Hemodynamic effects of continuous urodilatin infusion: A dose-finding study

Objective: To evaluate the effects of urodilatin (INN, ularitide) on systemic and renal hemodynamic parameters. Methods: Twenty healthy male subjects were included in this double-blind, randomized placebo-controlled trial and assigned to receive either continuous intravenous infusion of different doses of 7.5, 15, or 22.5 ng/kg body weight/min urodilatin or placebo over 300 minutes. Cardiac performance, systolic time intervals, and airway function were measured noninvasively. The effects on renal hemodynamic values were assessed with para-aminohippurate and inulin clearance techniques. Results: Urodilatin was well tolerated by all subjects at doses of 7.5 and 15 ng/kg/min. Infusion was stopped prematurely for the group that received 22.5 ng/kg/min urodilatin group because of systemic hypotensive responses with nausea and dizziness. Infusion of 15 ng/kg/min urodilatin significantly increased urine flow by a maximum of 165%, filtration fraction by 46%, renal resistance by 49%, and systemic vascular resistance by 45%. It decreased renal plasma flow by a maximum of 31% from baseline value. No change in cardiac inotropic function was detectable, but cardiac output decreased in all dose groups. Effects on glomerular filtration rate, forced expiratory volume, blood pressure, and pulse were not different from those with placebo. Conclusion: Continuous infusion of 7.5 ng/kg/min and 15 ng/kg/min urodilatin exerts a significant increase in systemic and renal vascular resistance. Results of our experiments suggested that the therapeutic window for continuous urodilatin infusion is small and that doses higher than approximately 20 ng/kg/min urodilatin carry high risk for adverse drug reactions.