Previous studies of ANF production during cardiopulmonary bypass (CPB) showed a paradoxical rise despite low (negative) RAP. We thus postulated that ANF secretion could be stimulated by inward atrial stretch (atrial inversion due to emptying of the RA by siphonage through the venous cannula, accompanied by negative RAP) or by trauma by the surgeon. To test this hypotheses RA preload was controlled by right heart bypass, and trauma to the RA was avoided by extrapericardial cannulation of SVC, IVC and PA in 7 anesthetized dogs. Blood sampling catheters and pressure micromanometers were placed in RA and aorta. Blood was collected at 42 different hemodynamic states and ANF concentration determined by radioimmunoassay. Concentration in RA ([RA]) and in aorta ([Ao]) increased with RAP within the physiological (positive) range: [RA] = 38.8*RAP-5.9, (r = 0.91, p<0.001); [Ao] = 24.7*RAP-3.0 (r = 0.93, p<0.01). The increase in concentration of ANF in the RA and in the Aorta also correlated strongly with the negative magnitude of RA pressure: [RA] = 26.9*RAP+0.1 (r = 0.83, p<0.01); [Ao] = -14.8*RAP-3.1 (r = 0.81, p<0.02). We conclude: normal right atrial pressure control of ANF secretion is abolished during CPB. The unphysiological stimulus of atrial inversion causes high right atrial ANF production. This fact may explain the sudden fall in vascular resistence with onset of CPB.