Urocortin 2 infusion in healthy humans: hemodynamic, neurohormonal, and renal responses.

Objectives: We sought to examine the effects of urocortin (UCN) 2 infusion on hemodynamic status, cardiovascular hormones, and renal function in healthy humans.

Background: Urocortin 2 is a vasoactive and cardioprotective peptide belonging to the corticotrophin-releasing factor peptide family. Recent reports indicate the urocortins exert important effects beyond the hypothalamo-pituitary-adrenal axis upon cardiovascular and vasohumoral function in health and cardiac disease.

Methods: We studied 8 healthy unmedicated men on 3 separate occasions 2 to 5 weeks apart. Subjects received placebo, 25-microg low-dose (LD), and 100-microg high-dose (HD) of UCN 2 intravenously over the course of 1 h in a single-blind, placebo-controlled, dose-escalation design. Noninvasive hemodynamic indexes, neurohormones, and renal function were measured.

Results: The administration of UCN 2 dose-dependently increased cardiac output (mean peak increments +/- SEM) (placebo 0.5 +/- 0.2 l/min; LD 2.1 +/- 0.6 l/min; HD 5.0 +/- 0.8 l/min; p < 0.001), heart rate (placebo 3.3 +/- 1.0 beats/min; LD 8.8 +/- 1.8 beats/min; HD 17.8 +/- 2.1 beats/min; p < 0.001), and left ventricular ejection fraction (placebo 0.6 +/- 1.4%; LD 6.6 +/- 1.5%; HD 14.1 +/- 0.8%; p < 0.001) while decreasing systemic vascular resistance (placebo -128 +/- 50 dynes x s/cm(5); LD -407 +/- 49 dynes x s/cm(5); HD -774 +/- 133 dynes.s/cm(5); p < 0.001). Activation of plasma renin activity (p = 0.002), angiotensin II (p = 0.001), and norepinephrine (p < 0.001) occurred only with the higher 100-mug dose. Subtle decreases in urine volume (p = 0.012) and natriuresis (p = 0.001) were observed.

Conclusions: Brief intravenous infusions of UCN 2 in healthy humans induced pronounced dose-related increases in cardiac output, heart rate, and left ventricular ejection fraction while decreasing systemic vascular resistance. Subtle renal effects and activation of plasma renin, angiotensin II, and norepinephrine (at high-dose only) were observed. These findings warrant further investigation of the role of UCN 2 in circulatory regulation and its potential therapeutic application in heart disease.