Background— Urocortin 2 (Ucn2) has potent cardiovascular actions and may participate in the pathophysiology of heart failure (HF). The integrated hemodynamic, endocrine, and renal effects of Ucn2 are unknown. Methods and Results— Eight sheep received incremental intravenous boluses of murine Ucn2 (10, 50, and 100 μg at 2-hour intervals) before (normal) and during pacing-induced HF. Compared with control data, Ucn2 induced rapid and dose-dependent increases in cardiac output (peak effects: normal 4.3±0.2 versus 6.1±0.2 L/min, P <0.001; HF 2.3±0.1 versus 4.5±0.2 L/min, P <0.001) and reductions in peripheral resistance (normal 20.2±1.0 versus 15.2±0.8 mm Hg/L per minute, P <0.01; HF 32.2±1.7 versus 13.6±0.5 mm Hg/L per minute, P <0.001) and left atrial pressure (normal 4.3±0.3 versus 0.5±0.2 mm Hg, P <0.01; HF 22.9±0.6 versus 5.1±1.8 mm Hg, P <0.001). Mean arterial pressure was minimally elevated in normals and decreased in HF (both P <0.01). In both states, Ucn2 reduced plasma atrial natriuretic peptide levels (normal 13±2 versus 10±2 pmol/L; HF 200±20 versus 72±10 pmol/L) and similarly increased corticotropin, cortisol, and Ucn1 (all P <0.001). In HF only, Ucn2 dose dependently decreased plasma vasopressin (3.09±0.36 versus 1.62±0.12 pmol/L, P <0.01), renin (2.98±1.17 versus 0.69±0.10 nmol/L per hour, P <0.001), aldosterone (1186±303 versus 364±122 pmol/L, P <0.001), endothelin-1 (3.39±0.23 versus 2.56±0.18 pmol/L, P <0.01), epinephrine (1633±260 versus 657±142 pmol/L, P <0.01), and brain natriuretic peptide (36±3 versus 18±4 pmol/L, P <0.001) concentrations. Renal effects, including increased urine volume (1.7-fold, P <0.05), sodium excretion (>12-fold, P <0.01), and creatinine excretion (1.3-fold, P <0.001), also occurred only in HF. Conclusions— Ucn2 has marked and beneficial hemodynamic, hormonal, and renal effects in experimental HF. These results support a role for Ucn2 in pressure/volume homeostasis in HF and suggest that the peptide may have therapeutic potential in this disease.

Urocortin has profound and sustained hemodynamic, hormonal, and renal effects in experimental HF. Urocortin may have a role in pressure/volume homeostasis in HF and may provide a novel therapeutic approach to this disease.

Intravenous UCN2 in HF induced increases in CO and LVEF with falls in SVR and CW. No hormone response occurred. The role of UCN2 in circulatory regulation and its potential therapeutic application in heart disease warrant further investigation.

Adrenomedullin reduced ventricular preload and afterload and improved cardiac output in sheep with congestive heart failure. Despite the clear fall in arterial pressure, adrenomedullin increased creatinine clearance and sodium excretion and maintained urine output. These results imply an important pathophysiological role for adrenomedullin in the regulation of pressure and volume in heart failure and raise the possibility of a new therapeutic approach to this disease.

Urocortin-1 (Ucn-1), a member of the corticotropin-releasing factor family, has been shown in animal studies to have effects on the pituitary-adrenal axis, the cardiovascular system, circulating neurohormones, and renal function and to suppress appetite. For the first time in man we have evaluated these effects of infused Ucn-1 as well as actions on plasma ghrelin, a hormone known to increase appetite. We also assessed Ucn-1 pharmacokinetics. Eight healthy male volunteers consuming a diet of constant sodium and potassium content received 50 micro g Ucn-1 iv over 1 h in a placebo-controlled, randomized, time-matched, cross-over study. Ucn-1 infusion compared with placebo increased plasma levels of corticotropin [44.6 +/- 7.7 vs. 19.1 +/- 3.2 pg/ml (9.5 +/- 1.7 vs. 4.2 +/- 0.7 pmol/liter); P < 0.001], cortisol [15.6 +/- 1.6 vs. 7.7 +/- 1.4 micro g/dl (432 +/- 43 vs. 213 +/- 40 nmol/liter); P < 0.001], and atrial natriuretic peptide [26.2 +/- 3.4 vs. 21.3 +/- 2.2 pg/ml [8.5 +/- 1.1 vs. 6.9 +/- 0.7 pmol/liter); P = 0.019] while suppressing plasma ghrelin (P = 0.008). No hemodynamic or renal effects were observed at the dose used. The plasma Ucn-1 t(1/2) was 52 min based on a one-compartment model. In conclusion, a brief iv infusion of 50 micro g Ucn-1 stimulates plasma ACTH, cortisol, and atrial natriuretic peptide secretion and suppresses plasma ghrelin in healthy male volunteers. The latter effect might contribute to the anorexic action of Ucn-1.