Cardiac physiologic regulation of sub-type specific adrenergic receptors in transgenic mice overexpressing β₁- and β₂-adrenergic receptors

ABSTRACT

OBJECTIVE: Combination of β₁-adrenergic receptor (AR) blockade and β₂-AR activation might be a potential novel therapy for treating heart failure. However, use of β-AR agonists and/or antagonists in the clinical setting is controversial because of the lack of information on cardiac inotropic or chronotropic regulation by AR signaling. METHODS: In this study, we performed hemodynamic evaluation by examining force frequency response (FFR), Frank-Starling relationship, and response to a non-selective β-AR agonist (isoproterenol) in hearts isolated from 6-month-old transgenic (TG) mice overexpressing β₁- and β₂-ARs (β₁- and β₂-AR TG mice, respectively). RESULTS: Cardiac physiologic consequences of β₁- and β₂-AR overexpression resulted in similar maximal response to isoproterenol and faster temporary decline of positive inotropic response in β₂-AR TG mice. β₁-AR TG mice showed a pronounced negative limb of FFR, whereas β₂-AR TG mice showed high stimulation frequencies with low contractile depression during FFR. In contrast, Frank-Starling relationship was equally enhanced in both β₁- and β₂-AR TG mice. CONCLUSION: Hemodynamic evaluation performed in the present showed a difference in β₁- and β₂-AR signaling, which may be due to the difference in the desensitization of β₁- and β₂-ARs.