Recent studies have shown that the renal CYP450 (cytochrome P450) metabolites of AA (arachidonic acid), the vasoconstrictor 20-HETE (20-hydroxyeicosatetraenoic acid) and the vasodilator EETs (epoxyeicosatrienoic acids), play an important role in the pathophysiology of AngII (angiotensin II)-dependent forms of hypertension and the associated target organ damage. The present studies were performed in Ren-2 renin transgenic rats (TGR) to evaluate the effects of chronic selective inhibition of 20-HETE formation or elevation of the level of EETs, alone or in combination, on the course of hypertension and hypertension-associated end-organ damage. Both young (30 days of age) prehypertensive TGR and adult (190 days of age) TGR with established hypertension were examined. Normotensive HanSD (Hannover Sprague–Dawley) rats served as controls. The rats were treated with N-methylsulfonyl-12,12-dibromododec-11-enamide to inhibit 20-HETE formation and/or with N-cyclohexyl-N-dodecyl urea to inhibit soluble epoxide hydrolase and prevent degradation of EETs. Inhibition in TGR of 20-HETE formation combined with enhanced bioavailability of EETs attenuated the development of hypertension, cardiac hypertrophy, proteinuria, glomerular hypertrophy and sclerosis as well as renal tubulointerstitial injury. This was also associated with attenuation of the responsiveness of the systemic and renal vascular beds to AngII without modifying their responses to noradrenaline (norepinephrine). Our findings suggest that altered production and/or action of 20-HETE and EETs plays a permissive role in the development of hypertension and hypertension-associated end-organ damage in this model of AngII-dependent hypertension. This information provides a basis for a search for new therapeutic approaches for the treatment of hypertension.
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February 23 2010
Combined inhibition of 20-hydroxyeicosatetraenoic acid formation and of epoxyeicosatrienoic acids degradation attenuates hypertension and hypertensioninduced end-organ damage in Ren-2 transgenic rats
Věra Čertíková Chábová;
Věra Čertíková Chábová
1
*Department of Nephrology, 1st Medical Faculty, Charles University, Prague, Czech Republic
†Department for Experimental Medicine, Institute for Clinical and Experimental Medicine, 1958/9 Vídeňská, CZ-140 21 Prague 4, Czech Republic
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Agnieszka Walkowska;
Agnieszka Walkowska
1
‡Laboratory of Renal and Body Fluid Physiology, Mossakowski Medical Research Centre, Polish Academy of Science, Warsaw, Poland
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Elzbieta Kompanowska-Jezierska;
Elzbieta Kompanowska-Jezierska
‡Laboratory of Renal and Body Fluid Physiology, Mossakowski Medical Research Centre, Polish Academy of Science, Warsaw, Poland
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Janusz Sadowski;
Janusz Sadowski
‡Laboratory of Renal and Body Fluid Physiology, Mossakowski Medical Research Centre, Polish Academy of Science, Warsaw, Poland
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Petr Kujal;
Petr Kujal
†Department for Experimental Medicine, Institute for Clinical and Experimental Medicine, 1958/9 Vídeňská, CZ-140 21 Prague 4, Czech Republic
§Department of Pathology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
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Zdenka Vernerová;
Zdenka Vernerová
†Department for Experimental Medicine, Institute for Clinical and Experimental Medicine, 1958/9 Vídeňská, CZ-140 21 Prague 4, Czech Republic
§Department of Pathology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
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Zdeňa Vaňourková;
Zdeňa Vaňourková
†Department for Experimental Medicine, Institute for Clinical and Experimental Medicine, 1958/9 Vídeňská, CZ-140 21 Prague 4, Czech Republic
‖Center for Cardiovascular Research, Prague, Czech Republic
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Libor Kopkan;
Libor Kopkan
†Department for Experimental Medicine, Institute for Clinical and Experimental Medicine, 1958/9 Vídeňská, CZ-140 21 Prague 4, Czech Republic
‖Center for Cardiovascular Research, Prague, Czech Republic
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Herbert J. Kramer;
Herbert J. Kramer
¶Section of Nephrology, Medical Policlinic, Department of Medicine, University of Bonn, Bonn, Germany
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John R. Falck;
John R. Falck
**Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 606-538, U.S.A.
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John D. Imig;
John D. Imig
††Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
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Bruce D. Hammock;
Bruce D. Hammock
‡‡Department of Entomology, University of California at Davis Cancer Center, Davis, CA 95616, U.S.A.
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Ivana Vaněčková;
Ivana Vaněčková
†Department for Experimental Medicine, Institute for Clinical and Experimental Medicine, 1958/9 Vídeňská, CZ-140 21 Prague 4, Czech Republic
‖Center for Cardiovascular Research, Prague, Czech Republic
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Luděk Červenka
†Department for Experimental Medicine, Institute for Clinical and Experimental Medicine, 1958/9 Vídeňská, CZ-140 21 Prague 4, Czech Republic
§§Department of Physiology, 2nd Medical Faculty, Charles University, Prague, Czech Republic
Correspondence: Dr Luděk Červenka (email [email protected]).
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Publisher: Portland Press Ltd
Received:
September 09 2009
Revision Received:
December 17 2009
Accepted:
January 05 2010
Accepted Manuscript online:
January 05 2010
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2010 Biochemical Society
2010
Clin Sci (Lond) (2010) 118 (10): 617–632.
Article history
Received:
September 09 2009
Revision Received:
December 17 2009
Accepted:
January 05 2010
Accepted Manuscript online:
January 05 2010
Citation
Věra Čertíková Chábová, Agnieszka Walkowska, Elzbieta Kompanowska-Jezierska, Janusz Sadowski, Petr Kujal, Zdenka Vernerová, Zdeňa Vaňourková, Libor Kopkan, Herbert J. Kramer, John R. Falck, John D. Imig, Bruce D. Hammock, Ivana Vaněčková, Luděk Červenka; Combined inhibition of 20-hydroxyeicosatetraenoic acid formation and of epoxyeicosatrienoic acids degradation attenuates hypertension and hypertensioninduced end-organ damage in Ren-2 transgenic rats. Clin Sci (Lond) 1 May 2010; 118 (10): 617–632. doi: https://doi.org/10.1042/CS20090459
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