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 cardio protective 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-mu g low-dose (LID), and 100-mu g high-dose (HID) of UCN 2 intravenously over the course of I 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; HID 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%; HID 14.1 +/- 0.8%; p < 0.001) while decreasing systemic vascular resistance (placebo -128 +/- 50 dynes.s/cm(5); LD -407 +/- 49 dynes.s/cm(5); HD -774 +/- 133 dynes.s/cm5; p < 0.001). Activation of plasma renin activity (p = 0.002), angiotensin 11 (p = 0.001), and norepinephrine (p < 0.001) occurred only with the higher 100-mu g 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 11, 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.