Abstract 2945: Normalization of Beta Adrenergic Receptor Signaling Improves Left Ventricular Myocyte Function with Urotensin II Receptor Blockade in Murine Heart Failure

Abstract

Background. Urotensin II (UII), the most potent vasoconstrictor and its receptors (UT) are upregulated in heart failure (HF). Although the role of UII in cardiac regulation is not fully understood, increasing evidence suggests that in the failing myocardium, UII may exert an enhanced negative modulation on cardiac contractile performance and cardiac β-AR regulation, thus providing a potential mechanism for progressive deterioration in cardiac function in HF. We assessed the hypothesis that blocking UII may prevent HF-induced alterations in cardiac β-adrenergic receptor (AR) expression, restore normal β-adrenergic regulation, and improve left ventricular (LV) myocyte functional performance. Methods. We compared β 1 - and β 3 -AR expression and responses to β- and β 3 -AR stimulation in freshly isolated LV myocytes obtained from 3 groups of mice (6/group): 1) HF-2 months after receiving isoproterenol (ISO, 170 mg/kg, sq, for 2 days); 2) HF/UIIBK-one month after receiving ISO, then urantide, a potent UIIBK (10 −5 M/kg/day via sq implanted osmotic minipump) initiated after the onset of HF and given for 1 month; and 3) Controls. Results. Compared with controls, ISO-treated mice had established HF. Isolated cardiomyocyte studies showed about 42% reductions in cell contraction (dL/dt max , 78 vs 134 μm/s) and relaxation (dR/dt max , 69 vs 120 μm/s) with a much less increase in dL/dt max (29 vs 68%) and dR/dt max (31 vs 62%) in response to superfusion of ISO (10 −8 M). These changes were associated with significantly decreased β 1 -AR mRNA (40%, 0.57 vs 0.95), but increased β 3 -AR mRNA (54%, 0.43 vs 0.28) expression. Treatment with UII BK prevented HF-induced contrast changes of β 1 - and β 3 -AR mRNA expression. The signal ratios of β 1 -AR mRNA (0.85) and β 3 -AR mRNA (0.34) remained close to control levels. Basal and ISO-stimulated adenylate cyclase activity were normal, and ISO-induced increase in dL/dt max (61%) and dR/dt max (58%) were significantly augmented. Conclusion. In a murine model of progressive HF, chronic UIIBK prevents HF-induced contrast alterations of LV β 1 - and β 3 -AR expression, restores normal responsiveness of myocyte to β-AR stimulation, and improves LV myocyte function. Thus, UIIBK may provide a new therapeutic strategy for the treatment of HF.