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

Introduction Alpha-1-adrenergic receptors (alpha 1-ARs) are G-protein coupled receptors (GPCRs) with three highly homologous subtypes (alpha 1A, alpha 1B, and alpha 1D). Of these three subtypes, only the alpha 1A and alpha 1B are expressed in the heart. Multiple pre-clinical models of heart injury demonstrate cardioprotective roles for the alpha 1A. Non-selective alpha 1-AR activation promotes glycolysis in the heart, but the functional alpha 1-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 alpha 1A activation, we chose to investigate the effects of alpha 1A activation on the cardiac metabolome in vivo. Methods Mice were treated for 1 week with a low, subpressor dose of A61603, a highly selective and potent alpha 1A agonist. Cardiac tissue and serum were analyzed using a non-targeted metabolomics approach. Results We identified previously unrecognized metabolic responses to alpha 1A 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 alpha 1A-ARs in the regulation of inflammation and may offer novel insight into the mechanisms underlying the cardioprotective benefit of selective pharmacologic alpha 1A activation.