To investigate the potential contribution of cardiopulmonary reflexes in myocardial ischemia, the coronary vascular response to cardiopulmonary baroreceptor unloading and the number and the duration of spontaneous episodes of symptomatic and asymptomatic myocardial ischemia were evaluated in 23 patients with coronary heart disease. Lower-body negative pressure at -10 mm Hg, which causes selective deactivation of cardiopulmonary receptors, reduced left ventricular filling pressure in all patients, but calculated coronary vascular resistance increased in only 14 patients (from 0.846±0.1 to 1.07±0.1 mm Hg/ml/min,p<0.01) (group 1). In the remaining nine patients, coronary resistance did not change during cardiopulmonary receptor unloading (group 2). A 60-mm Hg increase in neck tissue pressure, which induces arterial baroreflex-mediated sympathetic activation, caused comparable coronary vasoconstriction in the two groups. Clinical characteristics of the two groups were similar, except that a lower ejection fraction was measured in group 1 (45±2% vs. 56±1%, p<0.01). In the 14 patients in group 1, 24-hour electrocardiographic monitoring showed 151 episodes of myocardial ischemia (average individual value, 10.8±1), 137 of which were asymptomatic, with an individual daily ischemic period of 62±6 minutes. In contrast, the nine patients in group 2 had only symptomatic episodes of myocardial ischemia, and the daily ischemic period in these patients was longer than in patients of group 1 (104±10 minutes, p<0.01). After a 3-day treatment with digitalis, the patients of group 2 showed 38 asymptomatic episodes of myocardial ischemia and a shorter daily ischemic period (85±6 minutes, p < 0.01 vs. control conditions). In contrast, no change in number and duration of the ischemic episodes was detected in group 1. The effects of acute administration of digitalis (Lanatoside-C 0.02 mg/kg body wt e.v.) on the coronary vascular response to cardiopulmonary receptor unloading were assessed in a separate group of patients with ischemic heart disease. Digitalis treatment did not significantly modify the magnitude of the coronary vascular response induced by -10 mm Hg lower-body negative pressure in the patients showing in control conditions an increase of coronary vascular resistance greater than 20% of the basal value during cardiopulmonary receptor unloading. On the contrary, digitalis potentiated the coronary reflex response to -10 mm Hg lower-body negative pressure in the patients with impaired cardiopulmonary responsiveness (A percent increase in coronary vascular resistance: 1±1% in control conditions; 23±3.9% after digitalis, p<0.001). In conclusion, in patients with coronary heart disease, impaired low-pressure receptor responsiveness is associated with prolonged duration of myocardial ischemia. When cardiopulmonary reflexes are restored by digitalis, the duration of myocardial ischemia is significantly reduced. (Circulation 1990;81:1792-1802