Some studies have suggested that angiotensin-converting enzyme (ACE) inhibition in patients with heart failure is associated with a decrease in frequency of spontaneous premature ventricular complexes (PVCs). It is not clear whether such a finding represents a primary effect of ACE inhibition or, instead, a secondary result of treatment of heart failure. For a primary drug effect to be present, PVC suppression during ACE inhibition should also occur in patients with preserved left ventricular systolic function. We therefore undertook a randomized double-blind placebo-controlled crossover clinical trial to assess the effect of oral captopril (50 mg. b.i.d.) on ventricular arrhythmia frequency in 11 patients with > 30 PVCs/h (during a 48-h ambulatory recording) and a left ventricular ejection fraction of > or = 45% (measured by radionuclide multigated acquisition scan). Pharmacologic activity of the administered drug was evidenced by an increase in median plasma renin activity to 2.4 ng/AI/ml/h from a value of 1.1 ng/AI/ml/h during placebo (p = 0.001) and an 8.5 +/- 10.3 drop in mean diastolic blood pressure during captopril versus placebo (p < 0.03). During captopril treatment, a mean of 491 +/- 378 PVCs/h were observed compared with 389 +/- 169 PVCs/h during placebo, a nonsignificant difference. There was also no significant change in left ventricular ejection fraction, plasma catecholamines, or serum potassium during captopril treatment. Thus, ACE inhibition in patients with preserved left ventricular systolic function fails to suppress ventricular ectopic activity. Extrapolated to patients with heart failure, our observations argue against a primary PVC suppressive action of ACE inhibitors but do not rule out possible secondary antiarrhythmic effects of these agents.