Adenosine infusion can potentially be used as a diagnostic test for sick sinus syndrome (SSS) based on its negative chronotropic effects. Whether autonomic tone underlies adenosine's negative chronotropic effects remains unknown. This study was to investigate the bradycardiac response of sinus node to ATP in patients with and without clinical SSS by measuring atrial cycle length (ACL) before and after bolus of ATP in different states of autonomic tone. The negative chronotropic effect of ATP was assessed by comparing the mean ACL before ATP administration with the longest ACL after a bolus of ATP infusion (Delta ACL). Our results showed that Delta ACL in patients with SSS were significantly greater than that without SSS (P<.001) in all 4 states, and IHR in patients with SSS were significantly lower than calculated IHR (P<.0001). Moreover, there was no significant difference in Delta ACL between the 4 states in patients with SSS (P = .99). However, Delta ACL was significantly greater during isoproterenol infusion and after propranolol administration in patients without sinus node dysfunction, comparing with baseline state (P<.01), but not after combination of atropine (P = .33). Our results indicate that the negative chronotropic effect of ATP on sinus node is much more dramatic in patients with SSS, in which the intrinsic disease of sinus node is responsible for the abnormal adenosine-mediated sinus arrest, and this effect is influenced by autonomic tone in patients without sinus node dysfunction but not in patients with SSS.