ANTIDIURETIC EFFECTS OF THE ENDOTHELIN RECEPTOR ANTAGONIST AVOSENTAN
Several clinical studies have investigated the potential benefits of endothelin receptor antagonism in chronic pathologies such as diabetic kidney disease. However, fluid retention and edema have been identified as major side effects of endothelin receptor antagonists. In the present study we hypoth...
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| Format: | Article |
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Frontiers Media S.A.
2012-04-01
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| Series: | Frontiers in Physiology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphys.2012.00103/full |
| _version_ | 1818986605548929024 |
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| author | Ovidiu Constantin Baltatu Ovidiu Constantin Baltatu Radu eIliescu Christian eZaugg Jane F. Reckelhoff Pat eLouie Christoph eSchumacher Luciana Aparecida Campos Luciana Aparecida Campos |
| author_facet | Ovidiu Constantin Baltatu Ovidiu Constantin Baltatu Radu eIliescu Christian eZaugg Jane F. Reckelhoff Pat eLouie Christoph eSchumacher Luciana Aparecida Campos Luciana Aparecida Campos |
| author_sort | Ovidiu Constantin Baltatu |
| collection | DOAJ |
| description | Several clinical studies have investigated the potential benefits of endothelin receptor antagonism in chronic pathologies such as diabetic kidney disease. However, fluid retention and edema have been identified as major side effects of endothelin receptor antagonists. In the present study we hypothesized that avosentan which was described as a predominant ETA receptor antagonist would produce fluid retention at high concentrations where non-specific blockade of ETB receptors may occur. Incremental doses of the predominant ETA receptor antagonist SPP301 (0.003; 0.03; 3 mg/kg) were administered intravenously to anesthetized Sprague-Dawley rats undergoing saline diuresis. Diuresis, glomerular filtration rate and blood pressure were monitored. SPP301 decreased urine output (5.6; 34.8; 58.8% decrease from vehicle) and fractional excretion of water (5.7; 31.7; 56.4% decrease from vehicle) in a concentration-dependent manner. Glomerular filtration rate was unchanged while blood pressure was reduced by 10 mmHg only by the highest dose of SPP301. Administration of the ETB selective receptor antagonist BQ-788 (3 mg/kg) following SPP301 3 mg/kg did not further decrease urine output or water excretion and was without effect on glomerular filtration rate. These data indicate that increasing concentrations of SPP301 may also block ETB receptors and cause antidiuresis. This effect could explain why fluid retention and edema occur during treatment with predominant ETA receptor blockers. |
| first_indexed | 2024-12-20T18:53:27Z |
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| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-20T18:53:27Z |
| publishDate | 2012-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Physiology |
| spelling | doaj.art-ac5c099fd1a548848811af3295bfdb3e2022-12-21T19:29:33ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2012-04-01310.3389/fphys.2012.0010325056ANTIDIURETIC EFFECTS OF THE ENDOTHELIN RECEPTOR ANTAGONIST AVOSENTANOvidiu Constantin Baltatu0Ovidiu Constantin Baltatu1Radu eIliescu2Christian eZaugg3Jane F. Reckelhoff4Pat eLouie5Christoph eSchumacher6Luciana Aparecida Campos7Luciana Aparecida Campos8University Camilo Castelo BrancoGr. T. Popa Center for Biomedical Research University of Medicine and PharmacyGr. T. Popa Center for Biomedical Research University of Medicine and PharmacyUniversity of BaselUniversity of Mississippi Medical CenterNovartis Pharma AGNovartis Pharma AGUniversity Camilo Castelo BrancoGr. T. Popa Center for Biomedical Research University of Medicine and PharmacySeveral clinical studies have investigated the potential benefits of endothelin receptor antagonism in chronic pathologies such as diabetic kidney disease. However, fluid retention and edema have been identified as major side effects of endothelin receptor antagonists. In the present study we hypothesized that avosentan which was described as a predominant ETA receptor antagonist would produce fluid retention at high concentrations where non-specific blockade of ETB receptors may occur. Incremental doses of the predominant ETA receptor antagonist SPP301 (0.003; 0.03; 3 mg/kg) were administered intravenously to anesthetized Sprague-Dawley rats undergoing saline diuresis. Diuresis, glomerular filtration rate and blood pressure were monitored. SPP301 decreased urine output (5.6; 34.8; 58.8% decrease from vehicle) and fractional excretion of water (5.7; 31.7; 56.4% decrease from vehicle) in a concentration-dependent manner. Glomerular filtration rate was unchanged while blood pressure was reduced by 10 mmHg only by the highest dose of SPP301. Administration of the ETB selective receptor antagonist BQ-788 (3 mg/kg) following SPP301 3 mg/kg did not further decrease urine output or water excretion and was without effect on glomerular filtration rate. These data indicate that increasing concentrations of SPP301 may also block ETB receptors and cause antidiuresis. This effect could explain why fluid retention and edema occur during treatment with predominant ETA receptor blockers.http://journal.frontiersin.org/Journal/10.3389/fphys.2012.00103/fullDiuresisRenalendothelin receptor antagonistfluid retention |
| spellingShingle | Ovidiu Constantin Baltatu Ovidiu Constantin Baltatu Radu eIliescu Christian eZaugg Jane F. Reckelhoff Pat eLouie Christoph eSchumacher Luciana Aparecida Campos Luciana Aparecida Campos ANTIDIURETIC EFFECTS OF THE ENDOTHELIN RECEPTOR ANTAGONIST AVOSENTAN Frontiers in Physiology Diuresis Renal endothelin receptor antagonist fluid retention |
| title | ANTIDIURETIC EFFECTS OF THE ENDOTHELIN RECEPTOR ANTAGONIST AVOSENTAN |
| title_full | ANTIDIURETIC EFFECTS OF THE ENDOTHELIN RECEPTOR ANTAGONIST AVOSENTAN |
| title_fullStr | ANTIDIURETIC EFFECTS OF THE ENDOTHELIN RECEPTOR ANTAGONIST AVOSENTAN |
| title_full_unstemmed | ANTIDIURETIC EFFECTS OF THE ENDOTHELIN RECEPTOR ANTAGONIST AVOSENTAN |
| title_short | ANTIDIURETIC EFFECTS OF THE ENDOTHELIN RECEPTOR ANTAGONIST AVOSENTAN |
| title_sort | antidiuretic effects of the endothelin receptor antagonist avosentan |
| topic | Diuresis Renal endothelin receptor antagonist fluid retention |
| url | http://journal.frontiersin.org/Journal/10.3389/fphys.2012.00103/full |
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