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Recent studies have shown that the renal cytochrome P-450 metabolites of arachidonic acid: thevasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE), and the vasodilatorepoxyeicosatrienoic acids (EETs) play an important role in the pathophysiology of angiotensin II(ANG II)-dependent forms of hypertension and the associated target organ damage. The presentstudies were performed in Ren-2 renin transgenic rats (TGR) to evaluate the effects of chronicselective inhibition of 20-HETE formation or elevation of the level of EETs, alone or incombination, on the course of hypertension and hypertension-associated end-organ damage. Bothyoung (30 days of age) prehypertensive TGR and adult (190 days of age) TGR with establishedhypertension were examined. Normotensive Hannover Sprague-Dawley (HanSD) rats served ascontrols. The rats were treated with N-methylsulfonyl-12,12-dibromododec-11-enamide to inhibit20-HETE formation and/or with N-cyclohexyl-N-dodecyl urea to inhibit soluble epoxidehydrolase and prevent degradation of EETs. Inhibition in TGR rats of 20-HETE formationcombined with enhanced bioavailability of EETs attenuated the development of hypertension,cardiac hypertrophy, proteinuria, glomerular hypertrophy and sclerosis as well as renaltubulointerstitial injury. This was also associated with an attenuation of the responsiveness of thesystemic and renal vascular beds to ANG II without modifying their responses to norepinephrine.Our data 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 thismodel of ANG II-dependent hypertension. This information provides a basis for a search of newtherapeutic approaches to the treatment of hypertension.



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Mossakowski Medical Research Center PAS

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Library of the Mossakowski Medical Research Center PAS

Projects co-financed by:

Programme Innovative Economy, 2010-2014, Priority Axis 2. R&D infrastructure



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