INFLUENCE OF AGE AND DOSE ON THE END-ORGAN RESPONSES TO ATRIAL-NATRIURETIC-PEPTIDE IN HUMANS

To test the hypothesis that age differentially affects the natriuretic, hemodynamic, and humoral response to exogenous ANP, we studied seven young (Y, 20 to 39 years) and five old (O, 65 to 83 years) healthy, normotensive, nonobese men during infusion of synthetic human ANP1,28 at two different rates: 1) 0.05-mu-g/kg/min (high dose) for 1 h and 2) 0.005-mu-g/kg/min (low dose) for 1 h. Compared to young, the old had higher basal ANP levels (O = 142 +/- 41 v Y = 29 +/- 4 pmol/L, P < .025), achieved higher plasma levels with low-dose infusion (O = 327 +/- 24 v Y = 155 +/- 37 pmol/L, P < .001) and had a longer ANP half-life (O = 7.8 +/- 0.6 v Y = 4.3 +/- 0.6 min, P < .001), suggesting decreased catabolism in the old compared to the young. Despite these age-related differences in ANP levels, there was no difference in urinary sodium or cyclic GMP excretion. After termination of the low-dose infusion, plasma ANP and urinary cGMP promptly returned to baseline levels. Despite this, a sustained natriuresis (2-fold above control) was observed for 3 h in both groups. Low-dose infusion was associated with sustained suppression of aldosterone with minimal hemodynamic changes. During high-dose infusions there was no difference in natriuresis or peak ANP levels between the two groups (O = 1299 +/- 93 v Y = 1140 +/- 54 pmol/L). In contrast to the low-dose infusion, the high-dose infusion produced a transient natriuresis lasting only for the duration of the infusion. High-dose infusion resulted in a significant decrease in blood pressure with stimulation of norepinephrine and escape from aldosterone suppression. In conclusion, there appears to be diminished clearance of ANP along with renal resistance at physiologic levels in the elderly, and ANP-induced natriuresis persists longer than the increase in circulating plasma levels or urinary cGMP at low doses (physiologic range), perhaps due to a suppression of aldosterone. This effect is negated at high doses (pathologic range), likely as it is secondary to hemodynamically induced activation of counterregulatory hormones.