Abstract 215: In Vivo Modulation of Beta Adrenergic Receptor Desensitization Through Angiotensin Receptor-1 Antagonism Attenuates Left Ventricular Hypertrophy Development In Aortic Banded Rats.
Left ventricular (LV) remodeling is characterized by sustained adrenergic drive resulting in abnormalities of β-adrenergic receptor (βAR) signaling, as well as a diminished number of angiotensin II type 1 receptors (AT1Rs). Impaired βAR responsiveness is in part due to increased levels of βΑR Kinase 1. Recently, an in vitro evidence has shown that interfering with either the βAR or the AT1R results in the uncoupling and inhibition of signaling by the reciprocal, interacting receptor. We therefore postulated that AT1R antagonism could reduce development of overt LV hypertrophy by affecting also βARs signaling pathway. Fourteen Wistar male rats at 7 weeks of age underwent banding of the ascending aorta (BAN) by applying a tantalum clip (internal diameter 0,58 mm). Seven rats were randomly assigned to receive valsartan (BAN+VAL) 10 mg/kg added daily in the drinking water. Additional nine rats underwent sham surgery and randomly assigned to receive either VAL (SHAM+VAL, n=4) or vehicle (SHAM, n=5). Echocardiographic assessments performed at 12 weeks after surgery demonstrated preservation of fractional shortening (FS) and velocity of circumferential fiber shortening (VCF) in BAN+VAL compared to BAN rats (58,8±0,02 % vs 49,7±0,02 % and 4,97±0,38 circ/s vs 3,79±0,31 circ/s, respectively, p<0,05). Moreover, LV weight to body weight ratio was significantly increased after banding but in a lower degree in BAN+VAL compared to BAN group (1,87±0,13 mg/g vs 2,38±0,10 mg/g, p<0,05). Densitometric analysis of immunoprecipitated membrane lysates showed significant increase in βΑR Kinase 1 and Gi levels in BAN compared to SHAM rats (2.1 and 2.3 fold increase, respectively, p<0,001). These increases were nearly completely prevented by VAL administration, whereas there was no significant difference in the cytosolic fraction among the groups. Finally, ERK activation was reduced in BAN+VAL compared to BAN group. In conclusion, this study represents an in vivo evidence that AT1R selective inhibition preserves cardiac function and improves adverse LV remodeling after pressure overload in the rat. Intriguingly, VAL administration was found to reduce βAR desensitization therefore providing new insight in understanding detrimental signalling during LV hypertrophy.