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

Abstract Adrenergic receptors (ARs) play an important role in the regulation of cardiac function. Cardiac inotropy is primarily regulated by β 1 -ARs. However, α 1 -ARs may play an important role in inotropy during heart failure. Previous work has suggested that the α 1B -AR modulates β 1 -AR function in the heart. The potential role of the α 1A -AR has not been previously studied. We used transgenic mice that express constitutively active mutant (CAM) forms of the α 1A -AR or α 1B -AR regulated by their endogenous promoters. Expression of the CAM α 1A -AR or CAM α 1B -AR had no effect on basal cardiac function (developed pressure, +dP/dT, –dP/dT, heart rate, flow rate). However, both α 1 -AR subtypes significantly decreased isoproterenol-stimulated +dP/dT. Pertussis toxin had no effect on +dP/dT in CAM α 1A -AR hearts but restored +dP/dT to non-transgenic values in CAM α 1B -AR hearts. Radioligand binding indicated a selective decrease in the density of β 1 -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 α 1A - and α 1B -ARs both downregulate β 1 -AR-mediated inotropy in the mouse heart. However, α 1 -AR subtypes are coupled to different β-AR mediated signaling pathways with the α 1B -AR being pertussis toxin sensitive.