Abstract 9932: Chronic Urotensin II Receptor Blockade Causes Regression of Heart Failure: Beneficial Effects on Neurohormonal Activation, Cardiomyocyte Contractile Function [Ca 2+ ]i Regulation and Beta-Adrenergic Modulation

Abstract

Background. Heart failure (HF) is associated with increased levels of urotensin-II (UII) and upregulation of UII-mediated cardiac inhibitory pathway. This suggests that cardiac UII activation contributes to HF progression and may be a therapeutic target. However, the role and mechanism of chronic UII receptor antagonist (UII-ANT) in HF are unclear. We assessed the hypothesis that blocking UII improves cardiomyocyte function, [Ca 2+ ] i regulation, and β-adrenergic receptor (AR) signaling effectiveness, thus limiting HF progression. Methods. We compared sympathetic nervous system (SNS) activation, LV myocyte β 1 -AR protein expression, and myocyte contractile and Ca 2+ current (I Ca,L ) responses to isoproterenol (ISO) in 3 groups of age-matched adult mice (8/group) over 8 weeks (W): 1) HF [after onset of HF induced by ISO (170 mg/kg sq for 2 days) for 4 W and then receiving placebo], 2) HF/UII-ANT [after onset of HF and then receiving urantide, a potent UII-ANT (10 -5 M/kg/day sq via osmotic mini pump), given for 4W], and 3) C (controls). Results. Compared with C, ISO-treated mice had established HF with significantly increased plasma norepinephrine (NE) (3474 vs 668 pg/ml) and decreased ejection fraction (EF, 35% vs 63%). In HF, cardiomyocyte basal functional performance and I Ca,L were significantly depressed with 42% reductions in cell contraction (dL/dt max , 78 vs 134 µm/s), relaxation (dR/dt max , 69 vs 120 µm/s) and a 48% decreased I Ca,L (3.7 vs 7.2 pA/pF). Importantly, compared with normal myocytes, superfusion of ISO (10 -8 M) caused significantly less increases in dL/dt max (30% vs 69%), dR/dt max (29% vs 64%), and I Ca,L (12% vs 36%) in HF myocytes. These changes were associated with significantly decreased myocyte β 1 -AR (0.37 vs 0.61) protein. In HF/UII-ANT mice, plasma NE (908 pg/ml), EF (59%), and myocyte β 1 -AR (0.57) expression returned close to C levels. Basal myocyte contraction and I Ca,L significantly improved, and ISO-induced increase in dL/dt max (66%), dR/dt max (60%), and peak I Ca,L (34%) were significantly augmented. Conclusion. Chronic UII-ANT prevents HF-induced SNS activation and downregulation of LV myocyte β 1 -ARs and leads to the preservation of myocyte function, I Ca,L , and β-adrenergic responsiveness in a mouse model of progressive HF.