Vascular Medicine GRK2-Mediated Inhibition of Adrenergic and Dopaminergic Signaling in Right Ventricular Hypertrophy Therapeutic Implications in Pulmonary Hypertension

Background—The cause and consequences of impaired adrenergic signaling in right ventricular failure/hypertrophy (RVH) are poorly understood. We hypothesized that G protein– coupled receptor kinase-2 (GRK2)–mediated uncoupling of ␤-adrenergic receptor signaling impairs inotropic reserve. The implications of right ventricular (RV) adrenergic remodeling for inotrope selection and the therapeutic benefit of interrupting G␤␥–GRK2 interaction, using gallein, were tested. Methods and Results— Chamber-specificity and cellular localization of adrenergic remodeling were compared in rodent RVH associated with pulmonary arterial hypertension (PAH-RVH; SU5416ϩchronic-hypoxia or Monocrotaline) versus pulmonary artery banding–induced RVH (PAB-RVH). Results were corroborated in RV arrays from 10 PAH patients versus controls. Inotropic reserve was assessed in RV-and left ventricular–Langendorff models and in vivo. Gallein therapy (1.8 mg/kg/day ϫ2-weeks) was assessed. Despite similar RVH, cardiac output (58.3Ϯ4.9 versus 82.9Ϯ4.8 mL/min; PϽ0.001) and treadmill distance (41.5Ϯ11.6 versus 244.1Ϯ12.4 m; PϽ0.001) were lower in PAH-RVH versus PAB-RVH. In PAH-RVH versus PAB-RVH there was greater downregulation of ␤1-, ␣1-and dopamine-1 receptors, more left ventricular involvement, and greater impairment of RV contractile reserve. RV GRK2 activity increased in parallel with a reduction in both adrenergic receptor expression and inotrope-stimulated cAMP levels (PϽ0.01). ␤1-receptor downregulation also occurred in human PAH-RVH. Dobutamine was superior to dopamine as an RV inotrope, both ex vivo and in vivo. Conclusions—GRK2-mediated desensitization-downregulation of adrenergic and dopaminergic receptors impairs inotro-pic reserve in PAH-RVH. Acute inotropic support in RVH is best accomplished by dobutamine, reflecting its better coupling to adenylyl cyclase and the reliance of dopamine on dopamine-1–receptor signaling, which is impaired in RVH. Inhibiting G␤␥–GRK2 interactions has therapeutic benefit in RVH.