Apelin increases contractility in failing cardiac muscle

Apelin, a ligand for apelin-angiotension receptor-like 1 (APJ), has recently been shown to be a potent positive inotropic agent in normal hearts. In humans, levels of apelin have been shown to rise in early-stage heart failure and to fall in late-stage heart failure. In this study, we tested the hypothesis that apelin augments contraction directly in failing rat cardiac muscle. Right ventricular heart failure secondary to pulmonary hypertension was induced by exposing the rats to hypoxia (10% O-2 inhaled air) for 14-16 weeks. Trabeculae were dissected and mounted between a force transducer and a motor arm, superfused with Krebs-Henseleit (K-H) solution (pH 7.4, 22 degrees C), and loaded with fura-2. Both force development and [Ca2+], transient amplitude increased in a dose-dependent manner in the presence of Apelin-12 (10 similar to 70 nM, [Ca2+](o) = 0.5 mM) in failing muscles as compared to control (36 +/- 7% vs. 7.4 +/- 5% at 70 nM, P < 0.05). Also, [Ca2+](i) transients increased up to 18.4 +/- 9.5% as compared to control (4.5 1.9%, P < 0.05). The increases in contraction in the presence of apelin were also maintained over a range of external Ca2+ (0.5-2.0 mM). Steady-state force-[Ca2+](i) relation of the failing muscles reveals decreased maximal Ca2+-activated force (F-max) (51.45 +/- 5.3 vs. 98.5 +/- 11.5 mN/mm(2), p < 0.001), with no Changes in Ca2+ required for 50% of maximal activation (Ca-50) (0.45 +/- 0.07 vs. 0.30 +/- 0.04 mu M, P > 0.05) and Hill coefficient (4.60 +/- 0.73 vs. 3.17 +/- 0.92, P > 0.05). Apelin (70 nM) had no effect on the steady-state force-[Ca2+]j relation in failing muscles (F-max: 63.03 +/- 3.5 mN/mm(2); Ca-50: 0.50 +/- 0.08 mu M; Hill coefficient: 4.73 +/- 0.89). These results indicate that apelin exerts a selective positive inotropic action in failing myocardium, The increased force development is the result of increased [Ca2+](i) transients rather than changes in myofilament calcium responsiveness. (c) 2006 Elsevier B.V All rights reserved.