The preferential β 3-adrenoceptor agonist BRL 37344 increases force via β 1-/β 2-adrenoceptors and induces endothelial nitric oxide synthase via β 3-adrenoceptors in human atrial myocardium

Abstract

1. The present study investigated the effects of the preferential β 3-AR agonist BRL 37344 (BRL) on force of contraction (FOC), Ca 2+-transient and eNOS-activity in human right atrial myocardium. 2. BRL concentration-dependently caused an increase in FOC that was paralleled by an increase in Ca 2+-transient and a shortening of time to half peak relaxation (T0.5T). These effects were abolished in the presence of propranolol (0.3 μM). 3. BRL acted as a competitive antagonist towards isoprenaline and in binding experiments it was shown to have a distinct affinity towards β 1/2-AR. 4. In immunohistochemical experiments BRL (10 μM) increased detection of activated eNOS. This effect remained constant in the presence of propranolol (0.3 μM). 5. BRL increased directly detected NO in DAF-staining experiments. This increase was significantly smaller in the presence of the NO-inhibitor L-NAME. 6. The inotropic effects of BRL were not changed in the presence of L-NMA. 7. These results suggest that the inotropic effects of BRL in human atrium are mediated via β 1/2-AR, whereas the increase of atrial eNOS-activity is due to β 3- adrenergic stimulation. This increase in eNOS-activity did not influence atrial myocardial contractility. In conclusion, this study shows that β 3-adrenergic stimulation is present in human atrium, but may not be functionally as significant as in the left ventricle.