1. Recently, we have demonstrated that hypoxic breathing is followed by an increase in plasma digoxin-like substance in normal men. 2. This study was undertaken in order to evaluate whether or not a low arterial O2 partial pressure is combined with an increase in plasma digoxin-like substance in chronic pathological conditions also. 3. Sixteen male patients (mean age 53.1 +/- 3.7 years) affected by chronic obstructive pulmonary disease of a mild stage were studied. They were further subdivided according to their arterial O2 partial pressure into 'mild hypoxic' (n = 8, mean age 52.5 +/- 2.7 years), with an arterial O2 partial pressure between 66 and 75 mmHg, and 'severe hypoxic' (n = 8, mean age 54.3 +/- 5.1 years), with an arterial O2 partial pressure < or = 65 mmHg, groups. Seven healthy men (mean age 48.5 +/- 4.8 years) voluntarily participated as the control group. 4. Plasma digoxin-like substance levels were significantly higher in 'severe hypoxic' patients (203.5 +/- 9.9 pg/ml) than in both 'mild hypoxic' patients (169.5 +/- 31.4 pg/ml, P < 0.02) and normal subjects (158.9 +/- 12.4 pg/ml, P < 0.0001) and were directly correlated with urinary Na+ excretion (severe hypoxic group, r = 0.756, P < 0.007; mild hypoxic group, r = 0.789, P < 0.02). Considering the two hypoxic groups together, plasma digoxin-like substance levels were negatively correlated with arterial O2 partial pressure (r = -0.740, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)