Abstract 16121: An Alpha-1A Adrenergic Receptor Agonist to Prevent and Treat Cardiomyopathy
INTRODUCTION Alpha-1 adrenergic receptors (a1ARs) have beneficial effects in the heart and cardiac myocytes in animals and humans. In neonatal rat ventricular myocytes, a1 agonists activate protective and hypertrophic signaling, and the a1A-selective agonist A61603 is very potent and efficacious. In mice, we identified a sub-hypertensive dose of A61603 that activates cardioprotective signaling. We studied this cardio-selective dose of A61603 in mouse cardiomyopathy (CM) models.
HYPOTHESIS We tested the hypothesis that the a1A-selective agonist A61603 protects and treats CM in mice.
METHODS We measured protective signaling by A61603, an a1A agonist, in adult mouse ventricular myocytes (AMVMs). We asked if A61603 10 ng/kg/d prevented doxorubicin (DOX)-induced CM in mice (25 mg/kg once ip), and treated CM from pressure overload (TAC) and ischemia (MI). Drug was continuously infused by subcutaneous osmotic pump, and heart function was measured by ECHO in awake mice.
RESULTS A61603 increased ERK activation 3-fold over control in AMVMs and prevented myocyte death from DOX. The protective effect of A61603 was lost in a1A knockout (KO) cells, showing a1A-dependence. In DOX CM, 7-day A61603 10 ng/kg/d, a sub-hypertensive dose, prevented DOX cardiotoxicity in WT mice, with reduced cardiac apoptosis (caspase 3/7, TUNEL), necrosis (serum creatine kinase), and fibrosis (sirius red), and improved cardiac function (fractional shortening FS). A61603 improved survival of WT mice given DOX (n = 23; vehicle VEH n = 49), but did not improve survival of a1A KO mice (n = 12; VEH n = 10). In TAC CM in WT mice, FS dropped from 59±2% to 37±1% over 2 weeks (gradient 100 mmHg). A61603 treatment from weeks 2-4 after TAC increased FS in every mouse (n = 4) to a mean 50%, whereas FS remained low with VEH (n = 4, mean 40%). In MI CM, A61603 treatment from weeks 4-8 after MI (12% of LV) increased FS (10% from 41%, n = 10), but FS decreased with VEH (22% from 41%, n = 5).
CONCLUSIONS In adult myocytes, A61603, an a1A agonist, activates protective signaling and prevents death with DOX toxicity. In mice, A61603 prevents DOX-induced CM and improves survival, and rescues cardiac function after pressure overload or ischemic CM. A61603 is an excellent candidate for further study as a new therapy for CM and heart failure.
- © 2012 by American Heart Association, Inc.