OBJECTIVE Recent studies have demonstrated that adenosine is an endogenous modulator of the cardiac excitatory afferent nerves, and could provoke a vasovagal response during head-up tilt test. Isoproterenol has been the drug of choice to increase the sensitivity of this testing. The aim of the present study was to analyze the role of adenosine in head-up tilt-induced syncope in susceptible patients, and to compare the relative sensitivities of adenosine and isoproterenol. METHODS Thirty patients with unexplained syncope (16 female and 14 male, mean age 37.1 +/- 18 years), no heart disease and negative baseline head-up tilt test were studied. After the baseline test, patients were randomized to receive adenosine triphosphate (bolus injections of 3, 6 and 9 mg/ 5 min) or isoproterenol (bolus injections of 2, 4 and 6 micrograms/5 min) and underwent a second tilt test. After 15 min at rest, patients received the alternative drug and a third test was performed. Eleven normal control subjects were tested with adenosine in the upright position to determine its effects. RESULTS A vasovagal response was induced in 7 patients (23.3%) after ATP administration. Nine patients (30%) showed a positive response with isoproterenol. Only 2 patients (6.6%) showed a positive response with both drugs. Of the control subjects, one (9%) had a vasovagal response after ATP administration. CONCLUSIONS We conclude that adenosine triphosphate seems to be a useful tool to provoke vasovagal reaction in susceptible patients during head-up tilt test.