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 microg 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.
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 murineUcn2 (10, 50, and 100 microg 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.
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