title: The effect of caffeine on peripheral vascular resistance in isolated perfused guinea pig hind limbs.
abstract: BACKGROUND
  The role of caffeine in cardiovascular disease is controversial. Most of its pharmacologic actions are attributed to its role as an adenosine antagonist. Adenosine is one of the most important endogenous vasodilatative substances and is released under ischemic conditions, for example, in the skeletal muscle of patients with peripheral arterial occlusive disease. We aimed to investigate the influence of caffeine on peripheral vascular resistance and on the beneficial vasodilatory effect of adenosine in isolated perfused guinea pig hind limbs.
  
  
  METHODS
  (1) Caffeine was administered at 0.5, 5, and 50 micromol/L under normoxic conditions. (2) The vasculature of the perfused guinea pig hind limb was precontracted with noradrenaline (3 micromol/L), followed by adenosine (10 micromol/L) under normoxic conditions. When vascular resistance (VR) had reached a steady state, caffeine was administered additionally at dosages of 0.5, 5, and 50 micromol/L. (3) This protocol was repeated using iloprost 0.1 micromol/L instead of adenosine as vasodilatory substance. (4) Under hypoxia, caffeine was again administered at the above dosages. (5) Under hypoxia, experiments with adenosine A2-receptor antagonists (alloxazine 10 micromol/L and ZM 241385 100 nmol/L) were done.
  
  
  RESULTS
  Under normoxic conditions, 0.5 and 5 micromol/L caffeine had nearly no effect on vascular resistance compared with baseline conditions. A slight, but statistically not significant decrease in VR was achieved with 50 micromol/L caffeine. In the presence of noradrenaline, the vasodilatory effect of adenosine was reduced by 7.6 +/- 1.6% after the addition of 0.5 micromol/L caffeine, and by 37.3 +/- 3.8% at a dosage of 5 micromol/L caffeine. A dosage of 50 micromol/L caffeine completely abolished the vasodilatative effect of adenosine. In the presence of iloprost, only a slight but statistically insignificant inhibitory influence (0.9%) of caffeine at a dosage of 50 micromol/L could be seen. Hypoxia significantly reduced VR. Caffeine at 0.5 micromol/L diminished this effect by about 53.2 +/- 4.6% and abolished it at 5 and 50 micromol/L. The hypoxia-induced adenosine-mediated vasodilatation seems to be an adenosine A2A-receptor-mediated effect.
  
  
  CONCLUSIONS
  The observed effect of hypoxia-induced vasodilatation in peripheral arteries may be the result of the vasodilatory effect of elevated endogenous adenosine during hypoxia. For patients with peripheral arterial disease, drinking of caffeine-containing beverages may reduce the beneficial vasodilatory effect of elevated endogenous adenosine levels.
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D000818:Animals; D002110:Caffeine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005415:Flavins / Q000008:administration & dosage / Q000493:pharmacokinetics; D006168:Guinea Pigs; D006614:Hindlimb / Q000098:blood supply* / Q000187:drug effects*; D000860:Hypoxia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D007083:Iliac Artery; D016285:Iloprost / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D009584:Nitrogen / Q000009:adverse effects; D009638:Norepinephrine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D010477:Perfusion; D014227:Triazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D014655:Vascular Resistance / Q000187:drug effects* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D005415:Flavins; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D002110:Caffeine; C008173:isoalloxazine; D016285:Iloprost; D000241:Adenosine; D009584:Nitrogen; D009638:Norepinephrine