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Phosphodiesterase 4D disruption causes β2 adrenergic receptors to behave like β1 adrenergic receptors in vivo
Critical Care volume 10, Article number: P235 (2006)
β1 and β2 adrenergic receptors (βARs) are G-protein-coupled receptors that mediate physiologic responses to catecholamines in the heart. β1ARs couple to stimulatory G protein (Gs) and elicit increases in inotropic and chronotropic performance during acute activation. Continuous activation of β1ARs is cardiotoxic, causing ventricular remodeling. β2ARs couple first to Gs then to inhibitory G protein (Gi). Continuous β2AR activation may protect the heart from continuous β1AR stimulation.
Distribution of cAMP within myocytes differs after β1AR stimulation relative to β2AR stimulation. β1AR activation results in a global increase in cAMP while β2AR activation generates an increase only within restricted cellular subdomains. Phosphodiesterase 4D (PDE4D) degrades cAMP and is recruited to activated β2ARs after agonist-induced internalization of the receptors. In cultured myocytes, inhibition of PDE4D leads to a global rise in cAMP levels after β2AR stimulation and causes β2AR signaling to resemble that of the β1AR.
We hypothesized that mice with disruption of both β1AR and PDE4D (β1/PDE4D DKO) would experience myocardial remodeling similar to that associated with continuous β1AR stimulation.
Seven β1/PDE4D DKO, 11 β2KO, and seven wild-type mice were evaluated. The wild-type and β2KO mice received 14-day infusions of the βAR agonist isoproterenol. ECG-gated magnetic resonance imaging was used to determine the left ventricle end diastolic volume (LVEDV), left ventricle end systolic volume, and heart rate. The stroke volume and cardiac output were calculated.
See Fig. 1.
Disruption of PDE4D causes β2ARs to behave like β1ARs in vivo, just as it does in vitro.
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Pearl, N., Chang, C., Bruss, M. et al. Phosphodiesterase 4D disruption causes β2 adrenergic receptors to behave like β1 adrenergic receptors in vivo. Crit Care 10, P235 (2006). https://doi.org/10.1186/cc4582
- Myocardial Remodel
- Acute Activation
- Global Rise
- Agonist Isoproterenol