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Updated: Mar 8, 2026
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice
Megan D Montgomery1,2, Trevor Chan1,2, Philip M Swigart1,2
1Department of Medicine, Cardiology Division, VA Medical Center, San Francisco, CA, United States of America.
Abstract:
Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35-40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies.
Insights
Alpha-1A adrenergic receptor agonists, like A61603, protect male mice from doxorubicin-induced heart damage. This suggests potential for new heart failure therapies targeting this receptor pathway.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Alpha-1 adrenergic receptors influence cardiac function and myocyte survival.
- A pathway involving the alpha-1A receptor subtype and ERK activation promotes myocyte survival in vitro.
- In vivo data on alpha-1A adrenergic receptor function in the heart are limited.
Purpose of the Study:
- To investigate the in vivo effects of the selective alpha-1A adrenergic receptor agonist A61603.
- To determine if A61603 protects against doxorubicin-induced cardiotoxicity.
- To explore the therapeutic potential of alpha-1A adrenergic receptor agonists for heart failure.
Main Methods:
- Tested A61603, a selective imidazoline agonist for alpha-1A, in neonatal rat and adult mouse ventricular myocytes.
- Administered A61603 in vivo to mice and assessed ERK activation, blood pressure, cardiac function, and cell death markers.
- Induced doxorubicin cardiotoxicity in male and female mice, with and without A61603 treatment, and in alpha-1A-knockout mice.
Main Results:
- A61603 potently activated ERK in myocytes and protected them from doxorubicin-induced death.
- Low-dose A61603 activated cardiac ERK in vivo without altering blood pressure.
- A61603 treatment significantly improved survival, cardiac function, and reduced cardiac damage in male mice receiving doxorubicin; these effects were absent in alpha-1A-knockout mice.
Conclusions:
- The alpha-1A adrenergic receptor agonist A61603 prevents doxorubicin cardiomyopathy in male mice via the alpha-1A receptor.
- These findings support the potential of alpha-1A adrenergic receptor agonists as novel therapies for heart failure.
- Sex-dependent differences in doxorubicin cardiotoxicity were observed.
