Cirsimarin and cirsimaritin, flavonoids of Microtea debilis (phytolaccaceae) with adenosine antagonistic properties in rats: Leads for new therapeutics in acute renal failure

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 [H-3]1,3-dipropyl-8-cyclopentylxanthine ([H-3]DPCPX) to adenosine-A(r)eceptors 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-A(1) receptor in-vitro. In this study we have investigated the adenosine-A(2) 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 [H-3]DPCPX to the adenosine-A(1) receptor by urine samples obtained after oral administration of crude extract of Microtea debilis, cirsimarin or cirsimaritin to rats. Cirsimarin inhibited the binding of [H-3]5'-N-ethylcarboxamidoadenosine ([H-3]NECA) to adenosine-A(2) receptors in rat striatum with an inhibition constant, K-i, of 6.5 +/- 0.3 mu M. 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 mu M, 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 mu M, respectively. The inhibition of the binding of [H-3]DPCPX to the adenosine-A(1) 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.