Effect of angiotensin-converting enzyme blockade, alone or combined with blockade of soluble epoxide hydrolase, on the course of congestive heart failure and occurrence of renal dysfunction in Ren-2 transgenic hypertensive rats with aorto-caval fistula.

We showed recently that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, retarded the development of renal dysfunction and progression of aorto-caval fistula(ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). In that study the final survival rate of untreated ACF TGR was only 14 % but increased to 41 % after sEH blockade. Here we examined if sEH inhibition added to renin-angiotensin system (RAS) blockade would further enhance protection against ACF-induced CHF in TGR. The treatment regimens were started one week after ACF creation and the follow-up period was 50 weeks. RAS was blocked using angiotensin-converting enzyme inhibitor (ACEi, trandolapril, 6 mg/l) and sEH with an sEH inhibitor (sEHi, c-AUCB, 3 mg/l). Renal hemodynamics and excretory function were determined two weeks post-ACF, just before the onset of decompensated phase of CHF. 29 weeks post-ACF no untreated animal survived. ACEi treatment greatly improved the survival rate, to 84 % at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53 %). Untreated ACF TGR exhibited marked impairment of renal function and the treatment with ACEi alone or combined with sEH inhibition did not prevent it. In conclusion, addition of sEHi to ACEi treatment does not provide better protection against CHF progression and does not increase the survival rate in ACF TGR: indeed, the rate decreases significantly. Thus, combined treatment with sEHi and ACEi is not a promising approach to further attenuate renal dysfunction and retard progression of CHF.

Inhibition of soluble epoxide hydrolase does not improve the course of congestive heart failure and the development of renal dysfunction in rats with volume overload induced by aorto-caval fistula.

The detailed mechanisms determining the course of congestive heart failure (CHF) and associated renal dysfunction remain unclear. In a volume overload model of CHF induced by creation of aorto-caval fistula (ACF) in Hannover Sprague-Dawley (HanSD) rats we explored the putative pathogenetic contribution of epoxyeicosatrienoic acids (EETs), active products of CYP-450 dependent epoxygenase pathway of arachidonic acid metabolism, and compared it with the role of the renin-angiotensin system (RAS). Chronic treatment 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 to levels observed in sham-operated HanSD rats, but did not improve the survival or renal function impairment. In contrast, chronic angiotensin-converting enzyme inhibition (ACEi, trandolapril, 6 mg/l in drinking water) increased renal blood flow, fractional sodium excretion and markedly improved survival, without affecting left ventricular structure and performance. Hence, renal dysfunction rather than cardiac remodeling determines long-term mortality in advanced stage of CHF due to volume overload. Strong protective actions of ACEi were associated with suppression of the vasoconstrictor/sodium retaining axis and activation of vasodilatory/natriuretic axis of the renin-angiotensin system in the circulating blood and kidney tissue.

[The effect of electrostimulation with the Rebox apparatus on ischemic renal injury in rats]. / Vliv elektrostimulátoru Rebox na prubeh ischemického poskození ledvin u krys.

BACKGROUND: With developing transplantation programmes the problem of protection against ischaemic renal damage had become important. The results of experimental pharmacological protection of the kidneys are not quite conclusive. The objective of the presented paper was to assess the effect of electrostimulation by means of a Rebox apparatus (generator of direct rectangular impulses at a frequency of 1 to 10 kHz), on the development of ischaemic damage of the renal parenchyma induced experimentally in rats. METHODS AND RESULTS: The experiments were made on Wistar strains rats (n = 15) which were subjected to dextrolateral nephrectomy and the left renal artery was closed by a clamp which was released in the tested and the control group after 30 minutes. In the rebox group electrostimulation with the Rebox apparatus was implemented immediately after release of the clamp. In rats which were in metabolic cages the following parameters were assessed: diuresis, period of survival, endogenous creatinine clearance, plasma creatinine level, urea level and excretion, as well as sodium and potassium urinary excretion. No significant difference in the survival time of the rats was found nor in the plasma levels of creatinine, urea and urinary excretion of potassium and urea between the control and the Rebox group. In the Rebox group, as compared with the control group, a significantly higher diuresis was found 22.8 vs 5.6 (p < 0.001) and natriuresis 0.44 vs 0.11 (p < 0.01). CONCLUSIONS: Electrostimulation by rebox currents in rats increases significantly the diuresis and natriuresis of the solitary kidney exposed to 30-minute ischaemia but has no impact on other parameters. The mechanism of action is not quite clear, apparently the reabsorption of sodium in the proximal tubule is inhibited.

Comparison of the effects of a low-protein diet with the effects of a converting enzyme inhibitor on the progression of renal insufficiency in hypertensive rats.

The beneficial effects of a low-protein diet vs. angiotensin-converting enzyme inhibitor (ACEI, enalapril) on the course of ablation nephropathy (5/6 nephrectomy, 5/6NX) were compared in a new strain of genetic hypertensive rats, the Prague hypertensive rat (PHR). Both maneuvers were followed by a significant drop in proteinuria (1.27 and 8.8 vs. 56.2 mg/24 hod, p < 0.001, low-protein diet vs. ACEI vs. untreated), plasma levels of creatinine (175.3 and 177.1 vs. 245.3 mumol/L, p < 0.001) and urea (7.95 and 13.51 vs. 37.6 mmol/L, p < 0.001). Endogenous creatinine clearance was higher after both low-protein diet and ACEI than without them (134.6 and 127.8 vs. 56.7 microL/min/100 g BW, p < 0.001). Both maneuvers had a similar beneficial effect: no additional amelioration was observed with a combination of both low-protein diet and ACEI. Compared to normotensive Wistar rats, the results were quite similar in PHR except the blood pressure values; hypertension had no substantial effect on the course of 5/6NX or on the beneficial action of both low-protein diet and ACEI.

A comparison of the effect of feeding a low-protein diet and of pharmacological intervention on the course of ablation nephropathy in the rat.

In Wistar rats just after weaning, 5/6 of renal parenchyma were removed surgically. Thereafter, the rats were fed either a "high-protein" (21%) or two types of a "low-protein" (6%) diet; in one of the latter the lack of protein was substituted by saccharide, in the other by fat, making the substitution "isocaloric" in either case. In all three diet groups, subgroups were formed drinking either tap water or water containing either the ACE inhibitor enalapril (Ena) or the calcium antagonist diltiazem (Dil), or both (Ena + Dil). In the high-protein diet group, increases in the weight of kidney remnants, in proteinuria and in systolic blood pressure (SBP) were seen. This was prevented by feeding either type of the low-protein diet but also by Ena and Ena + Dil. Ena and Ena + Dil not only prevented the increase in SBP but actually lowered it significantly. Dil alone also had a SBP-lowering action but offered no protection from kidney hypertrophy and proteinuria. No additive protective action of Ena + Dil or Ena + low protein or Ena + Dil + low protein was seen, suggesting that a bottom limit of these protective action was reached by the low-protein diet alone. There was no substantial difference between either type of the low-protein diet except a small and transient decrease in body weight in the first week of fat-rich diet administration.