Inhibition of soluble epoxide hydrolase counteracts the development of renal dysfunction and progression of congestive heart failure in Ren-2 transgenic hypertensive rats with aorto-caval fistula
Language English Country Australia Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- aorto-caval fistula, congestive heart failure, epoxyeicosatrienoic acids, hypertension, renal dysfunction, renin-angiotensin system, soluble epoxide hydrolase,
- MeSH
- Angiotensin I metabolism MeSH
- Angiotensin II metabolism MeSH
- Aorta MeSH
- Time Factors MeSH
- Epoxide Hydrolases antagonists & inhibitors chemistry MeSH
- Hemodynamics drug effects MeSH
- Angiotensin-Converting Enzyme Inhibitors pharmacology therapeutic use MeSH
- Enzyme Inhibitors pharmacology therapeutic use MeSH
- Blood Pressure drug effects MeSH
- Rats MeSH
- Fatty Acids, Monounsaturated metabolism MeSH
- Kidney drug effects physiopathology MeSH
- Peptide Fragments metabolism MeSH
- Fistula complications MeSH
- Rats, Transgenic MeSH
- Disease Progression * MeSH
- Renin-Angiotensin System drug effects MeSH
- Renin genetics MeSH
- Solubility MeSH
- Heart Rate drug effects MeSH
- Heart Failure drug therapy etiology physiopathology MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- Vena Cava, Inferior MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- angiotensin I (1-7) MeSH Browser
- Angiotensin I MeSH
- Angiotensin II MeSH
- eicosenoic acid MeSH Browser
- Epoxide Hydrolases MeSH
- Angiotensin-Converting Enzyme Inhibitors MeSH
- Enzyme Inhibitors MeSH
- Fatty Acids, Monounsaturated MeSH
- Peptide Fragments MeSH
- Renin MeSH
- Cytochrome P-450 Enzyme System MeSH
The detailed mechanisms determining the course of congestive heart failure (CHF) in hypertensive subjects with associated renal dysfunction remain unclear. In Ren-2 transgenic rats (TGR), a model of angiotensin II (ANG II)-dependent hypertension, CHF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). In these rats we investigated the putative pathophysiological contribution of epoxyeicosatrienoic acids (EETs) and compared it with the role of the renin-angiotensin system (RAS). We found that untreated ACF TGR exhibited marked intrarenal and myocardial deficiency of EETs and impairment of renal function. Chronic treatment of these rats with cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB, 3 mg/L in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs, markedly improved survival rate, and increased renal blood flow, glomerular filtration rate and fractional sodium excretion, without altering RAS activity. Chronic angiotensin-converting enzyme inhibition (ACEi) with trandolapril, (6 mg/L in drinking water) improved survival rate even more, and also inhibited the development of renal dysfunction; these beneficial actions were associated with significant suppression of the vasoconstrictor/sodium retaining axis and further activation of the vasodilatory/natriuretic axis of the systemic and intrarenal RAS, without modifying tissue availability of biologically active fatty acid epoxides. In conclusion, these findings strongly suggest that chronic sEH inhibition and chronic treatment with ACEi, each of them altering a different vasoactive system, delay or even prevent the onset of decompensation of CHF in ACF TGR, probably by preventing the development of renal dysfunction.
Department of Cardiology Institute for Clinical and Experimental Medicine Prague Czech Republic
Department of Pathophysiology 2nd Faculty of Medicine Charles University Prague Czech Republic
References provided by Crossref.org
Right versus left ventricular remodeling in heart failure due to chronic volume overload
