Integrated hemodynamic, hormonal, and renal actions of urocortin 2 in normal and paced sheep - Beneficial effects in heart failure

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 mu g 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.