title: Cirsimarin and cirsimaritin, flavonoids of Microtea debilis (Phytolaccaceae) with adenosine antagonistic properties in rats: leads for new therapeutics in acute renal failure.
abstract: In traditional medicine Microtea debilis is used against proteinuria. In ligand-binding studies extracts of Microtea debilis have been shown to inhibit the binding of [3H]1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) to adenosine-A1 receptors in rat forebrain membranes. Subsequently, cirsimarin, a flavonoid, was isolated as the active component and was shown to function as adenosine antagonist at the adenosine-A1 receptor in-vitro. In this study we have investigated the adenosine-A2 receptor activity of cirsimarin the in-vivo inhibition of the effects of adenosine by cirsimarin in rats, the absorption of cirsimarin and the inhibition of the binding of [3H]DPCPX to the adenosine-A1 receptor by urine samples obtained after oral administration of crude extract of Microtea debilis, cirsimarin or cirsimaritin to rats. Cirsimarin inhibited the binding of [3H]5'-N-ethylcarboxamidoadenosine ([3H]NECA) to adenosine-A2 receptors in rat striatum with an inhibition constant, Ki, of 6.5 +/- 0.3 microM. The decrease of heart rate and blood pressure induced by adenosine was significantly inhibited by cirsimarin. After oral administration of 8 and 80 mg kg-1 cirsimarin, the compound could not be detected in either plasma or urine, but the presence of cirsimaritin was established. By use of beta-glucuronidase, glucuronides of cirsimaritin were also detected in the urine. The concentrations of cirsimaritin in the plasma were 0.126 +/- 0.04, 0.138 +/- 0.015, and 0.120 +/- 0.022 microM, respectively, 2, 5 and 12 h after administration of 8 mg kg-1 cirsimarin. The concentrations of cirsimaritin in the urine at the same times after administration of the same dose were 2.05 +/- 1.86, 5.05 +/- 2.6 and 2.06 +/- 0.09 microM, respectively. The inhibition of the binding of [3H]DPCPX to the adenosine-A1 receptor by urine samples collected 2, 5 and 12 h after oral administration of 8 mg kg-1 cirsimarin or a crude extract of Microtea debilis containing approximately 8 mg kg-1 cirsimarin and 2.8 mg kg-1 cirsimaritin, or 6.8 mg kg-1 cirsimaritin, was not significantly different from that of urine samples collected from untreated rats, in contrast with urine samples collected 1 and 2 days after oral administration of 80 mg kg-1 cirsimarin. Approximately 3% of the cirsimarin was excreted in the urine as cirsimaritin. The results indicate that in the kidney and urinary tract the concentrations of cirsimaritin produced after ingestion of more than 8 mg kg-1 cirsimarin can be high enough to inhibit the interaction of adenosine with its receptors; this might explain the effectiveness of Microtea debilis preparations against proteinuria in traditional medicine.
authors.affiliation: Department of Pharmaceutical Sciences, University of Antwerp, Belgium.
authors.forename: J A
authors.initials: JA
authors.lastname: Hasrat
authors.forename: T
authors.initials: T
authors.lastname: De Bruyne
authors.forename: J P
authors.initials: JP
authors.lastname: De Backer
authors.forename: G
authors.initials: G
authors.lastname: Vauquelin
authors.forename: A J
authors.initials: AJ
authors.lastname: Vlietinck
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy*; D000241:Adenosine / Q000037:antagonists & inhibitors*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000378:metabolism; D000818:Animals; D005260:Female; D047309:Flavones; D005419:Flavonoids / Q000097:blood / Q000627:therapeutic use* / Q000652:urine; D018755:GABA Agonists / Q000627:therapeutic use; D006027:Glycosides / Q000097:blood / Q000627:therapeutic use* / Q000652:urine; D006439:Hemodynamics / Q000187:drug effects; D008024:Ligands; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D014665:Vasodilator Agents / Q000378:metabolism
chemical_list: D047309:Flavones; D005419:Flavonoids; D018755:GABA Agonists; D006027:Glycosides; D008024:Ligands; D018047:Receptors, Purinergic P1; D014665:Vasodilator Agents; C107783:cirsimarin; D019830:Adenosine-5'-(N-ethylcarboxamide); C007072:cirsimaritin; D000241:Adenosine