The Cardiovascular Effects of Methylxanthines

  • Niels P. RiksenEmail author
  • Paul Smits
  • Gerard A. Rongen
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 200)


In the concentration range that is normally achieved in humans, e.g., after the drinking of coffee or in patients treated with theophylline, the cardiovascular effects of methylxanthines are primarily due to antagonism of adenosine A1 and A2 receptors. Inhibition of phosphodiesterases or mobilization of intracellular calcium requires much higher concentrations. In conscious humans, acute exposure to caffeine results in an increase in blood pressure by an increased total peripheral resistance, and a slight decrease in heart rate. This overall hemodynamic response is composed of direct effects of caffeine on vascular tone, on myocardial contractility and conduction, and on the sympathetic nervous system. Caffeine is the most widely consumed methylxanthine, mainly derived from coffee intake. Regular coffee consumption can affect various traditional cardiovascular risk factors, including a slight increase in blood pressure, an increase in plasma cholesterol and homocysteine levels, and a reduced incidence of type 2 diabetes mellitus. Although most prospective studies have not reported an association between coffee consumption and coronary heart disease, these findings do not exclude that the acute hemodynamic and neurohumoral effects of coffee consumption could have an adverse effect in selected patient groups who are more vulnerable for these effects, based on their genetic profile or medication use.


Adenosine Blood pressure Caffeine Cardiovascular effects 


  1. Agwunobi J, Abedin M, Young M, Beeram M, Sinkford S (1996) Impact of theophylline use in Wolff-Parkinson-White syndrome. J Natl Med Assoc 88:450–452PubMedGoogle Scholar
  2. Ammon HP, Bieck PR, Mandalaz D, Verspohl EJ (1983) Adaptation of blood pressure to continuous heavy coffee drinking in young volunteers. A double-blind crossover study. Br J Clin Pharmacol 15:701–706PubMedCrossRefGoogle Scholar
  3. Andreas S, Reiter H, Luthje L et al (2004) Differential effects of theophylline on sympathetic excitation, hemodynamics, and breathing in congestive heart failure. Circulation 110:2157–2162PubMedCrossRefGoogle Scholar
  4. Bak AA, Grobbee DE (1990) A randomized study on coffee and blood pressure. J Hum Hypertens 4:259–264PubMedGoogle Scholar
  5. Bardou M, Goirand F, Bernard A et al (2002) Relaxant effects of selective phosphodiesterase inhibitors on U46619 precontracted human intralobar pulmonary arteries and role of potassium channels. J Cardiovasc Pharmacol 40:153–161PubMedCrossRefGoogle Scholar
  6. Barraco RA, Clough-Helfman C, Goodwin BP, Anderson GF (1995) Evidence for presynaptic adenosine A2A receptors associated with norepinephrine release and their desensitization in the rat nucleus tractus solitarius. J Neurochem 65:1604–1611PubMedCrossRefGoogle Scholar
  7. Baylin A, Hernandez-Diaz S, Kabagambe EK, Siles X, Campos H (2006) Transient exposure to coffee as a trigger of a first nonfatal myocardial infarction. Epidemiology 17:506–511PubMedCrossRefGoogle Scholar
  8. Belardinelli L, Linden J, Berne RM (1989) The cardiac effects of adenosine. Prog Cardiovasc Dis 32:73–97PubMedCrossRefGoogle Scholar
  9. Belardinelli L, Shryock JC, Snowdy S et al (1998) The A2A adenosine receptor mediates coronary vasodilation. J Pharmacol Exp Ther 284:1066–1073PubMedGoogle Scholar
  10. Belardinelli L, Shryock JC, Song Y, Wang D, Srinivas M (1995) Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes. FASEB J 9:359–365PubMedGoogle Scholar
  11. Biaggioni I, Olafsson B, Robertson RM, Hollister AS, Robertson D (1987) Cardiovascular and respiratory effects of adenosine in conscious man. Evidence for chemoreceptor activation. Circ Res 61:779–786PubMedCrossRefGoogle Scholar
  12. Biaggioni I, Onrot J, Hollister AS, Robertson D (1986) Cardiovascular effects of adenosine infusion in man and their modulation by dipyridamole. Life Sci 39:2229–2236PubMedCrossRefGoogle Scholar
  13. Biaggioni I, Paul S, Puckett A, Arzubiaga C (1991) Caffeine and theophylline as adenosine receptor antagonists in humans. J Pharmacol Exp Ther 258:588–593PubMedGoogle Scholar
  14. Bijlstra P, van Ginneken EE, Huls M, van Dijk R, Smits P, Rongen GA (2004) Glyburide inhibits dipyridamole-induced forearm vasodilation but not adenosine-induced forearm vasodilation. Clin Pharmacol Ther 75:147–156PubMedCrossRefGoogle Scholar
  15. Brodmann M, Lischnig U, Lueger A, Pilger E, Stark G (2003) The effect of caffeine on peripheral vascular resistance in isolated perfused guinea pig hind limbs. J Cardiovasc Pharmacol 42:506–510PubMedCrossRefGoogle Scholar
  16. Brown NJ, Ryder D, Nadeau J (1993) Caffeine attenuates the renal vascular response to angiotensin II infusion. Hypertension 22:847–852PubMedCrossRefGoogle Scholar
  17. Burr ML, Gallacher JE, Butland BK, Bolton CH, Downs LG (1989) Coffee, blood pressure and plasma lipids: a randomized controlled trial. Eur J Clin Nutr 43:477–483PubMedGoogle Scholar
  18. Butcher RW, Sutherland EW (1962) Adenosine 3′,5′-phosphate in biological materials. I. Purification and properties of cyclic 3′,5′-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3′,5′-phosphate in human urine. J Biol Chem 237:1244–1250PubMedGoogle Scholar
  19. Cannon ME, Cooke CT, McCarthy JS (2001) Caffeine-induced cardiac arrhythmia: an unrecognised danger of healthfood products. Med J Aust 174:520–521PubMedGoogle Scholar
  20. Carr CS, Hill RJ, Masamune H et al (1997) Evidence for a role for both the adenosine A1 and A3 receptors in protection of isolated human atrial muscle against simulated ischaemia. Cardiovasc Res 36:52–59PubMedCrossRefGoogle Scholar
  21. Casiglia E, Bongiovi S, Paleari CD et al (1991) Haemodynamic effects of coffee and caffeine in normal volunteers: a placebo-controlled clinical study. J Intern Med 229:501–504PubMedCrossRefGoogle Scholar
  22. Cawley MJ, Al-Jazairi AS, Stone EA (2001) Intravenous theophylline–an alternative to temporary pacing in the management of bradycardia secondary to AV nodal block. Ann Pharmacother 35:303–307PubMedCrossRefGoogle Scholar
  23. Christensen B, Mosdol A, Retterstol L, Landaas S, Thelle DS (2001) Abstention from filtered coffee reduces the concentrations of plasma homocysteine and serum cholesterol: a randomized controlled trial. Am J Clin Nutr 74:302–307PubMedGoogle Scholar
  24. Conlay LA, Conant JA, deBros F, Wurtman R (1997) Caffeine alters plasma adenosine levels. Nature 389:136PubMedCrossRefGoogle Scholar
  25. Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H (2006) Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA 295:1135–1141PubMedCrossRefGoogle Scholar
  26. Costa F, Biaggioni I (1994) Role of adenosine in the sympathetic activation produced by isometric exercise in humans. J Clin Invest 93:1654–1660PubMedCrossRefGoogle Scholar
  27. Cox DA, Vita JA, Treasure CB, Fish RD, Selwyn AP, Ganz P (1989) Reflex increase in blood pressure during the intracoronary administration of adenosine in man. J Clin Invest 84:592–596PubMedCrossRefGoogle Scholar
  28. Daniels JW, Mole PA, Shaffrath JD, Stebbins CL (1998) Effects of caffeine on blood pressure, heart rate, and forearm blood flow during dynamic leg exercise. J Appl Physiol 85:154–159PubMedGoogle Scholar
  29. DeLago A, El-Hajjar M, Kirnus M (2008) Aminophylline for prevention of bradyarrhythmias induced by rheolytic thrombectomy. J Invasive Cardiol 20:9A–11APubMedGoogle Scholar
  30. Dimarco AF, Nochomovitz M, DiMarco MS, Altose MD, Kelsen SG (1985) Comparative effects of aminophylline on diaphragm and cardiac contractility. Am Rev Respir Dis 132:800–805PubMedGoogle Scholar
  31. Donoso MV, Aedo F, Huidobro-Toro JP (2006) The role of adenosine A2A and A3 receptors on the differential modulation of norepinephrine and neuropeptide Y release from peripheral sympathetic nerve terminals. J Neurochem 96:1680–1695PubMedCrossRefGoogle Scholar
  32. Edlund A, Conradsson T, Sollevi A (1995) A role for adenosine in coronary vasoregulation in man. Effects of theophylline and enprofylline. Clin Physiol 15:623–636PubMedCrossRefGoogle Scholar
  33. Edlund A, Sollevi A (1995) Theophylline increases coronary vascular tone in humans: evidence for a role of endogenous adenosine in flow regulation. Acta Physiol Scand 155:303–311PubMedCrossRefGoogle Scholar
  34. Eppel GA, Ventura S, Evans RG (2006) Regional vascular responses to ATP and ATP analogues in the rabbit kidney in vivo: roles for adenosine receptors and prostanoids. Br J Pharmacol 149:523–531PubMedCrossRefGoogle Scholar
  35. Farag NH, Vincent AS, McKey BS, Whitsett TL, Lovallo WR (2005) Hemodynamic mechanisms underlying the incomplete tolerance to caffeine′s pressor effects. Am J Cardiol 95: 1389–1392PubMedCrossRefGoogle Scholar
  36. Feoktistov I, Biaggioni I (1995) Adenosine A2B receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma. J Clin Invest 96:1979–1986PubMedCrossRefGoogle Scholar
  37. Francis SH, Sekhar KR, Ke H, Corbin JD (2010) Inhibition of cyclic nucleotide phosphodiesterases by methylxanthines and related compounds. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
  38. Fredholm BB (1980) Are methylxanthine effects due to antagonism of endogenous adenosine? Trends Pharmacol Sci 1:129–132CrossRefGoogle Scholar
  39. Fredholm BB (1984) Cardiovascular and renal actions of methylxanthines. Prog Clin Biol Res 158:303–330PubMedGoogle Scholar
  40. Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133PubMedGoogle Scholar
  41. Fredholm BB, Hedqvist P, Vernet L (1978) Effect of theophylline and other drugs on rabbit renal cyclic nucleotide phosphodiesterase, 5′-nucleotidase and adenosine deaminase. Biochem Pharmacol 27:2845–2850PubMedCrossRefGoogle Scholar
  42. Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (2001a) International union of pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552PubMedGoogle Scholar
  43. Fredholm BB, Irenius E, Kull B, Schulte G (2001b) Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. Biochem Pharmacol 61:443–448PubMedCrossRefGoogle Scholar
  44. Fredholm BB, Persson CG (1982) Xanthine derivatives as adenosine receptor antagonists. Eur J Pharmacol 81:673–676PubMedCrossRefGoogle Scholar
  45. Frost L, Vestergaard P (2005) Caffeine and risk of atrial fibrillation or flutter: the Danish diet, cancer, and health study. Am J Clin Nutr 81:578–582PubMedGoogle Scholar
  46. Greenland S (1993) A meta-analysis of coffee, myocardial infarction, and coronary death. Epidemiology 4:366–374PubMedCrossRefGoogle Scholar
  47. Grossmann M, Braune J, Ebert U, Kirch W (1998) Dilatory effects of phosphodiesterase inhibitors on human hand veins in vivo. Eur J Clin Pharmacol 54:35–39PubMedCrossRefGoogle Scholar
  48. Grubben MJ, Boers GH, Blom HJ et al (2000) Unfiltered coffee increases plasma homocysteine concentrations in healthy volunteers: a randomized trial. Am J Clin Nutr 71:480–484PubMedGoogle Scholar
  49. Guerreiro S, Marien M, Michel PP (2010) Methylxanthines and ryanodine receptor channels. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
  50. Happonen P, Voutilainen S, Tuomainen TP, Salonen JT (2006) Catechol-O-methyltransferase gene polymorphism modifies the effect of coffee intake on incidence of acute coronary events. PLoS ONE 1:e117PubMedCrossRefGoogle Scholar
  51. Harada K, Ohashi K, Kumagai Y, Fujimura A (1995) Comparison of venodilatory effect of amrinone and theophylline in human subjects. J Clin Pharmacol 35:1067–1070PubMedGoogle Scholar
  52. Hasko G, Linden J, Cronstein B, Pacher P (2008) Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov 7:759–770PubMedCrossRefGoogle Scholar
  53. Hausenloy DJ, Yellon DM (2007) Preconditioning and postconditioning: united at reperfusion. Pharmacol Ther 116:173–191PubMedCrossRefGoogle Scholar
  54. Hinschen AK, Rose'Meyer RB, Headrick JP (2003) Adenosine receptor subtypes mediating coronary vasodilation in rat hearts. J Cardiovasc Pharmacol 41:73–80PubMedCrossRefGoogle Scholar
  55. Hu G, Jousilahti P, Nissinen A, Bidel S, Antikainen R, Tuomilehto J (2007) Coffee consumption and the incidence of antihypertensive drug treatment in Finnish men and women. Am J Clin Nutr 86:457–464PubMedGoogle Scholar
  56. Ishibashi Y, Duncker DJ, Zhang J, Bache RJ (1998) ATP-sensitive K+ channels, adenosine, and nitric oxide-mediated mechanisms account for coronary vasodilation during exercise. Circ Res 82:346–359PubMedCrossRefGoogle Scholar
  57. Ishida S, Ito M, Takahashi N, Fujino T, Akimitsu T, Saikawa T (1996) Caffeine induces ventricular tachyarrhythmias possibly due to triggered activity in rabbits in vivo. Jpn Circ J 60:157–165PubMedCrossRefGoogle Scholar
  58. Jansen DF, Nedeljkovic S, Feskens EJ et al (1995) Coffee consumption, alcohol use, and cigarette smoking as determinants of serum total and HDL cholesterol in two Serbian cohorts of the Seven Countries Study. Arterioscler Thromb Vasc Biol 15:1793–1797PubMedGoogle Scholar
  59. Jee SH, He J, Appel LJ, Whelton PK, Suh I, Klag MJ (2001) Coffee consumption and serum lipids: a meta-analysis of randomized controlled clinical trials. Am J Epidemiol 153:353–362PubMedCrossRefGoogle Scholar
  60. Jee SH, He J, Whelton PK, Suh I, Klag MJ (1999) The effect of chronic coffee drinking on blood pressure: a meta-analysis of controlled clinical trials. Hypertension 33:647–652PubMedCrossRefGoogle Scholar
  61. Kabagambe EK, Baylin A, Campos H (2007) Nonfatal acute myocardial infarction in Costa Rica: modifiable risk factors, population-attributable risks, and adherence to dietary guidelines. Circulation 115:1075–1081PubMedCrossRefGoogle Scholar
  62. Kamphuis J, Smits P, Thien T (1994) Vascular effects of pentoxifylline in humans. J Cardiovasc Pharmacol 24:648–654PubMedCrossRefGoogle Scholar
  63. Karatzis E, Papaioannou TG, Aznaouridis K et al (2005) Acute effects of caffeine on blood pressure and wave reflections in healthy subjects: should we consider monitoring central blood pressure? Int J Cardiol 98:425–430PubMedCrossRefGoogle Scholar
  64. Kawachi I, Colditz GA, Stone CB (1994) Does coffee drinking increase the risk of coronary heart disease? Results from a meta-analysis. Br Heart J 72:269–275PubMedCrossRefGoogle Scholar
  65. Kemp BK, Cocks TM (1999) Adenosine mediates relaxation of human small resistance-like coronary arteries via A2B receptors. Br J Pharmacol 126:1796–1800PubMedCrossRefGoogle Scholar
  66. Klag MJ, Wang NY, Meoni LA et al (2002) Coffee intake and risk of hypertension: the Johns Hopkins precursors study. Arch Intern Med 162:657–662PubMedCrossRefGoogle Scholar
  67. Klatsky AL, Koplik S, Kipp H, Friedman GD (2008) The confounded relation of coffee drinking to coronary artery disease. Am J Cardiol 101:825–827PubMedCrossRefGoogle Scholar
  68. Klotz KN, Hessling J, Hegler J et al (1998) Comparative pharmacology of human adenosine receptor subtypes – characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch Pharmacol 357:1–9PubMedCrossRefGoogle Scholar
  69. Kong H, Jones PP, Koop A, Zhang L, Duff HJ, Chen SR (2008) Caffeine induces Ca2+ release by reducing the threshold for luminal Ca2+ activation of the ryanodine receptor. Biochem J 414:441–452PubMedCrossRefGoogle Scholar
  70. Lai EY, Patzak A, Steege A et al (2006) Contribution of adenosine receptors in the control of arteriolar tone and adenosine-angiotensin II interaction. Kidney Int 70:690–698PubMedCrossRefGoogle Scholar
  71. Lieu HD, Shryock JC, von Mering GO et al (2007) Regadenoson, a selective A2A adenosine receptor agonist, causes dose-dependent increases in coronary blood flow velocity in humans. J Nucl Cardiol 14:514–520PubMedCrossRefGoogle Scholar
  72. Lindahl B, Johansson I, Huhtasaari F, Hallmans G, Asplund K (1991) Coffee drinking and blood cholesterol: effects of brewing method, food intake and life style. J Intern Med 230:299–305PubMedCrossRefGoogle Scholar
  73. Little JA, Shanoff HM, Csima A, Toronto MA, Yano R (1966) Coffee and serum-lipids in coronary heart-disease. Lancet 1:732–734PubMedGoogle Scholar
  74. Lo YC, Tsou HH, Lin RJ et al (2005) Endothelium-dependent and -independent vasorelaxation by a theophylline derivative MCPT: roles of cyclic nucleotides, potassium channel opening and phosphodiesterase inhibition. Life Sci 76:931–944PubMedCrossRefGoogle Scholar
  75. Lopez-Garcia E, van Dam RM, Li TY, Rodriguez-Artalejo F, Hu FB (2008) The relationship of coffee consumption with mortality. Ann Intern Med 148:904–914PubMedGoogle Scholar
  76. Lovallo WR, Wilson MF, Vincent AS, Sung BH, McKey BS, Whitsett TL (2004) Blood pressure response to caffeine shows incomplete tolerance after short-term regular consumption. Hypertension 43:760–765PubMedCrossRefGoogle Scholar
  77. MacDonald TM, Sharpe K, Fowler G et al (1991) Caffeine restriction: effect on mild hypertension. BMJ 303:1235–1238PubMedCrossRefGoogle Scholar
  78. Mahmud A, Feely J (2001) Acute effect of caffeine on arterial stiffness and aortic pressure waveform. Hypertension 38:227–231PubMedCrossRefGoogle Scholar
  79. McNamara R, Maginn M, Harkin A (2007) Caffeine induces a profound and persistent tachycardia in response to MDMA (“Ecstasy”) administration. Eur J Pharmacol 555:194–198PubMedCrossRefGoogle Scholar
  80. McPherson PS, Kim YK, Valdivia H et al (1991) The brain ryanodine receptor: a caffeine-sensitive calcium release channel. Neuron 7:17–25PubMedCrossRefGoogle Scholar
  81. Mehta MC, Jain AC, Billie M (2004) Effects of cocaine and caffeine alone and in combination on cardiovascular performance: an experimental hemodynamic and coronary flow reserve study in a canine model. Int J Cardiol 97:225–232PubMedCrossRefGoogle Scholar
  82. Meijer P, Oyen WJ, Dekker D et al (2009) Rosuvastatin increases extracellular adenosine formation in humans in vivo: a new perspective on cardiovascular protection. Arterioscler Thromb Vasc Biol 29:963–968PubMedCrossRefGoogle Scholar
  83. Melchert PJ, Duncker DJ, Traverse JH, Bache RJ (1999) Role of K(+)(ATP) channels and adenosine in regulation of coronary blood flow in the hypertrophied left ventricle. Am J Physiol 277:H617–H625PubMedGoogle Scholar
  84. Müller C, Jacobson KA (2010) Xanthines as adenosine receptor antagonists. In: Fredholm BB (ed) Methylxanthines. Springer, HeidelbergGoogle Scholar
  85. Myers MG, Basinski A (1992) Coffee and coronary heart disease. Arch Intern Med 152:1767–1772PubMedCrossRefGoogle Scholar
  86. Newton GE, Azevedo ER, Parker JD (1999) Inotropic and sympathetic responses to the intracoronary infusion of a beta2-receptor agonist: a human in vivo study. Circulation 99: 2402–2407PubMedCrossRefGoogle Scholar
  87. Noordzij M, Uiterwaal CS, Arends LR, Kok FJ, Grobbee DE, Geleijnse JM (2005) Blood pressure response to chronic intake of coffee and caffeine: a meta-analysis of randomized controlled trials. J Hypertens 23:921–928PubMedCrossRefGoogle Scholar
  88. Notarius CF, Atchison DJ, Rongen GA, Floras JS (2001) Effect of adenosine receptor blockade with caffeine on sympathetic response to handgrip exercise in heart failure. Am J Physiol Heart Circ Physiol 281:H1312–H1318PubMedGoogle Scholar
  89. Notarius CF, Rongen GA, Floras JS (2003) Caffeine and coffee tolerance. Circulation 108:e38–e40PubMedCrossRefGoogle Scholar
  90. Nurminen ML, Niittynen L, Korpela R, Vapaatalo H (1999) Coffee, caffeine and blood pressure: a critical review. Eur J Clin Nutr 53:831–839PubMedCrossRefGoogle Scholar
  91. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE (1997) Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 337:230–236PubMedCrossRefGoogle Scholar
  92. Olthof MR, Hollman PC, Zock PL, Katan MB (2001) Consumption of high doses of chlorogenic acid, present in coffee, or of black tea increases plasma total homocysteine concentrations in humans. Am J Clin Nutr 73:532–538PubMedGoogle Scholar
  93. Panagiotakos DB, Pitsavos C, Zampelas A et al (2004) The association between coffee consumption and plasma total homocysteine levels: the “ATTICA” study. Heart Vessels 19:280–286PubMedCrossRefGoogle Scholar
  94. Paoloni HJ, Wilcken DE (1975) The action of aminophylline on the acutely transplanted dog heart: effect of alpha- and beta-adrenoceptor blockade. Br J Pharmacol 53:163–171PubMedCrossRefGoogle Scholar
  95. Papamichael CM, Aznaouridis KA, Karatzis EN et al (2005) Effect of coffee on endothelial function in healthy subjects. The role of caffeine. Clin Sci (Lond) 109:55–60CrossRefGoogle Scholar
  96. Patti G, Pasceri V, Colonna G et al (2007) Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 49:1272–1278PubMedCrossRefGoogle Scholar
  97. Paynter NP, Yeh HC, Voutilainen S et al (2006) Coffee and sweetened beverage consumption and the risk of type 2 diabetes mellitus: the atherosclerosis risk in communities study. Am J Epidemiol 164:1075–1084PubMedCrossRefGoogle Scholar
  98. Pereira MA, Parker ED, Folsom AR (2006) Coffee consumption and risk of type 2 diabetes mellitus: an 11-year prospective study of 28 812 postmenopausal women. Arch Intern Med 166:1311–1316PubMedCrossRefGoogle Scholar
  99. Persson PB (2001) Tubuloglomerular feedback in adenosine A1 receptor-deficient mice. Am J Physiol Regul Integr Comp Physiol 281:R1361PubMedGoogle Scholar
  100. Phillis JW, Song D, O'Regan MH (1998) The role of adenosine in rat coronary flow regulation during respiratory and metabolic acidosis. Eur J Pharmacol 356:199–206PubMedCrossRefGoogle Scholar
  101. Pietinen P, Aro A, Tuomilehto J, Uusitalo U, Korhonen H (1990) Consumption of boiled coffee is correlated with serum cholesterol in Finland. Int J Epidemiol 19:586–590PubMedCrossRefGoogle Scholar
  102. Pincomb GA, Lovallo WR, Passey RB, Whitsett TL, Silverstein SM, Wilson MF (1985) Effects of caffeine on vascular resistance, cardiac output and myocardial contractility in young men. Am J Cardiol 56:119–122PubMedCrossRefGoogle Scholar
  103. Plagemann PG, Wohlhueter RM (1984) Inhibition of the transport of adenosine, other nucleosides and hypoxanthine in Novikoff rat hepatoma cells by methylxanthines, papaverine, N6-cyclohexyladenosine and N6-phenylisopropyladenosine. Biochem Pharmacol 33:1783–1788PubMedCrossRefGoogle Scholar
  104. Rakic V, Burke V, Beilin LJ (1999) Effects of coffee on ambulatory blood pressure in older men and women: a randomized controlled trial. Hypertension 33:869–873PubMedCrossRefGoogle Scholar
  105. Ramakers BP, Pickkers P, Deussen A et al (2008) Measurement of the endogenous adenosine concentration in humans in vivo: methodological considerations. Curr Drug Metab 9:679–685PubMedCrossRefGoogle Scholar
  106. Rasmussen CA Jr, Sutko JL, Barry WH (1987) Effects of ryanodine and caffeine on contractility, membrane voltage, and calcium exchange in cultured heart cells. Circ Res 60:495–504PubMedCrossRefGoogle Scholar
  107. Riksen NP, Rongen GA, Smits P (2009) Acute and long-term cardiovascular effects of coffee: implications for coronary heart disease. Pharmacol Ther 121:185–191PubMedCrossRefGoogle Scholar
  108. Riksen NP, Rongen GA, Yellon D, Smits P (2008) Human in vivo research on the vascular effects of adenosine. Eur J Pharmacol 585:220–227PubMedCrossRefGoogle Scholar
  109. Riksen NP, Zhou Z, Oyen WJ et al (2006) Caffeine prevents protection in two human models of ischemic preconditioning. J Am Coll Cardiol 48:700–707PubMedCrossRefGoogle Scholar
  110. Robertson D, Frolich JC, Carr RK et al (1978) Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med 298:181–186PubMedCrossRefGoogle Scholar
  111. Robertson D, Wade D, Workman R, Woosley RL, Oates JA (1981) Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest 67:1111–1117PubMedCrossRefGoogle Scholar
  112. Rongen GA, Brooks SC, Ando S, Abramson BL, Floras JS (1998a) Angiotensin AT1 receptor blockade abolishes the reflex sympatho-excitatory response to adenosine. J Clin Invest 101:769–776PubMedCrossRefGoogle Scholar
  113. Rongen GA, Brooks SC, Ando S, Notarius CF, Floras JS (1998b) Caffeine abstinence augments the systolic blood pressure response to adenosine in humans. Am J Cardiol 81:1382–1385PubMedCrossRefGoogle Scholar
  114. Rongen GA, Floras JS, Lenders JW, Thien T, Smits P (1997) Cardiovascular pharmacology of purines. Clin Sci (Lond) 92:13–24Google Scholar
  115. Rongen GA, Lenders JW, Lambrou J et al (1996) Presynaptic inhibition of norepinephrine release from sympathetic nerve endings by endogenous adenosine. Hypertension 27:933–938PubMedCrossRefGoogle Scholar
  116. Rongen GA, Smits P, Verdonck K et al (1995) Hemodynamic and neurohumoral effects of various grades of selective adenosine transport inhibition in humans. Implications for its future role in cardioprotection. J Clin Invest 95:658–668PubMedCrossRefGoogle Scholar
  117. Rosmarin PC, Applegate WB, Somes GW (1990) Coffee consumption and blood pressure: a randomized, crossover clinical trial. J Gen Intern Med 5:211–213PubMedCrossRefGoogle Scholar
  118. Rosner SA, Akesson A, Stampfer MJ, Wolk A (2007) Coffee consumption and risk of myocardial infarction among older Swedish women. Am J Epidemiol 165:288–293PubMedCrossRefGoogle Scholar
  119. Rutherford JD, Vatner SF, Braunwald E (1981) Effects and mechanism of action of aminophylline on cardiac function and regional blood flow distribution in conscious dogs. Circulation 63:378–387PubMedCrossRefGoogle Scholar
  120. Sanada S, Asanuma H, Minamino T et al (2004) Optimal windows of statin use for immediate infarct limitation: 5′-nucleotidase as another downstream molecule of phosphatidylinositol 3-kinase. Circulation 110:2143–2149PubMedCrossRefGoogle Scholar
  121. Sattin A, Rall TW (1970) The effect of adenosine and adenine nucleotides on the cyclic adenosine 3′,5′-phosphate content of guinea pig cerebral cortex slices. Mol Pharmacol 6:13–23PubMedGoogle Scholar
  122. Schwabe U, Ukena D, Lohse MJ (1985) Xanthine derivatives as antagonists at A1 and A2 adenosine receptors. Naunyn Schmiedebergs Arch Pharmacol 330:212–221PubMedCrossRefGoogle Scholar
  123. Sekiguchi F, Miyake Y, Kashimoto T, Sunano S (2002) Unaltered caffeine-induced relaxation in the aorta of stroke-prone spontaneously hypertensive rats (SHRSP). J Smooth Muscle Res 38:11–22PubMedCrossRefGoogle Scholar
  124. Smits P, Boekema P, De Abreu R, Thien T, van 't Laar A (1987) Evidence for an antagonism between caffeine and adenosine in the human cardiovascular system. J Cardiovasc Pharmacol 10:136–143PubMedCrossRefGoogle Scholar
  125. Smits P, Lenders JW, Thien T (1990) Caffeine and theophylline attenuate adenosine-induced vasodilation in humans. Clin Pharmacol Ther 48:410–418PubMedCrossRefGoogle Scholar
  126. Smits P, Pieters G, Thien T (1986) The role of epinephrine in the circulatory effects of coffee. Clin Pharmacol Ther 40:431–437PubMedCrossRefGoogle Scholar
  127. Smits P, Schouten J, Thien T (1989) Cardiovascular effects of two xanthines and the relation to adenosine antagonism. Clin Pharmacol Ther 45:593–599PubMedCrossRefGoogle Scholar
  128. Smits P, Thien T, Van’t Laar A (1985a) The cardiovascular effects of regular and decaffeinated coffee. Br J Clin Pharmacol 19:852–854PubMedCrossRefGoogle Scholar
  129. Smits P, Thien T, Laar A (1985b) Circulatory effects of coffee in relation to the pharmacokinetics of caffeine. Am J Cardiol 56:958–963PubMedCrossRefGoogle Scholar
  130. Sofi F, Conti AA, Gori AM et al (2007) Coffee consumption and risk of coronary heart disease: a meta-analysis. Nutr Metab Cardiovasc Dis 17:209–223PubMedCrossRefGoogle Scholar
  131. Song Y, Shryock JC, Knot HJ, Belardinelli L (2001) Selective attenuation by adenosine of arrhythmogenic action of isoproterenol on ventricular myocytes. Am J Physiol Heart Circ Physiol 280:H2789–H2795PubMedGoogle Scholar
  132. Stolzenberg-Solomon RZ, Miller ER III, Maguire MG, Selhub J, Appel LJ (1999) Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population. Am J Clin Nutr 69:467–475PubMedGoogle Scholar
  133. Strandhagen E, Thelle DS (2003) Filtered coffee raises serum cholesterol: results from a controlled study. Eur J Clin Nutr 57:1164–1168PubMedCrossRefGoogle Scholar
  134. Strandhagen E, Zetterberg H, Aires N et al (2004) The methylenetetrahydrofolate reductase C677T polymorphism is a major determinant of coffee-induced increase of plasma homocysteine: a randomized placebo controlled study. Int J Mol Med 13:811–815PubMedGoogle Scholar
  135. Superko HR, Bortz W Jr, Williams PT, Albers JJ, Wood PD (1991) Caffeinated and decaffeinated coffee effects on plasma lipoprotein cholesterol, apolipoproteins, and lipase activity: a controlled, randomized trial. Am J Clin Nutr 54:599–605PubMedGoogle Scholar
  136. Superko HR, Myll J, DiRicco C, Williams PT, Bortz WM, Wood PD (1994) Effects of cessation of caffeinated-coffee consumption on ambulatory and resting blood pressure in men. Am J Cardiol 73:780–784PubMedCrossRefGoogle Scholar
  137. Sutton-Tyrrell K, Najjar SS, Boudreau RM et al (2005) Elevated aortic pulse wave velocity, a marker of arterial stiffness, predicts cardiovascular events in well-functioning older adults. Circulation 111:3384–3390PubMedCrossRefGoogle Scholar
  138. Taddei S, Virdis A, Mattei P, Favilla S, Salvetti A (1991) Adenosine causes angiotensin II release in human forearm arterioles. J Hypertens Suppl 9:S232–S233PubMedGoogle Scholar
  139. Tawfik HE, Schnermann J, Oldenburg PJ, Mustafa SJ (2005) Role of A1 adenosine receptors in regulation of vascular tone. Am J Physiol Heart Circ Physiol 288:H1411–H1416PubMedCrossRefGoogle Scholar
  140. Thelle DS, Heyden S, Fodor JG (1987) Coffee and cholesterol in epidemiological and experimental studies. Atherosclerosis 67:97–103PubMedCrossRefGoogle Scholar
  141. Timmers HJ, Rongen GA, Karemaker JM, Wieling WW, Marres HA, Lenders JW (2004) The role of carotid chemoreceptors in the sympathetic activation by adenosine in humans. Clin Sci (Lond) 106:75–82CrossRefGoogle Scholar
  142. Tsuzuki J, Newburgh RW (1975) Inhibition of 5′-nucleotidase in rat brain by methylxanthines. J Neurochem 25:895–896PubMedCrossRefGoogle Scholar
  143. Uiterwaal CS, Verschuren WM, Bueno-de-Mesquita HB et al (2007) Coffee intake and incidence of hypertension. Am J Clin Nutr 85:718–723PubMedGoogle Scholar
  144. Umemura T, Ueda K, Nishioka K et al (2006) Effects of acute administration of caffeine on vascular function. Am J Cardiol 98:1538–1541PubMedCrossRefGoogle Scholar
  145. Urgert R, Katan MB (1997) The cholesterol-raising factor from coffee beans. Annu Rev Nutr 17:305–324PubMedCrossRefGoogle Scholar
  146. Urquhart RA, Broadley KJ (1992a) The effects of P1- and muscarinic-receptor agonists upon cAMP-dependent and independent inotropic responses of guinea-pig cardiac preparations. Gen Pharmacol 23:619–626PubMedCrossRefGoogle Scholar
  147. Urquhart RA, Broadley KJ (1992b) The indirect negative inotropic effects of the P1-receptor agonist, L-phenylisopropyladenosine, in guinea-pig isolated cardiac preparations: comparison with cromakalim. Can J Physiol Pharmacol 70:910–915PubMedCrossRefGoogle Scholar
  148. van Dam RM, Feskens EJ (2002) Coffee consumption and risk of type 2 diabetes mellitus. Lancet 360:1477–1478PubMedCrossRefGoogle Scholar
  149. van Dam RM, Hu FB (2005) Coffee consumption and risk of type 2 diabetes: a systematic review. JAMA 294:97–104PubMedCrossRefGoogle Scholar
  150. van Dam RM, Willett WC, Manson JE, Hu FB (2006) Coffee, caffeine, and risk of type 2 diabetes: a prospective cohort study in younger and middle-aged U.S. women. Diab Care 29:398–403CrossRefGoogle Scholar
  151. van Woudenbergh GJ, Vliegenthart R, van Rooij FJA et al (2008) Coffee consumption and coronary calcification: the Rotterdam coronary calcification study. Arterioscler Thromb Vasc Biol 28:1018–1023PubMedCrossRefGoogle Scholar
  152. van Dusseldorp M, Smits P, Lenders JW, Thien T, Katan MB (1991) Boiled coffee and blood pressure. A 14-week controlled trial. Hypertension 18:607–613PubMedCrossRefGoogle Scholar
  153. Varani K, Portaluppi F, Gessi S et al (2000) Dose and time effects of caffeine intake on human platelet adenosine A2A receptors: functional and biochemical aspects. Circulation 102:285–289PubMedCrossRefGoogle Scholar
  154. Varani K, Portaluppi F, Merighi S, Ongini E, Belardinelli L, Borea PA (1999) Caffeine alters A2A adenosine receptors and their function in human platelets. Circulation 99:2499–2502PubMedCrossRefGoogle Scholar
  155. Verhoef P, Pasman WJ, Van VT, Urgert R, Katan MB (2002) Contribution of caffeine to the homocysteine-raising effect of coffee: a randomized controlled trial in humans. Am J Clin Nutr 76:1244–1248PubMedGoogle Scholar
  156. Vlachopoulos C, Hirata K, O'Rourke MF (2003) Effect of caffeine on aortic elastic properties and wave reflection. J Hypertens 21:563–570PubMedCrossRefGoogle Scholar
  157. Weggemans RM, Zock PL, Ordovas JM, Pedro-Botet J, Katan MB (2001a) Apoprotein E genotype and the response of serum cholesterol to dietary fat, cholesterol and cafestol. Atherosclerosis 154:547–555PubMedCrossRefGoogle Scholar
  158. Weggemans RM, Zock PL, Ordovas JM, Ramos-Galluzzi J, Katan MB (2001b) Genetic polymorphisms and lipid response to dietary changes in humans. Eur J Clin Invest 31:950–957PubMedCrossRefGoogle Scholar
  159. Wierema TK, Houben AJ, Kroon AA et al (2005) Mechanisms of adenosine-induced renal vasodilatation in hypertensive patients. J Hypertens 23:1731–1736PubMedCrossRefGoogle Scholar
  160. Winkelmayer WC, Stampfer MJ, Willett WC, Curhan GC (2005) Habitual caffeine intake and the risk of hypertension in women. JAMA 294:2330–2335PubMedCrossRefGoogle Scholar
  161. Woo OF, Pond SM, Benowitz NL, Olson KR (1984) Benefit of hemoperfusion in acute theophylline intoxication. J Toxicol Clin Toxicol 22:411–424PubMedCrossRefGoogle Scholar
  162. Yang JN, Bjorklund O, Lindstrom-Tornqvist K et al (2009) Mice heterozygous for both A1 and A2A adenosine receptor genes show similarities to mice given long-term caffeine. J Appl Physiol 106:631–639PubMedCrossRefGoogle Scholar
  163. Ye Y, Abu Said G, Lin Y et al (2008) Caffeinated coffee blunts the myocardial protective effects of statins against ischemia-reperfusion injury in the rat. Cardiovasc Drugs Ther 22:275–282PubMedCrossRefGoogle Scholar
  164. Yellon DM, Downey JM (2003) Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 83:1113–1151PubMedGoogle Scholar
  165. Zhang W, Lopez-Garcia E, Li TY, Hu FB, van Dam RM (2009) Coffee consumption and risk of cardiovascular diseases and all-cause mortality among men with type 2 diabetes. Diab Care 32:1043–1045CrossRefGoogle Scholar

Copyright information

© Springer Berlin Heidelberg 2011

Authors and Affiliations

  • Niels P. Riksen
    • 1
    Email author
  • Paul Smits
    • 1
  • Gerard A. Rongen
    • 1
  1. 1.Departments of Pharmacology-Toxicology and Internal MedicineRadboud University Nijmegen Medical CentreNijmegenThe Netherlands

Personalised recommendations