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1 Department of Pharmacology and Toxicology, University of Medical Center Nijmegen, Nijmegen Center for Molecular Life Sciences, Nijmegen, The Netherlands; Mount Desert Island Biological Laboratory, Salisbury Cove, Maine, USA
2 Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Science, National Institutes of Health, Research Triangle Park, North Carolina, USA; Mount Desert Island Biological Laboratory, Salisbury Cove, Maine, USA
3 Department of Pharmacology and Toxicology, University of Medical Center Nijmegen, Nijmegen Center for Molecular Life Sciences, Nijmegen, The Netherlands
* To whom correspondence should be addressed. E-mail: R.Masereeuw{at}ncmls.kun.nl.
In killifish renal proximal tubules, endothelin-1 (ET-1), acting through a basolateral ETB receptor, nitric oxide synthase (NOS), and protein kinase C (PKC), decreases cellto- lumen organic anion transport mediated by the multidrug resistance protein isoform 2 (Mrp2) . In the present study, we examined the roles of guanylyl cyclase and cGMP in ET signaling to Mrp2. Using confocal microscopy and quantitative image analysis to measure Mrp2-mediated transport of the fluorescent drug, fluorescein methotrexate (FLMTX), we found that oxadiazole quinoxalin (ODQ), an inhibitor of NO-sensitive guanylyl cyclase, blocked ET-1 signaling. ODQ was also effective when signaling was initiated by nephrotoxicants (gentamicin, amikacin, diatrizoate, HgCl2 and CdCl2), which appear to stimulate ET release from the tubules themselves. ODQ blocked the effects of the NO donor, sodium nitroprusside, but not of the phorbol ester which activates PKC. Exposing tubules to 8Br-cGMP, a cell permeable cGMP analog, decreased luminal FL-MTX accumulation. This effect was abolished by bisindolmaleimide (BIM), a PKC inhibitor, but not by L-NMMA, an NOS inhibitor. Together, these data indicate that ET regulation of Mrp2 involves activation of guanylyl cyclase and generation of cGMP. Signaling by cGMP follows NO release and precedes PKC activation.
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