Atrial natriuretic factor lowers blood pressure in normotensive and hypertensive animal models. The present study examined the mechanism of the blood pressure-lowering effect in 10 normotensive dogs. Four awake dogs previously instrumented with electromagnetic flow probes for measurement of cardiac output and catheters for systemic hemodynamic and cardiac dynamic measurements were studied. After a 30-minute control period, a 3 Mg/kg bolus followed by 0.3 μg/min/kg of a 24-residue synthetic atrial natriuretic factor was infused for 30 minutes, followed by a 1-hour recovery period. Mean arterial pressure fell significantly during infusion (control, 125 ± 4; infusion, 108 ± 5; recovery, 125 ± 9 mm Hg;p< 0.05) and was accompanied by a slight but significant bradycardia (control, 144 ± 7; infusion, 134 ± 5; recovery, 145 ± 7 beats/min;p< 0.05). Significant reductions in cardiac output (control, 2.66 ± 0.60; infusion, 2.18 ± 0.60; recovery, 2.74 ± 0.60 L/min;p< 0.05), stroke volume (control, 18.4 ± 3.9; infusion, 16.0 ± 4.2; recovery, 19.0 ± 3.7 ml/beat;p< 0.05), and maximum increase in rate of change of left ventricular systolic pressure (control, 2475 ± 200; infusion, 2088 ± 216; recovery, 2487 ± 243 mm Hg/sec;p< 0.05) were also observed during infusion. No significant changes in total peripheral resistance or central venous pressure were noted, although the latter tended to fall during infusion. A similar pattern was observed in six pentobarbital-anesthetized dogs, except that infusion of atrial natriuretic factor did not induce bradycardia. These data indicate that mean arterial pressure is lowered in these models by a mechanism other than reduction in total peripheral resistance, namely a reduction in cardiac output.