To evaluate the existence of a relationship between atrial natriuretic factor (ANF) and plasma Na+/K+ATPase inhibitory activity in humans, we examined the hemodynamic and humoral response to volume expansion in 41 borderline hypertensive patients (BHT) with either normal (n = 33) or low plasma renin activity (n = 8). The study was carried out by measuring blood pressure, forearm circulation, plasma renin activity (PRA), ANF, and plasma levels of an endogenous Na+/K+ATPase inhibitor before and after 2 h of acute intravenous NaCl infusion (0.22 mL/min/kg bodyweight). The early (45 min) changes of ANF and those of Na+/K+ATPase inhibitory activity attained at the end of saline infusion were inversely related in BHT with normal PRA and directly related in the low-PRA population (r = 0.64). The time-course of ANF response to sodium loading was significantly delayed in BHT characterized by normal venous distensibility. They also showed a greater increase in plasma Na+/K+ATPase inhibitory activity occurring with an hypertensive, vasoconstrictive, and sodium retaining response as well. We conclude that in normal PRA borderline hypertensives, ANF may modulate the release of a plasma Na+/K+ATPase inhibitor in a setting where extracellular volume is acutely expanded. Our findings also suggest that dissimilarities in peripheral venous distensibility are able to influence the time-course of ANF response. The blunted ANF increase observed in response to NaCl loading in a subset of BHT could represent an early marker of the attitude of such patients to develop high blood pressure leading to the release of a Na(+)-pump inhibitor and influencing individual salt-sensitivity.