Abstract 982: Cardiac Restricted α1A-Adrenergic Receptor Overexpression in the Adult Rodent Heart Induces a Hypersensitive Contractile Response to Adrenergic Stimulation with Reduced Baseline Contractility But No Hypertrophy
Background: We have shown that transgenic (TG) mice with cardiac-restricted α1A-adrenergic receptor overexpression (CRα1A-AR) exhibit enhanced left ventricular (LV) contractility but not hypertrophy (LVH) in vivo. We assessed contractility in isolated hearts and myocytes from CRα1A-AR mice. As previous evidence implicating α1A-ARs in LVH was derived from neonatal rat myocytes, we also generated CRα1A-AR TG rats.
Methods and Results: Mouse CRα1A-AR Langendorff hearts and isolated myocytes exhibited reduced baseline contractility (isovolumic pressure and shortening, respectively) but hypersensitivity to α1A-AR stimulation. LV/bw and LV/tibial length ratios, fractional shortening, end-diastolic volume and cardiac output in 3 and 8-month old TG rats were not different from those in non-TG littermates (NTL). TG rats at 3 months with 40-fold α1A-AR overexpression displayed significant reductions in LV systolic pressure (87±2.6 mmHg versus 104±3.3 mmHg in NTL, p<0.01), heart rate (250±8 bpm versus 300±13 bpm in NTL, p<0.001), LV dP/dtmax (27%, p<0.0001) and dP/dtmin (27%, p<0.0001). TG rats exhibited hypersensitivity to α1-adrenergic stimulation with phenylephrine (PE). Small PE doses (up to 0.5mg/kg) in TG rats induced significantly greater increases in dP/dtmax (102%, p<0.0001) and dP/dtmax:dP/dtmin (40%, p<0.0001) than in NTL. TG rats with 15-fold α1A-AR overexpression exhibited an intermediate phenotype. These responses were unchanged in 8-month old TG rats.
Conclusion: Consistent with our previous evidence that the α1A-AR neither mediates nor modulates pathological LVH, adult CRα1A-AR rats, like CRα1A-AR mice, do not develop LVH, although a role in physiological LVH cannot be excluded. The similar contractility phenotypes of CR α1A-AR isolated mouse hearts/myocytes and the rat heart in vivo are consistent with the enhanced LV contractility of CRα1A-AR mice in vivo being due to enhanced basal sympathetic activity.