Chronic activation of the low affinity site of β 1 ‐adrenoceptors stimulates haemodynamics but exacerbates pressure‐overload cardiac remodelling

Background and Purpose The β 1 ‐adrenoceptor has at least two binding sites, high and low affinity sites (β 1H and β 1L , respectively), which mediate cardiostimulation. While β 1H ‐adrenoceptor can be blocked by all clinically used β‐blockers, β 1L ‐adrenoceptor is relatively resistant to blockade. Thus, chronic β 1L ‐adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of β 1H ‐adrenoceptors. Hence, it is important to determine the potential significance of β 1L ‐adrenoceptors in vivo , particularly in pathological situations. Experimental Approach C57Bl /6 male mice were used. Chronic (4 or 8 weeks) β 1L ‐adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (‐)‐ CGP 12177 (10 mg·kg −1 ·day −1 ). Cardiac function was assessed by echocardiography and micromanometry. Key Results (‐)‐ CGP 12177 treatment of healthy mice increased heart rate and left ventricular ( LV ) contractility. (‐)‐ CGP 12177 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. (‐)‐ CGP 12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (‐)‐ CGP 12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC . Conclusions and Implications β 1L ‐adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained β 1L ‐adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure.