Abstract 578: Urotensin-II Upregulation in Human Heart Failure: Direct Effects on Contractility and Sarcoplasmic Reticulum Calcium Load
While studies have reported that Urotensin II (UII) is upregulated in failing (F) hearts, the pathophysiologic implications of increased UII on cardiac function is incompletely understood. We investigated the direct effects of exogenous UII on in vitro contractile performance and sarcoplasmic reticulum (SR) Ca2+ load in F and non failing (NF) human myocardium.
Methods: Isometric force was measured in F (n=11) and NF (n=6) right ventricular trabeculae (0.5 Hz, 37°C) before and after bath application of UII (UII; 0.1, 1.0, 10, 100, 1000 nM). Single and paired rapid cooling contractures (RCCs) were employed to define SR Ca2+ load and the balance between SERCA and the NCX.
Results: UII induced increases in developed tension (DT) in NF trabeculae and dose-dependent decreases in DT in F trabeculae. UII did not alter resting tension in either group. RCC amplitude increased during graded increases in UII in NF trabeculae, suggesting increases in SR calcium load, but remained stable in F trabeculae. In NF trabeculae, UII did not alter the RCC2/RCC1 ratio at any concentration, but in F trabeculae the RCC2/RCC1 ratio increased at 0.1 nM UII then exhibited dose-dependent decreases at higher concentrations.
Conclusion: In contrast to the positive inotropic response elicited in NF hearts, UII is a negative inotrope in ventricular trabeculae obtained from F human hearts. Based on the RCC data, UII has little effect on SR Ca2+ load in F myocardium suggesting that negative inotropic responses reflect decreases in myofilament Ca2+ sensitivity. The paired RCC data suggests that U-II also affects the functional competition between SERCA and NCX differently in F and NF human hearts.