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.
Similar content being viewed by others
References
Andersson RE, Persson CG (1980) Extrapulmonary effects of theophylline. Eur J Respir Dis 61:17–28
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
Carney JM (1982) Effects of caffeine, theophylline and theobromine on scheduled controlled responding in rats. Br J Pharmacol 75:451–454
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
Dunwiddie TV, Hoffer BJ, Fredholm BB (1981) Alkylxanthines elevate hippocampal excitability. Naunyn-Schmiedebergs Arch Pharmacol 316:326–330
Edvinsson L, Fredholm BB (1983) Characterisation of adenosine receptors in isolated cerebral arteries of cat. Br J Pharmacol 80:631–637
Emerson TE, Raymond RM (1981) Involvement of adenosine in cerebral hypoxia hyperemia in the dog. Am J Physiol 241:H 134-H 138
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
Fredholm BB (1980) Are the effects of methylxanthines due to antagonism of endogenous adenosine? Trends Pharmacol Sci 1:129–132
Fredholm BB, Persson CG (1982) Xanthine derivatives as adenosine receptor antagonists. Eur J Pharmacol 81:673–676
Gregory PC, Boisvert, DPJ, Harper AM (1980) Adenosine response on pial arteries, influence of CO2 and local blood pressure. Pflügers Arch 368:187–192
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
Hofmann WW (1969) Caffeine effects on transmitter depletion and mobilization at motor nerve terminals. Am J Physiol 216:621–629
Ingvar DH (1978) Clinical neurophysiology of the cerebral circulation. In: Cobb WA, Van Duijn H (eds) Contemporary clinical neurophysiology. Elsevier, Amsterdam
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
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
König JFR, Klippel RA (1963) The rat brain: A stereotaxic atlas. Williams and Wilkins, Baltimore
Kuba K, Nish S (1976) Rhythmic hyperpolarisation and depolarisation of sympathetic ganglion cells induced by caffeine. J Neurophys 39:547–563
Kuschinsky W (1983) Coupling between functional, metabolism and blood flow in the brain: State of the art. Microcirculation 2:357–378
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
Mathew RJ, Barr DL, Weinman ML (1983) Caffeine and cerebral blood flow. Br J Psychiat 143:604–608
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
Miller RG (1966) Simultaneous statistical interference. Mac Graw-Hill, New York
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
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
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
Phillis JW, Wu PH (1981) The role of adenosine and its nucleotides in central synaptic transmission. Progr Neurobiol 16:187–239
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
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
Sachs L (1968) Angewandte Statistik. Springer Berlin Heidelberg New York
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
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
Shenkin HA (1951) Effects of various drugs upon cerebral circulation and metabolism of man. J Appl Physiol 3:465–471
Siesjö BK (1978) Brain energy metabolism. Wiley, New York
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
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
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
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
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
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
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00506522