To evaluate the role of extra-atrial atrial natriuretic peptide (ANP) in volume and blood pressure regulation, the plasma, atrial, ventricular, and hypothalamic levels of immunoreactive atrial natriuretic peptide (IR-ANP) were measured simultaneously in the spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at the ages of 2, 6, and 12 months. Plasma IR-ANP in the 12-month-old, conscious SHR was significantly higher than that of the WKY (300 +/- 18 versus 200 +/- 20 pg/ml, p less than 0.05, n = 9), while no differences in plasma IR-ANP levels were found between the strains in younger rats. Acute volume expansion with saline (1.1 ml/100 g body wt) in hypertensive as well as in normotensive rats resulted in marked increases in right atrial pressure and plasma IR-ANP concentration. The older SHR had attenuated ANP release to volume loading as shown by the shift of the ANP versus right atrial pressure curve to the right. Right auricular IR-ANP concentration decreased, while that of left auricle increased with increasing age in both strains. No substantial differences were noted in auricular ANP concentration between SHR and WKY. However, the total atrial IR-ANP content (micrograms/atria) was consistently lower in SHR compared with WKY. In both ventricles, IR-ANP concentrations and contents increased with increasing age in WKY and SHR, but the ventricular levels of ANP were reduced in ventricles of the SHR heart compared with normotensive controls. The depletion of total ventricular IR-ANP was greatest in SHR with greatest ventricular hypertrophy and coincided with the attenuated ANP release to acute volume load. The increase of left but not right ventricular weight occurring secondary to 6 weeks minoxidil treatment was accompanied by higher ANP concentration in both strains. In contrast to the ventricles, the hypothalamic IR-ANP concentration was significantly increased in SHR compared with that of WKY and decreased in both strains after 6 weeks' treatment with antihypertensive drugs. Thus, ventricular and hypothalamic, as well as atrial, ANP respond to increased pressure overload in genetically hypertensive rats. Our results suggest that chronic stimulation of ANP release from ventricles is associated with depleted stores of ANP from both ventricles and reduced response to acute volume load. Our findings that ventricular ANP increased with increasing weight and in response to a hypertrophic stimulus in WKY and was decreased in SHR with severe ventricular hypertrophy suggest that ANP may locally have an inhibitory effect on the development of cardiac hypertrophy.