The normal relationship between arterial and venous acid-base composition is altered in hemodynamic compromise. Because the mechanism of this phenomenon remains conjectural, we have studied the acid-base profile and the end-tidal PCO2 of dogs with normal or depressed hemodynamic status in association with either normal ventilation or respiratory arrest. Reductions in cardiac output widened the arteriovenous difference in PCO2 and pH, largely due to arterial hypocapnia but also to venous hypercapnia, and decreased end-tidal PCO2. The arteriovenous gradients for PCO2 and pH of -5.1 +/- 0.4 mmHg and 0.02 +/- 0.01, respectively, during normal hemodynamics widened progressively with graded circulatory compromise reaching values of -30 +/- 5 mmHg for PCO2 (P less than 0.01) and 0.35 +/- 0.05 for pH (P less than 0.01) during cardiac arrest. Development of this disparity, however, required the presence of substantial pulmonary ventilation, since respiratory arrest obliterated the arteriovenous gradients. We propose that arterial hypocapnia, which occurs in association with reduced CO2 excretion, is secondary to an increased ventilation-to-perfusion ratio that reflects a disproportionate decrement in cardiac output. Venous hypercapnia, on the other hand, results from a greater than normal addition of CO2 per unit of blood traversing the capillaries of the hypoperfused peripheral tissues and a diminished CO2 excretion because of pulmonary hypoperfusion. Titration of bicarbonate stores by ongoing production of organic acids might also contribute to venous hypercapnia.