Objective β3-adrenergic receptors (β3-AR) and its downstream signalling are recognised as novel modulators of heart function. We have recently shown impaired cardiac functional compensation in a model of pressure overload. We therefore hypothesised that the selective β3-AR agonist, BRL37344 (BRL), would protect the heart from pressure overload induced cardiac remodelling.

Methods and results C57BL/6J mice underwent transverse aortic constriction (TAC) for 3 weeks, resulting in increased cardiac hypertrophy and dysfunction assessed by echocardiography. 3 weeks of BRL treatment (0.1 mg/kg/day via subcutaneous osmotic infusion pump) starting from 1 day post TAC reduced hypertrophy, with lower heart weight normalised to tibia length (100±4 vs 120±7 mg/cm), LV mass (136±7 vs 163±8 mg), wall thickness (1.08±0.02 vs 1.16±0.02 mm) and systolic dimension (1.36±0.09 vs 12.08±0.23 mm; p<0.05 for all), and completely restored systolic function back to normal (58±2 vs 62±1%; p=NS vs sham, p<0.05 vs TAC). BRL reduced myocyte width by H&E staining, but had no effect on fibrosis scale. These benefits from β3-AR stimulation were associated with increased nitric oxide (NO) production (13.73±1.84 vs 5.03±0.52 μM/mg protein) and suppressed superoxide generation (14017±838 vs 21459±783 CPM/mg tissue; p<0.01 vs TAC for both). Neuronal NO synthase (nNOS) protein expression was up-regulated ∼3 fold by BRL treatment (1.11±0.22 vs 0.39±0.17; p<0.05). More interestingly, the suppressive effect of BRL on superoxide generation was abolished by acute nNOS inhibition by specific nNOS inhibitor N5-(1-imino-3-butenyl)-L-ornithine, monohydrochloride) (L-VNIO).

Conclusions These results are the first to show in vivo the cardioprotective effect of β3-AR specific agonism in pressure overload hypertrophy and heart failure, and support nNOS as a downstream molecule favouring NO and reactive oxygen species (ROS) balance in this pathologic process in the failing heart.