Abstract P173: Targeting α-1-Adrenergic Receptors for Heart Failure Therapy
Alpha-1 adrenergic receptors (α1-ARs) have beneficial effects in the heart and cardiac myocytes. In pilot studies in vivo, a sub-hypertensive dose of the α1A subtype-selective agonist A61603 has cardioprotective signaling and prevents and rescues cardiomyopathy in mouse models. These studies give a possible explanation for adverse cardiac effects of α1-antagonists in clinical trials and are a rationale to test α1-agonists in heart failure. Our objective was to establish models to screen α1-agonists for beneficial cardiac signaling. We tested the hypothesis that different α1-AR agonists have distinct beneficial cardiac effects at very low doses. To test this, we studied α1-AR-mediated cardioprotective and adaptive hypertrophic signaling in isolated neonatal rat ventricular myocytes (NRVM) and adult mouse ventricular myocytes (AMVM). We compared A61603 to all clinically approved α1-agonists: epinephrine (EPI), norepinephrine (NE), phenylephrine (PE), dobutamine (DOB), methoxamine (MET), and midodrine (MID) at 5 doses, all in the presence of the beta-blocker propranolol (200 nM). Cardioprotective signaling was measured by α1-AR-ERK survival pathway activation and cell viability by MTT assay after doxorubicin (20 μM)-induced toxicity. Cellular adaptive hypertrophy was measured by protein synthesis in NRVM and fetal gene protein expression in AMVM. In NRVM, A61603 was the most potent (EC50 = 4 nM) and efficacious agonist for ERK activation. The rank-order potency was: A61603 > NE > EPI > PE > MET > DOB > MID. For protein synthesis, A61603 had high efficacy and potency (EC50 = 12 nM). The rank-order potency was: A61603 > NE > DOB > PE > EPI > MET > MID. In AMVM, A61603 was potent for ERK (EC50 = 58 nM) and increased cell viability 48% (1.48 vs. 1.00 control) with doxorubicin toxicity. A61603 (200 nM) increased the number of myocytes expressing beta-myosin heavy chain and atrial natriuretic factor by immunocytochemistry. We conclude that myocyte culture models are predictive of α1-agonist efficacy and potency in adaptive and protective cardiac effects. A61603, an imidazoline with high affinity for the α1A-AR, is more potent and efficacious in myocyte models than are clinically available α1-agonists, and is a promising candidate for therapeutic testing in vivo.
- © 2011 by American Heart Association, Inc.