Peripheral 5-HT 2A-receptor-mediated formation of an inhibitor of atrial natriuretic peptide binding involves inflammation

Abstract

A peripheral 5-HT 2A receptor-mediated hemodynamic change prompted formation of indole-2,3-dione, an endogenous inhibitor of atrial natriuretic peptide (ANP) receptor binding and G protein-mediated intracellular signaling (IC 50: 0.4 μM). This effect was significantly suppressed by dexamethasone, indomethacin and the 5-HT 2 receptor antagonists, ketanserin or ritanserin. 5-HT 2A receptor-mediated acute hemodynamic change was not modified significantly by indomethacin, prazosin or propranolol pretreatment. A tyrosine hydroxylase inhibitor, α-methyl- p-tyrosine, but not a dopamine β hydroxylase inhibitor, diethyldithiocarbamate, abolished the 5-HT 2A receptor-mediated increase in indole-2,3-dione. Exogenous indole-2,3-dione induced a significant increase in plasma catecholamine levels and decrease in urine volume. A 5-HT 2A receptor-mediated decrease in capillary flow may have caused an inflammatory process and peripheral sympathetic activation via ANP signaling inhibition. 3,4-dihydroxyphenylalanine (DOPA)/dopamine may contribute to the progression of inflammation or the generation of a precursor of indole-2,3-dione. The observation that indole-2,3-dione abolished angiotensin AT 1 receptor-mediated NADPH activation in both human umbilical vein endothelial cells and smooth muscle cells at 20 μM may suggest that sulfhydryl-reactive indole-2,3-dione could influence mitochondrial function and cellular redox states via flavoenzyme inhibition and/or regulation of dehydrogenase–oxidase conversion.