Abstract
The transport of the angiotensin II receptor antagonist losartan and its interaction with organic anion transport were examined in the isolated perfused rabbit proximal tubule. Losartan reversibly inhibited the secretion of para-aminohippurate (PAH) in a concentration-dependent manner (IC50 = 15 ± 0.5 μM). Other angiotensin II receptor antagonists also inhibited PAH secretion with similar potencies: eprosartan, 11 ± 2.3 μM; irbesartan, 17 ± 2.2 μM; and valsartan 3 ± 0.6 μM. [3H]Losartan was secreted by the proximal tubule by a saturable and probenecid-sensitive mechanism. The affinity of losartan for the organic anion transporter (Km = 12.3 ±1.8 μM) was significantly greater than that of PAH (Km = 88.5 ± 10.7 μM). [3H]Losartan secretion was stimulated in the presence of α-ketoglutarate, suggesting that losartan, like PAH, enters the cell in exchange for a dicarboxylate. These results demonstrate that losartan and probably other nonpeptide angiotensin II receptor antagonists are secreted by an organic anion transporter that is similar to, if not identical with, the classic PAH transporter.
Footnotes
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Send reprint requests to: Dr. Richard Edwards, SmithKline Beecham Pharmaceuticals, Department of Renal Pharmacology, UW2521, 709 Swedeland Road, Box 1539, King of Prussia, PA 19406. E-mail:Richard_M_Edwards{at}sbphrd.com
- Abbreviations:
- PAH
- para-aminohippurate
- DMEM
- Dulbecco’s modified Eagle’s medium
- JPAH
- secretory flux of PAH
- JLOS
- secretory flux of losartan
- α-KG
- α-ketoglutarate
- Received December 22, 1998.
- Accepted March 27, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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