Abstract 20575: An Alpha-1A Adrenergic Receptor Agonist Prevents and Treats Heart Failure
INTRODUCTION: The neurohormonal hypothesis that sympathetic activation in heart failure (HF) is toxic to the heart led to class I recommended drugs. However, contrary data suggest that sympathetic blockade in HF has limits, such as the negative effects of alpha-1-adrenergic receptor (a1-AR) blockade in humans in ALLHAT and V-HeFT. Conversely, a1-agonists protect myocytes and hearts of multiple species in multiple models through pleiotropic mechanisms, but this is untested in HF in vivo.
HYPOTHESIS: We hypothesized that a1-AR agonism can treat HF in vivo.
METHODS: We screened drugs in neonatal rat and adult mouse ventricular myocytes (NRVM, AMVM), measured telemetry blood pressure (BP), and did subcutaneous infusion in mice with HF from cardiotoxin (doxorubicin, DOX) and pressure overload (TAC).
RESULTS: In NRVMs, the a1A agonist A61603 (A6) was the most efficacious and potent of 10 a1 agonists in ERK activation (EC50 6±1 nM, Emax 22±7) and protein synthesis (EC50 10±1 nM, Emax 1.7±0.1), and EC50s matched a1A binding affinity. In AMVMs, A6 activated ERK (EC50 39±5 nM) and protected against DOX (EC50 15±8 nM, Emax 35±6), an effect lost in the a1A KO. In isolated hearts, A6 activated ERK target genes. A6 10 ng/kg/d infused sc for 7 days had no effect on BP, but increased cardiac pERK (EC50 0.1±0.1 μg/kg/d). With DOX, A6 10 ng/kg/d started at the same time enhanced survival (A6+DOX 84%, n=21; Veh+DOX 34%, n=49). A6 also preserved function (A6 FS 61±2% vs. Veh 49±3%), and reduced serum CK (571±67 vs. 1204±98), TUNEL staining (0.5±0.1 vs. 1.3±0.2), and Sirius Red staining (25±1 vs. 32±1) (n=3-5). A6 effects on survival and FS after DOX were lost in the a1A KO. With TAC (gradient 109 mmHg), FS fell over 2 weeks to 40±1%. A6 from weeks 2 to 4 increased FS (to 51±2%, n=30), while FS remained low with Veh (39±2%, n=24). A6 after TAC did not change heart or myocytes size, but did increase pERK and bMyHC, and reduced cardiac troponin I (A6 5±2 vs. 11±2), cleaved caspase 3 (77±7% of Veh), collagens I and III (46±5% and 56±8% of Veh), and Sirius Red staining (5±4% vs. 9±8%) (n=3-22).
CONCLUSIONS: The high affinity a1A-AR agonist A61603, at a low dose that does not change BP, prevents cell death and fibrosis and improves function and mortality in two mouse models of HF. a1A-AR agonists might be potential HF therapies.
Author Disclosures: M.D. Montgomery: Ownership Interest; Significant; AdrenaRx, Inc.. T. Chan: None. R. Dash: None. P.M. Swigart: None. B. Myagmar: None. A.J. Baker: None. P.C. Simpson: Research Grant; Significant; NIH R01 grant, VA Merit grant. Ownership Interest; Significant; AdrenaRx, Inc..
- © 2014 by American Heart Association, Inc.