162:98–103

  36. Persantine-aspirin Re-infarction study research group (1980) Persantine and aspirin in coronary heart disease. Circulation 62:449–461

  37. Plagemann PGW, Richey DP (1974) Transport of nucleosides, nucleic acid bases, choline and glucose by animal cells in culture. Biochim Biophys Acta 344:263–305

  38. Plagemann PGW, Wohlheuter RM (1980) Permeation of nucleosides, nucleic acid bases and nucleotides in animal cells. Curr Top Membr Transp 14:225–330

  39. Renner ED, Plagemann PGW, Bernlohr RW (1972) Permeation of glucose by simple and facilitated diffusion by Novikoff rat hepatoma cells in suspension culture and its relationship to glucose metabolism. J Biol Chem 247:5765–5776

  40. Sollevi A, Fredholm BB (1981) The antilipolytic effect of endogenous and exogenous adenosine in canine adipose tissue in situ. Acta Physiol Scand 113:53–60

  41. Sparks HV, Bardenheuer H (1986) Regulation of adenosine formation by the heart. Circ Res 58:193–201

  42. Verma A, Marangos PJ (1985) Nitrobenzylthioinosine binding in brain: an interspecies study. Life Sci 36:283–290

  43. Wheeler TJ, Hinkle PC (1985) The glucose transporter of mammalian cells. Annu Rev Physiol 47:503–517

  44. Williams EF, Barker PH, Clanachan AS (1984) Nucleoside transport in heart: species differences in NBMPR binding, adenosine accumulation and drug-induced potentiation of adenosine action. Can J Physiol Pharmacol 62:31–37

  45. Wolff J, Londos C, Cooper DMF (1981) Adenosine receptors and the regulation of adenylate cyclase. Adv Cyclic Nucleotide Res 14:199–214

  46. Worku Y, Newby AC (1983) The mechanism of adenosine production in rat polymorphonuclear leucocytes. Biochem J 214:325–330

  47. Wu J-SR, Kwong FYP, Jarvis SM, Young JD (1983) Identification of the erythrocyte nucleoside transporter as a band 4.5 polypeptide: photoaffinity labelling studies using nitrobenzylthioniosine. J Biol Chem 258:13745–13751

  48. Young JD, Jarvis SM, Robins MJ, Paterson ARP (1983) Photoaffinity labelling of the human erythrocyte nucleoside transporter by N6-(p-azidobenzyl)adenosine and nitrobenzylthioinosine: evidence that the transporter is a band 4.5 poylpeptide. J Biol Chem 258:2202–2208

Download references

Author information

Correspondence to R. A. John Challiss.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lozeman, F.J., Challiss, R.A.J., Leighton, B. et al. Effects of dipyridamole on adenosine concentration, insulin sensitivity and glucose utilisation in soleus muscle of the rat. Pflugers Arch. 410, 192–197 (1987). https://doi.org/10.1007/BF00581915

Download citation

Key words

  • Dipyridamole
  • Insulin sensitivity
  • Adenosine
  • Glucose transport
  • Skeletal muscle