Interactive negative chronotropic actions of adenosine and verapamil on the canine sinus node in vivo

To study the interaction between adenosine and verapamil, adenosine (3 mumol/kg) was administered rapidly into the right atrium before and following verapamil (0.2 mg/kg, i.v.) in 25 pentobarbital anesthetized dogs divided into 4 groups: I (n = 7) - intact dogs; II (n = 6) - dogs pretreated with atropine (0.2 mg/kg, i.v.); III (n = 6) - dogs pretreated with propranolol (1 mg/kg, i.v.) and IV (n = 6) - bilateral stellectomized and cervical vagotomized dogs. Arterial blood pressure, standard lead II ECG, as well as right atrial, right ventricular and His bundle electrograms were continuously monitored and recorded. The negative chronotropic effect of adenosine was determined as the maximal prolongation in sinus cycle length (SCL). Verapamil maximally prolonged SCL by 70 +/- 14 msec (p less than 0.005) in Group I, 39 +/- 15 msec (0.1 greater than p greater than 0.005) in Group II, 86 +/- 18 msec (p less than 0.01) in Group III and by 100 +/- 12 msec (p less than 0.001) in Group IV. In Group I, control dogs, adenosine increased SCL by 82 +/- 21 msec before vs. 185 +/- 35 msec 15 minutes after verapamil, respectively (p less than 0.05). This potentiating effect of verapamil was completely abolished by atropine and markedly attenuated by propranolol. In stellectomized + vagotomized dogs, adenosine-verapamil interaction was more complex. In this group adenosine prolonged sinus cycle length maximally by 270 +/- 41 msec before verapamil, but following verapamil this effect of adenosine was transiently attenuated with a maximal sinus cycle length prolongation of only 165 +/- 24 msec (10 minutes following verapamil) (p less than 0.05, vs. before verapamil). These data indicate that the autonomic nervous system modulate the interactive negative chronotropic effects of adenosine and verapamil in the canine sinus node. Hence, the adenosine-verapamil interaction has clinical implications for conditions in which release of adenosine is increased (e.g. myocardial ischemia) or adenosine is administered in the presence of verapamil.