STUDY OBJECTIVE: The aim of the study was to evaluate the effect of chronic digoxin therapy on cardiac sensitivity to isoprenaline. DESIGN: Responses to isoprenaline were examined in both conscious and anaesthetised dogs pretreated with digoxin, and compared with conscious or anaesthetised controls with no digoxin pretreatment. Isoprenaline infusion (0.001-0.1 micrograms.kg-1.min-1) in pretreated groups was performed 7 d after digoxin dosing was stopped, when plasma digoxin concentrations were zero. SUBJECTS: Mongrel dogs of either sex (15-25 kg) were used in the experiments, done under anaesthetic. They were divided into three groups (n = 6 per group): group A were controls; groups B and C were pretreated with digoxin 500-750 micrograms.d-1, for 14 d (B) and 7 d (C). For the experiments in conscious animals, six mongrel dogs (25-30 kg) and two greyhounds (25-30 kg) were used; group D (n = 6) were treated with digoxin for 20-40 d; group E (n = 2) were treated for 7 d. MEASUREMENTS AND RESULTS: Heart rate, blood pressure and myocardial contractility (dP/dt: integrated isometric tension) were measured during isoprenaline infusion. Digoxin pretreatment for 14 d did not significantly change the chronotropic or depressor responses to isoprenaline in anaesthetised dogs but there was a 10-fold increase in inotropic sensitivity to isoprenaline following withdrawal. When the pretreatment period was reduced to 7 d there was no change in any of the responses to isoprenaline. In conscious dogs there was also a significant increase in inotropic sensitivity to isoprenaline after digoxin withdrawal, but this was not so marked as in anaesthetised dogs. In conscious dogs chronotropic sensitivity to isoprenaline was also increased. CONCLUSIONS: It is possible that the inotropic effect maintained during the 2 weeks of digoxin treatment may cause substantial withdrawal of sympathetic tone to the heart, with a consequent increase in beta adrenoceptor number or sensitivity, which could be detected a week after digoxin withdrawal.