Chronic activation of the low affinity site …
Kiriazis, H., et al. (2013). "Chronic activation of the low affinity site of beta(1)-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling." British Journal of Pharmacology 170(2): 352-365.
BACKGROUND AND PURPOSE The beta(1)-adrenoceptor has at least two binding sites, high and low affinity sites (beta(1H) and beta(1L), respectively), which mediate cardiostimulation. While beta(1H)-adrenoceptor can be blocked by all clinically used beta-blockers, beta(1L)-adrenoceptor is relatively resistant to blockade. Thus, chronic beta(1L)-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of beta(1H)-adrenoceptors. Hence, it is important to determine the potential significance of beta(1L)-adrenoceptors in vivo, particularly in pathological situations. EXPERIMENTAL APPROACH C57Bl/6 male mice were used. Chronic (4 or 8 weeks) beta(1L)-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 beta(1L)-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained beta(1L)-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure.