An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice

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.

α1A-Subtype adrenergic agonist therapy for the failing right ventricle

“…The findings in this study are consistent with growing experimental and clinical evidence suggesting that ␣ 1 -ARs mediate cardioprotective effects (3,14,23). Moreover, these findings are consistent with recent studies suggesting that chronic ␣ 1A -subtype stimulation is beneficial for improving LV function in the doxorubicin-induced cardiotoxicity model (4,20). Limitations.…”

“…Concurrently, mice were chronically treated for 2 wk with A61603 (Tocris Bioscience, Bristol, UK), a potent and highly specific agonist for the ␣ 1A-subtype that does not stimulate the other two ␣1-AR subtypes (␣1B or ␣1D). A subhypertensive dose of A61603 (10 ng•kg Ϫ1 •day Ϫ1 ) (20) or saline was given by continuous subcutaneous infusion with an osmotic mini-pump (model 1002, Alzet, Durect) that was implanted between the scapulae under isoflurane anesthesia. This is a disease prevention study design.…”

“…Clinical and experimental evidence suggests that in heart failure involving the LV, ␣ 1 -adrenergic receptors (␣ 1 -ARs) mediate multiple cardioprotective effects, in vivo and in vitro (3,14,23). Consistent with a beneficial effect mediated by ␣ 1 -ARs, recent studies have suggested that chronic stimulation of a single ␣ 1 -AR subtype (␣ 1A ) is beneficial in a doxorubicin toxicity model of LV failure (4,20). However, it is not known if this novel ␣ 1A -subtype therapy is effective for RV failure models.…”

Stimulation of Alpha1-Adrenergic Receptor Ameliorates Cellular Functions of Multiorgans beyond Vasomotion through PPARδ

“…Therefore, it is likely that the metabolic effect of α 1 -AR activation could be obtained in animal experiments at a concentration of midodrine that was even lower than the lowest effective concentration in our cell experiments. Although selective α 1 -AR agonists will play a crucial role in studying how different α 1 -AR subtypes are distributed in different organs and how they affect cell-specific effects, we used midodrine, a nonselective α 1 -AR agonist that binds to α 1 A-, α 1 B-, and α 1 D-AR [41] in this study. We deemed it suitable for studying integrated healthy exercise effects because it stimulates all the subtypes of α 1 -AR, which are allocated throughout the body according to physiological requirements.…”

Reduction of Hepatotoxicity Induced by Doxorubicin

“…Oxygen-free radicals produced during the metabolic activation of DOX may have toxic effects on heart muscle [11], which is provided with poor mechanisms of detoxification of such species DOX is likely to have toxic effects on liver [12] by increasing levels of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSHPx) enzyme in liver tissue of guinea pigs [13]. Nevertheless, distribution of a unique dose of DO x decreases the content of cytochrome P-450 and glutathione in rat liver [14] and high levels of glutathione have been found to protect isolated hepatocytes from DOX toxicity [15].…”