The α_1B-adrenergic receptor decreases the inotropic response in the mouse Langendorff heart model

Objective: α₁-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 α₁-AR subtypes (α_1A, α_1B and α_1D) to cardiac function is not clearly defined. In this study, we used a systemically expressing mouse model that overexpresses the α_1B-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 α_1B-AR in the heart does not change basal cardiac parameters compared to age-matched normals (heart rate, ±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 α_1A-AR antagonist, 5-methylurapidil, which correlated with decreases in α_1A-AR density, suggesting that the α_1B-AR had caused a compensatory downregulation of the α_1A-AR. Conclusions: These results suggest that the α_1B-AR does not have a major role in the positive inotropic response in the mouse myocardium but may negatively modulate the response of the α_1A-AR.