The a 1 B - adrenergic receptor decreases the inotropic response in the mouse Langendorff heart model Sean

Objective: a1-Adrenergic receptors (ARs) are known mediators of a positive inotropy in the heart, which may play even more important roles in heart disease. Due to a lack of sufficiently selective ligands, the contribution of each of the three a1-AR subtypes (a1A, a1B and a1D) to cardiac function is not clearly defined. In this study, we used a systemically expressing mouse model that overexpresses the a1B-AR to define the role of this subtype in cardiac function. Methods: We used the mouse Langendorff heart model to assess changes in contractility under basal and phenylephrine-induced conditions. Results: We find that a 50% increase of the a1B-AR in the heart does not change basal cardiac parameters compared to age-matched normals (heart rate, F dP/dT and coronary flow). However, the inotropic response to phenylephrine is blunted. The same results were obtained in isolated adult myocytes. The difference in inotropy could be blocked by the selective a1A-AR antagonist, 5-methylurapidil, which correlated with decreases in a1A-AR density, suggesting that the a1B-AR had caused a compensatory downregulation of the a1A-AR. Conclusions: These results suggest that the a1B-AR does not have a major role in the positive inotropic response in the mouse myocardium but may negatively modulate the response of the a1A-AR. D 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.