Both α1A- and α1B-adrenergic receptors crosstalk to downregulate β1-ARs in mouse heart: coupling to differential PTX-sensitive pathways

Adrenergic receptors (ARs) play an important role in the regulation of cardiac function. Cardiac inotropy is primarily regulated by β1-ARs. However, α1-ARs may play an important role in inotropy during heart failure. Previous work has suggested that the α1B-AR modulates β1-AR function in the heart. The potential role of the α1A-AR has not been previously studied. We used transgenic mice that express constitutively active mutant (CAM) forms of the α1A-AR or α1B-AR regulated by their endogenous promoters. Expression of the CAM α1A-AR or CAM α1B-AR had no effect on basal cardiac function (developed pressure, +dP/dT, -dP/dT, heart rate, flow rate). However, both α1-AR subtypes significantly decreased isoproterenol-stimulated +dP/dT. Pertussis toxin had no effect on +dP/dT in CAM α1A-AR hearts but restored +dP/dT to non-transgenic values in CAM α1B-AR hearts. Radioligand binding indicated a selective decrease in the density of β1-ARs in both CAM mice. However, G-proteins, cAMP, or the percentage of high and low affinity states were unchanged in either transgenic compared with control. These data demonstrate that CAM α1A- and α1B-ARs both downregulate β1-AR-mediated inotropy in the mouse heart. However, α1-AR subtypes are coupled to different β-AR mediated signaling pathways with the α1B-AR being pertussis toxin sensitive.