Peripheral 5-HT(2A)-receptor-mediated formation of an inhibitor of atrial natriuretic peptide binding involves inflammation.
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 microM). 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, alpha-methyl-p-tyrosine, but not a dopamine beta 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 microM 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.
Tozawa
Yumiko
Y
Department of Molecular Preventive Medicine, School of Medicine, University of Tokyo, Tokyo, Japan. yumiko.tozawa@pobox.com
Matsushima
Kouji
K
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002395:Catecholamines / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D007510:Isatin / Q000378:metabolism* / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D044402:Receptor, Serotonin, 5-HT2A; D011945:Receptors, Angiotensin / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012110:Reserpine / Q000494:pharmacology; D016713:Ritanserin / Q000494:pharmacology; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D014554:Urination / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology; D019805:alpha-Methyltyrosine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D016861:Cyclooxygenase Inhibitors; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D044402:Receptor, Serotonin, 5-HT2A; D011945:Receptors, Angiotensin; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D016713:Ritanserin; C042390:alpha-methylserotonin; D015016:Yohimbine; D012701:Serotonin; D019805:alpha-Methyltyrosine; D003907:Dexamethasone; D007510:Isatin; D009320:Atrial Natriuretic Factor; D012110:Reserpine; D007650:Ketanserin; D004050:Ditiocarb; D011433:Propranolol; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D011224:Prazosin; D007213:Indomethacin