Metabolism and action of urodilatin infusion in healthy volunteers

Objectives: The objective of this investigation was to study bath the pharmacokinetics and renal pharmacodynamic properties of intravenously infused urodilatin in human beings. Methods: Twelve healthy subjects received a short-term infusion (90 minutes) of urodilatin and placebo with a graded infusion rate (from 7.5 to 15 to 30 ng . kg body weight(-1) . min(-1)) in a randomized, double-blind, crossover study design. The renal parameters were evaluated by clearance technique with the use of Cr-51-ethylenediaminetetraacetic acid, I-125-hippuran, and lithium. Urodilatin concentrations were determined by a radioimmunoassay with a urodilatin-specific antibody. Results: Kinetics were characterized by a high apparent volume of distribution (43.7 +/- 11.2 L), a high total body clearance (5383 +/- 581 ml/min), and a short plasma half-life (5.57 +/- 0.8 minutes). The maximal plasma urodilatin level was 177.2 +/- 25.8 pmol/L. Less than 1% of total infused urodilatin was recovered in urine. Urodilatin significantly increased glomerular filtration rate (urodilatin, 7.0%, versus placebo, -1.9%; p < 0.05), reduced effective renal plasma flow (urodilatin, -17%, versus placebo, -3%; p < 0.01), increased fractional excretion of sodium (urodilatin, 137%, versus placebo, 27%; p < 0.05), and increased urine flow rate (urodilatin, 46%, versus placebo, -15%; p < 0.01). Fractional excretion of lithium did not change. Mean blood pressure decreased and vasoactive hormone levels remained unchanged or increased. Conclusion: The natriuretic and diuretic effects of urodilatin closely followed the profile of urodilatin concentration in plasma. A major part of the synthetic urodilatin was removed from circulation by a route other than filtration through the glomeruli.