RESUMO
BACKGROUND AND PURPOSE: The ß1-adrenoceptor has at least two binding sites, high and low affinity sites (ß1H and ß1L, respectively), which mediate cardiostimulation. While ß1H-adrenoceptor can be blocked by all clinically used ß-blockers, ß1L-adrenoceptor is relatively resistant to blockade. Thus, chronic ß1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of ß1H-adrenoceptors. Hence, it is important to determine the potential significance of ß1L-adrenoceptors in vivo, particularly in pathological situations. EXPERIMENTAL APPROACH: C57Bl/6 male mice were used. Chronic (4 or 8 weeks) ß1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)-CGP12177 (10 mg·kg(-1)·day(-1)). Cardiac function was assessed by echocardiography and micromanometry. KEY RESULTS: (-)-CGP12177 treatment of healthy mice increased heart rate and left ventricular (LV) contractility. (-)-CGP12177 treatment of mice subjected to transverse aorta constriction (TAC), during weeks 4-8 or 4-12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)-CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC. CONCLUSIONS AND IMPLICATIONS: ß1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained ß1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure.
