Objective: Dosing intervals of 12 and 24 hours for atenolol have been recommended, but an evidentiary basis is lacking. To test the hypothesis that repeated, once-daily oral administration of atenolol attenuates the heart rate response to isoproterenol for 24 hours, we performed a double-blind, randomized, placebo-controlled cross-over experiment.

Animals: Twenty healthy dogs

Procedures: Dogs were randomly assigned to receive either placebo (P) and then atenolol (A), [1 mg/kg PO q24h] or vice versa. Treatment periods were 5-7 days; time between periods was 7 days. Heart rates (bpm) at rest (HRr) and during constant rate [0.2 μg/kg/min] infusion of isoproterenol (HRi) were electrocardiographically obtained 0, 0.25, 3, 6, 12, 18, and 24 hours after final administration of drug or placebo. A mixed model ANOVA was used to evaluate the effects of treatment (Tr), time after drug or placebo administration (t), interaction of treatment and time (Tr*t) as well as period and sequence on HRr and HRi.

Results: Sequence or period effects were not detected. There was a significant effect of Tr (p <0.0001) and Tr*t (p <0.0001) on HRi. Atenolol significantly attenuated HRi for 24 hours but did so maximally at 3 hours (least squares means ± SE, A: 146±5 bpm, P: 208±5 bpm); the effect at 24 hours was small (A: 193±5, P: 206±5). Atenolol had a small but significant effect (p <0.0001) on HRr.

Conclusions and Clinical Relevance: The results of this study support a dosing interval that is less than 24 hours.