The purposes of the present study are to demonstrate the presence of atrial natriuretic peptide (ANP) in canine cerebrospinal fluid (CSF) and to determine its origin as either the brain or atrium. Fifty-seven mongrel canines weighing from 7.5 to 23.0kg (male: 28, female: 29) were anesthetized with sodium pentobarbital (30mg/mg, iv) and were ventilated with a Harvard respirator. 16 canines (11.5 to 16.0kg) were used to examine the effect of endogenously increased plasma ANP level on the ANP concentration of the CSF in acute heart failure induced by experimental aortic regurgitation. Subsequently to examine the effect of exogenously increased plasma ANP level on the ANP concentration of the CSF, physiological and pharmacological doses of synthetic human alpha-ANP were continuously infused into the right ventricle (25ng/kg/min. and 250ng/kg/min., respectively) for 32 min. in 15 canines (8.0 to 23.0kg), only physiological dose (25ng/kg/min.) was infused for 180 min. in 8 canines (12.5 to 23.0kg). The concentrations of ANP in canine CSF and plasma were measured by our highly sensitive and specific radioimmunoassay (RIA). The molecular forms in the plasma, CSF and the atrium and hypothalamus tissues were determined by gel permeation chromatography (GPC). The ANP concentration in CSF was 2.8 +/- 1.2pg/ml (mean +/- SD), lower than that in the plasma which was 51.5 +/- 19.9pg/ml, and no correlation was found between them (r = 0.16, p = ns). Plasma ANP concentrations increased from 46.5 +/- 13.0pg/ml to 94.6 +/- 27.7pg/ml according to a rise of the left atrial pressure by experimental aortic regurgitation. However, no significant change was noted from 3.7 +/- 0.7pg/ml to 3.8 +/- 1.0pg/ml in CSF ANP concentrations during the aortic regurgitation. The ANP concentration in the CSF did not change significantly while the plasma ANP concentration greatly increased following each intravenous infusion of the synthetic alpha-ANP. Only a single peak corresponding to a low molecular weight form of ANP in the position of authentic alpha-ANP in the canine CSF was observed by GPC, while there were peaks for both low and high molecular forms of ANP in the canine plasma. Furthermore, both low and high molecular weight peaks were observed for the right atrium and hypothalamus tissue extracts by GPC, and those tissues of the right atrium and hypothalamus contained ANP concentrations of 1.97ng/mg wet tissue and 2.6pg/ml wet tissue, respectively. These results indicate the presence of ANP in canine CSF and that it does not come from blood that has seeped across the blood-CSF barriers but may originate in the brain.