The chronotropic effect of adenosine and ATP in dogs. The antagonism by theophylline.

We analyzed the action of adenosine and adenosine triphosphate (ATP) on the chronotropism of the dog heart in situ. The compounds were administered either intravenously (i.v.) after bivagotomy and propranolol treatment, or intracoronary (i.c.) in the sinus node blood supply. Under these conditions the intervention of reflex reactions was eliminated, and a constant and dose-dependent negative chronotropic effect was obtained. From the dose-response curves the relative potencies of ATP and adenosine were calculated, and found to be similar for both routes of administration (potency ratio 0.77 (0.72-0.82) by i.v. administration, and 0.52 (0.36-0.78) by intracoronary administration). The effect was also mimicked by 2-chloroadenosine, (a long acting P1 agonist), and by 5'-adenylyl (beta, gamma-imido) diphosphonate, a non-hydrolysable ATP analog. The chronotropic effect of ATP and adenosine were not prevented by 1 mg/kg atropine intravenous. Theophylline, at 3 mg/kg i.v., shifted the dose-response curves of i.v. ATP and adenosine to the right, suggesting a competitive antagonism. At a dose of 6 mg/kg theophylline, the effects of i.c. adenosine were competitively blocked. Theophylline also antagonized, in a competitive manner, the hypotensive effect of the i.v. administration of both compounds. Our results suggest that the chronotropic effect of purine compounds in anaesthetized animals could be brought about by a specific purinergic theophylline-sensitive mechanism and not by direct vagal activation.