In previous studies investigators found that conditioned hypoventilatory breathing potentiated a sodium-sensitive form of hypertension in dogs that was not mediated by sympathetic nervous system arousal. Our study investigated effects of 30 minutes of voluntary hypoventilation, maintained by a respiratory gas monitor and feedback procedure, in 16 normotensive humans of both sexes on (1) plasma concentrations of endogenous digitalis-like factors (ouabain-like and marinobufagenin-like immunoreactivity), (2) activity of erythrocyte Na+, K+ -ATPase, (3) inhibitory activity of plasma Na+, K+ -ATPase, and (4) blood pressure. Increased end tidal PCO2 (41 +/- 0.78 mm Hg versus 37.6 +/- 1.03 mm Hg) was associated with (1) an increase in plasma marinobufagenin-like immunoreactivity (1.23 +/- 0.47 versus 4.96 +/- 1.19 nmol/L), (2) an inhibition of Na+, K+ -ATPase in red blood cells (3.68 +/- 0.22 versus 2.15 +/- 0.25 mmol Pi/mL-1/h-1; P < .01), (3) increase in plasma Na+, K+ -ATPase inhibitory activity (34.9 +/- 4.0% versus 48.8 +/- 2.1%, P < .02), and (4) increases in systolic (112.4 +/- 2.6 versus 107.6 +/- 1.8 mm Hg) and diastolic (73.5 +/- 2.1 versus 68.8 +/- 2.1 mm Hg) blood pressures. Plasma levels of ouabain-like immunoreactivity did not increase significantly. Incubation of erythrocytes obtained during hypoventilation with antidigoxin antibody restored the Na+, K+ -ATPase activity (3.99 +/- 0.34 mmol Pi/mL-1/h-1). Cessation of hypoventilation was associated with decreases in diastolic blood pressure (70.5 +/- 2.2 mm Hg) and restoration of Na+, K+ -ATPase activity in erythrocytes (2.99 +/- 0.43 mmol Pi/mL-1/h1).(ABSTRACT TRUNCATED AT 250 WORDS)