Whereas the short-term effects of atrial natriuretic factor (ANF) are well documented, less is known concerning the possible hypotensive action of sustained low-dose ANF infusions. Accordingly, we have examined the sequential renal, hormonal, and hemodynamic responses to 48-h low-dose ANF infusions in eight normotensive conscious sheep and evaluated the effects of these infusions on autonomic (baroreceptor), adrenocortical, and pressor responsiveness to exogenous stimulation. Plasma ANF levels tended to rise in response to ANF infusions, but the difference between ANF and control day levels was not significantly different. Systolic arterial pressure (SAP) was significantly lower after ANF infusion (P = 0.01) and was associated with a reduction in calculated total peripheral resistance (CTPR, P = 0.007). Mean arterial pressure also tended to be lower (P = 0.08) in response to ANF. No change was seen in urinary volume or sodium excretion or in plasma angiotensin II (ANG II), aldosterone, or cortisol levels. ANF significantly attenuated the pressor response to exogenous ANG II (P = 0.01) but did not affect the adrenocortical responsiveness or autonomic (baroreceptor) responsiveness to exogenous stimulation. This study demonstrates that chronic low-dose infusions of ANF that barely elevate plasma ANF levels induce significant cardiovascular effects, including lowering of SAP associated with a fall in CTPR and attenuation of pressor responsiveness to physiological increments in ANG II, thus providing further support for the importance of ANF in blood pressure homeostasis in normal sheep.