The alpha-1A adrenergic receptor agonist A61603 reduces cardiac polyunsaturated fatty acid and endocannabinoid metabolites associated with inflammation in vivo

Abstract

Introduction Alpha-1-adrenergic receptors (α1-ARs) are G-protein coupled receptors (GPCRs) with three highly homologous subtypes (α1A, α1B, and α1D). Of these three subtypes, only the α1A and α1B are expressed in the heart. Multiple pre-clinical models of heart injury demonstrate cardioprotective roles for the α1A. Non-selective α1-AR activation promotes glycolysis in the heart, but the functional α1-AR subtype and broader metabolic effects have not been studied. Objectives Given the high metabolic demands of the heart and previous evidence indicating benefit from α1A activation, we chose to investigate the effects of α1A activation on the cardiac metabolome in vivo. Methods Mice were treated for one week with a low, subpressor dose of A61603, a highly selective and potent α1A agonist. Cardiac tissue and serum were analyzed using a non-targeted metabolomics approach. Results We identified previously unrecognized metabolic responses to α1A activation, most notably broad reduction in the abundance of polyunsaturated fatty acids (PUFAs) and endocannabinoids (ECs). Conclusion Given the well characterized roles of PUFAs and ECs in inflammatory pathways, these findings suggest a possible role for cardiac α1A-ARs in the regulation of inflammation and may offer novel insight into the mechanisms underlying the cardioprotective benefit of selective pharmacologic α1A activation.

G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

“…Of particular interest is the evidence that a 1A -adrenoceptors are cardioprotective in heart failure. Activation of a 1 -adrenoceptors in the heart reduces pathologic remodelling, inhibits cell death, and improves myocyte contractility (Jensen et al, 2011;O'Connell et al, 2013;Willis et al, 2016;Beak et al, 2017) by mechanisms that include facilitation of glucose uptake (Tian and Abel, 2001;Shi et al, 2016). The role of a 1Aadrenoceptors in the failing heart is increasingly important for a number of reasons.…”

Stimulation of Alpha-1-Adrenergic Receptor Ameliorates Obesity-Induced Cataracts by Activating Glycolysis and Inhibiting Cataract-Inducing Factors

“…Moreover, α1-adrenergic receptor agonists, such as dabuzalgron, improved the cardiotoxicity caused by doxorubicin through mitochondrial activation [ 13 ]. Another α1-adrenergic receptor agonist, A61603, decreased the levels of polyunsaturated fatty acids in the heart and endocannabinoid metabolites involved in inflammation [ 37 ]. From previous reports on the effects of the α1-adrenergic receptor on glucose utilization, mitochondrial function, and anti-inflammation, there is sufficient evidence to argue for the therapeutic efficacy of midodrine on cataracts induced by diabetes and obesity.…”

α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease

“…The current hypothesis is that selective α 1A -AR agonists may be a potential treatment in heart failure [ 54 , 55 ], since chronic α 1B -AR stimulation, as evidenced through transgenic mouse models, appears to be maladaptive by inducing dilated cardiomyopathy [ 29 ] or heart failure [ 37 ]. While α-AR blockers are a current treatment option for heart failure, using α 1A -AR selective agonists may provide potentially greater benefits such as preventing dementia [ 56 ], improving metabolic function and glucose tolerance [ 56 , 57 , 58 ], increasing lifespan with reduce cancer risk [ 59 , 60 ] and reducing inflammation and cataracts [ 58 , 61 ].…”