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

Abstract

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.

The Role of Renal Vascular Reactivity in the Development of Renal Dysfunction in Compensated and Decompensated Congestive Heart Failure

“…In addition, ACF rats exhibited an elevation of ANG II, ANG 1-7 and catecholamine concentrations in the kidney, when assessed during the compensated (i.e., five weeks after creation of ACF) and decompensated CHF (20 weeks after ACF operation). These results are in agreement with recent findings in this model of CHF, and strongly suggest a marked activation of both vasoconstrictor/sodium retaining and the vasodilatory/natriuretic axis of the RAS in the kidney [29,38,39], along with activation of the sympathorenal axis. Altogether our findings support the notion that CHF is not a purely hemodynamic disorder that markedly affects renal hemodynamics.…”

“…Obviously, in ACF model renal dysfunction is present already in the early stage of CHF and it plays an important role in the disease progression. Additionally, our present findings accord with our earlier suggestion that persistent impairment of renal hemodynamics and sodium excretion rather than progressing cardiac remodeling determines long-term survival rate in ACF-induced model of CHF [39].…”

Kidney Response to Heart Failure: Proteomic Analysis of Cardiorenal Syndrome

“…Cystatin C was measured by immunoturbidimetric method, serum creatinine by enzymatic spetrophotometric method. Renal tissue angiotensin II (ANG-II) was measured by RIA as described previously [18].…”

Sex‐linked differences in the course of chronic kidney disease and congestive heart failure: a study in 5/6 nephrectomized Ren‐2 transgenic hypertensive rats with volume overload induced using aorto‐caval fistula

“…However, the effectiveness of renoprotective action of RAS inhibition is limited, especially in the advanced phase of CKD . Nor does RAS inhibition effectively attenuate eccentric remodelling of the left ventricle or improve its systolic function in CHF induced by experimental volume overload . Interestingly, in many investigations substantial but not entirely conclusive evidence was presented for the role of sex in the status of hypertension, renal and cardiovascular disease and activity of the RAS .…”

“…The rat with aorto‐caval fistula (ACF) presents a well‐defined model of CHF due to volume overload, characterized by activation of the circulating and intrarenal RAS, cardiac remodeling and signs of failure including congestion; in many respects the model imitates the course of CHF in untreated humans . Despite such suitable features, the model was employed in but few studies which focused mostly on the sex‐based differences in the pattern of global myocardial remodelling, mainly those observed during the compensation phase of CHF …”