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Differential effects of methylxanthines on local cerebral blood flow and glucose utilization in the conscious rat

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Summary

The aim of this study was to test the effects of the three “classical” methylxanthines, theophylline, caffeine and theobromine, on local cerebral blood flow and glucose utilization. Equimolar doses (1.6 μmol/kg/min i.v.) of theophylline and caffeine produced increases in local cerebral glucose utilization and decreases in local cerebral blood flow. These compounds, therefore, re-set the ratio of cerebral blood flow per unit of glucose utilization at a lower level. These results are interpreted with respect to the known adenosine antagonist properties of caffeine and theophylline. Theobromine, a substance with less significant adenosine antagonist properties, had minimal effects on local cerebral blood flow and glucose utilization at a dose of 1.6 μmol/kg/min i.v. These data may provide supportive evidence for the hypothesis that adenosine plays an important role in cerebral blood flow-metabolism coupling.

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References

  • Andersson RE, Persson CG (1980) Extrapulmonary effects of theophylline. Eur J Respir Dis 61:17–28

    Google Scholar 

  • Boulenger JP, Patel J, Marangos PJ (1982) Effects of caffeine and theophylline on adenosine and benzodiazepine receptors in human brain. Neurosc Lett 30:161–166

    Google Scholar 

  • Carney JM (1982) Effects of caffeine, theophylline and theobromine on scheduled controlled responding in rats. Br J Pharmacol 75:451–454

    Google Scholar 

  • Daly JW, Butts-Lamp P, Padegett W (1983) Subclasses of adenosine receptors in the central nervous system: Interaction with caffeine and related methylxanthines. Cell Mol Biol 3:69–80

    Google Scholar 

  • Dunwiddie TV, Hoffer BJ, Fredholm BB (1981) Alkylxanthines elevate hippocampal excitability. Naunyn-Schmiedebergs Arch Pharmacol 316:326–330

    Google Scholar 

  • Edvinsson L, Fredholm BB (1983) Characterisation of adenosine receptors in isolated cerebral arteries of cat. Br J Pharmacol 80:631–637

    Google Scholar 

  • Emerson TE, Raymond RM (1981) Involvement of adenosine in cerebral hypoxia hyperemia in the dog. Am J Physiol 241:H 134-H 138

    Google Scholar 

  • Forrester T, Harper AM, MacKenzie ET, Thomson EM (1979) Effect of adenosine triphosphate and some derivatives on cerebral blood flow and metabolism. J Physiol 296:343–355

    Google Scholar 

  • Fredholm BB (1980) Are the effects of methylxanthines due to antagonism of endogenous adenosine? Trends Pharmacol Sci 1:129–132

    Google Scholar 

  • Fredholm BB, Persson CG (1982) Xanthine derivatives as adenosine receptor antagonists. Eur J Pharmacol 81:673–676

    Google Scholar 

  • Gregory PC, Boisvert, DPJ, Harper AM (1980) Adenosine response on pial arteries, influence of CO2 and local blood pressure. Pflügers Arch 368:187–192

    Google Scholar 

  • Grome JJ, Harper AM (1983) The effects of quipazone, a putative serotonin agonist on local cerebral blood flow and glucose utilization in the rat, and pial vascular diameter in the cat. J Cereb Blood Flow Metab 3:S 202–203

    Google Scholar 

  • Hofmann WW (1969) Caffeine effects on transmitter depletion and mobilization at motor nerve terminals. Am J Physiol 216:621–629

    Google Scholar 

  • Ingvar DH (1978) Clinical neurophysiology of the cerebral circulation. In: Cobb WA, Van Duijn H (eds) Contemporary clinical neurophysiology. Elsevier, Amsterdam

    Google Scholar 

  • Kakiuchi S, Yamakazi R, Teshima Y, Uenishi K, Miyamoto E (1975) Multiple cyclic nucleotide phosphodiesterase activites from rat tissues and occurrence of calcium plus magnesium ion-dependent phosphodiesterase and its protein activator. Biochem J 146:108–120

    Google Scholar 

  • Kelly PAT, McCulloch J (1983) The effect of the GABAergic agonist muscimol upon the relationship between cerebral blood flow and glucose utilization. Brain Res 258:338–342

    Google Scholar 

  • König JFR, Klippel RA (1963) The rat brain: A stereotaxic atlas. Williams and Wilkins, Baltimore

    Google Scholar 

  • Kuba K, Nish S (1976) Rhythmic hyperpolarisation and depolarisation of sympathetic ganglion cells induced by caffeine. J Neurophys 39:547–563

    Google Scholar 

  • Kuschinsky W (1983) Coupling between functional, metabolism and blood flow in the brain: State of the art. Microcirculation 2:357–378

    Google Scholar 

  • Marangos PJ, Paul SM, Parma AM, Goodwin FK, Synapin P, Skolnik P (1979) Purinergic inhibition of diazepam binding to rat brain (in vitro). Life Sci 24:851–858

    Google Scholar 

  • Mathew RJ, Barr DL, Weinman ML (1983) Caffeine and cerebral blood flow. Br J Psychiat 143:604–608

    Google Scholar 

  • McCulloch J, Kelly PAT, Ford I (1982) Effect of apomorphine on the relationship between local cerebral glucose utilization and local cerebral blood flow (with an appendix on its statistical analysis). J Cereb Blood flow Metab 2:487–499

    Google Scholar 

  • Miller RG (1966) Simultaneous statistical interference. Mac Graw-Hill, New York

    Google Scholar 

  • Nakai M, Ladecola C, Ruggerio DA, Tucker LW, Reis DJ (1983) Electrical stimulation of cerebellar fastigial nucleus increases cerebral cortical blood flow without changes in local metabolism: Evidence for an intrinsic system in brain for primary vasodilatation. Brain Res 260:35–49

    Google Scholar 

  • Nehlig A, Lucignani G, Kadekaro M, Porrino LJ, Sokoloff L (1984) Effects of acute administration of caffeine on local cerebral glucose utilization in the rat. Eur J Pharmacol 101:91–100

    Google Scholar 

  • Oberdörster G, Lang R, Zimmer R (1975) Influence of adenosine and lowered cerebral blood flow on the cerebrovascular effects of theophylline. Eur J Pharmacol 30:197–204

    Google Scholar 

  • Phillis JW, Wu PH (1981) The role of adenosine and its nucleotides in central synaptic transmission. Progr Neurobiol 16:187–239

    Google Scholar 

  • Raichle ME, Grubb RL, Gado MH, Eichling JO, Ter-Pogossian MM (1977) In vivo correlations between regional cerebral blood flow and oxygen utilization in man. Acta Neurol Scand 56:240–241

    Google Scholar 

  • Rall TW (1980) Central nervous stimulants: Xanthines. In: Goodman AG, Goodman LS, Gilman A (eds), The pharmacological basis of therapeutics. MacMillan, New York, pp 367–376

    Google Scholar 

  • Sachs L (1968) Angewandte Statistik. Springer Berlin Heidelberg New York

    Google Scholar 

  • Sakurada O, Kennedy C, Jehle J, Brown JD, Carbin O, Sokoloff L (1978) Measurement of local cerebral blood flow with iodo (14C)antipyrine. Am J Physiol 234:H59-H66

    Google Scholar 

  • Schubert P, Mitzdorf U (1979) Analysis and quantitative evaluation of the depressive effect of adenosine on evoked potentials in hippocampal slices. Brain Res 172:186–190

    Google Scholar 

  • Shenkin HA (1951) Effects of various drugs upon cerebral circulation and metabolism of man. J Appl Physiol 3:465–471

    Google Scholar 

  • Siesjö BK (1978) Brain energy metabolism. Wiley, New York

    Google Scholar 

  • Snyder SH, Katims JJ, Annau Z, Bruns RF, Daly JW (1981) Adenosine receptors and behavioural actions of methylxanthines. Proc Natl Acad Sci USA 78:3260–3264

    Google Scholar 

  • Sokoloff L, Revich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shirohara M (1977) The deoxyglucose method for the measurement of local cerebral glucose utilization: Theory, procedure and normal values in the conscious and anaesthetised albino rat. J Neurochem 28:897–916

    Google Scholar 

  • Spindel ER, Wurtman RJ, McCall DB, Conlay L, Griffith L, Arnold MA (1984) Neuroendocrine effects of caffeine in normal subjects. Clin Pharmacol Ther 36:402–407

    Google Scholar 

  • Thithapanda A, Maling HM, Gillette JR (1972) Effects of caffeine and theophylline on activity of rats in relation to brain xanthine concentrations. Proc Soc Exp Biol Med 139:582–584

    Google Scholar 

  • Wahl M, Kuschinsky W (1976) The dilatory action of adenosine on pial arteries of cats and its inhibition by theophylline. Pflügers Arch 362:55–59

    Google Scholar 

  • Waldeck B (1975) Effect of caffeine on locomotor activity and central catecholamine mechanisms: A study with special reference to drug interaction. Acta Pharmacol Toxicol 36:(Suppl IV) 1–5

    Google Scholar 

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Grome, J.J., Stefanovich, V. Differential effects of methylxanthines on local cerebral blood flow and glucose utilization in the conscious rat. Naunyn-Schmiedeberg's Arch. Pharmacol. 333, 172–177 (1986). https://doi.org/10.1007/BF00506522

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  • DOI: https://doi.org/10.1007/BF00506522

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