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CLINICAL RESEARCH: CARDIOVASCULAR PHARMACOLOGY

Urocortin 2 Infusion in Healthy Humans

Hemodynamic, Neurohormonal, and Renal Responses

Christchurch Cardioendocrine Research Group, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand.

Manuscript received May 22, 2006; revised manuscript received August 7, 2006, accepted September 18, 2006.

^_* Reprint requests and correspondence: Dr. Mark E. Davis, Department of Medicine, Christchurch School of Medicine and Health Sciences, P.O. Box 4345, Christchurch, New Zealand. (Email: mark.davis{at}chmeds.ac.nz).

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-µg low-dose (LD), and 100-µg 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·s/cm⁵; LD –407 ± 49 dynes·s/cm⁵; HD –774 ± 133 dynes·s/cm⁵; 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-µg 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.

Abbreviations and Acronyms   A = transmitral diastolic flow velocity with atrial contraction   ACTH = adrenocorticotropic hormone   Am = diastolic myocardial velocity during atrial contraction   CRF = corticotrophin-releasing factor   E = transmitral early diastolic flow velocity   Em = early diastolic myocardial velocity   SVR = systemic vascular resistance   UCN = urocortin

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