Chronic activation of the low affinity site of beta -adrenoceptors stimulates haemodynamics but exacerbated pressure-overload cardiac remodelling

BACKGROUND AND PURPOSE: The beta1 -adrenoceptor has at least two binding sites, high and low affinity sites (beta1H and beta1L , respectively), which mediate cardiostimulation. While beta1H - adrenoceptor can be blocked by all clinically used beta-blockers, beta1L -adrenoceptor is relatively resistant to blockade. Thus, chronic beta1L -adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of beta1H -adrenoceptors. It is important to determine the potential significance of beta1L -adrenoceptors in vivo, particularly in the setting of disease. EXPERIMENTAL APPROACH: C57Bl/6 male mice were used. Chronic (4 or 8 weeks) beta1L -adrenoceptor activation was achieved by treatment, via osmotic minipumps, with (-)-CGP12177 (10 mg kg-1 day-1 ). Cardiac function was assessed by echocardiography and micromanometry. KEY RESULTS: (-)-CGP12177 treatment in healthy mice increased heart rate and left ventricular (LV) contractility. In mice subjected to transverse aorta constriction (TAC), (-)-CGP12177 treatment during 4-8 or 4-12 weeks, respectively, after TAC led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment to mice with TAC exacerbated myocardial expression of hypertrophic, fibrogenic and inflammatory genes (all P