scholarly journals 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

2017 ◽  
pp. 401-415 ◽  
Author(s):  
P. KALA ◽  
L. SEDLÁKOVÁ ◽  
P. ŠKAROUPKOVÁ ◽  
L. KOPKAN ◽  
Z. VAŇOURKOVÁ ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Survival Rate ◽  
Angiotensin Converting Enzyme ◽  
Renal Dysfunction ◽  
Epoxide Hydrolase ◽  
Combined Treatment ◽  
Soluble Epoxide Hydrolase ◽  
Converting Enzyme ◽  
Hypertensive Rats

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.

scholarly journals Sex-linked differences in the mortality in Ren-2 transgenic hypertensive rats with aorto-caval fistula: effects of treatment with angiotensin converting enzyme alone and combined with inhibitor of soluble epoxide hydrolase

2019 ◽  
pp. 589-601 ◽  
Author(s):  
P. Kala ◽  
L. Červenka ◽  
P. Škaroupková ◽  
M. Táborský ◽  
E. Kompanowska-Jezierska ◽  
...  
Keyword(s):  
Survival Rate ◽  
Angiotensin Converting Enzyme ◽  
Epoxide Hydrolase ◽  
Enzyme Inhibitor ◽  
Combined Treatment ◽  
Soluble Epoxide Hydrolase ◽  
Converting Enzyme ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Final Survival

We found recently that in Ren-2 transgenic hypertensive rats (TGR) addition of soluble epoxide hydrolase inhibitor (sEHi) to treatment with angiotensin-converting enzyme inhibitor (ACEi), surprisingly, increased the mortality due to heart failure (HF) induced by creation of the aorto-caval fistula (ACF). Since TGR exhibit sex-related differences in mortality, we examined here if such differentiation exists also in the response to the treatment with ACEi (trandolapril), alone or combined with sEHi [cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid, (c-AUCB)]. ACEi improved survival in males to 74 % (vs. 0 %) and in females to 65 % (vs. 32 %). ACEi and sEHi combined also improved the survival in male ACF TGR, however, it was significantly less (38 %) than after ACEi alone. In contrast, in females the combined treatment significantly improved the final survival rate (84 %). There were no significant sex-linked differences in survival rate in untreated or treated normotensive Hannover Sprague-Dawley rats. In conclusion, in HF patients with co-existing hypertension and RAS hyperactivity, the sex may co-determine the rate of HF progression, and can influence the effectiveness of the therapeutic measures applied. Therefore, in the relevant pre-clinical studies the sex-linked differences should be seriously considered. Our data indicate that TGR might be an optimal model for such studies.

Abstract P425: Ras Blockade Alone or Combined With Inhibition of Soluble Epoxide Hydrolase: Effects on the Course of Congestive Heart Failure in Ren-2 Transgenic Hypertensive Rats With Aorto-caval Fistula

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Petr Kala ◽  
Lenka Sedlakova ◽  
Zdenka Vanourkova ◽  
Libor Kopkan ◽  
Janusz Sadowski ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Drinking Water ◽  
Survival Rate ◽  
Renal Dysfunction ◽  
Sodium Excretion ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Renal Hemodynamics ◽  
Hypertensive Rats

Rationale and Objective: We recently showed that increasing epoxyeicosatrienoic acids (EETs) in kidney by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, markedly attenuated the development of renal dysfunction and progression of aorto-caval (ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). Therefore, in this study we examined if additional inhibition of sEH to RAS blockade could further improve the course of ACF-induced CHF in TGR. Methods: The treatment regimens were started from one week after creation of ACF and the follow-up period was 60 weeks. RAS blockade was achieved by administration of angiotensin-converting enzyme inhibitor (ACEi, trandolapril, 3 mg/L in drinking water) and sEH was blocked using a sEH inhibitor (sEHi, c -AUCB, 3 mg/L in drinking water). The following experimental groups were investigated: 1) Sham-operated TGR; 2) Untreated ACF TGR; 3) ACF TGR + ACEi; 4) ACF TGR + ACEi + sEHi (n = 36 in each ACF group). In separate groups renal hemodynamics and excretory function were evaluated two weeks post-ACF, just before the onset the decompensated phase of CHF. Results: After 29 weeks post-ACF, no animal survived. ACEi treatment greatly improved the survival rate (87%) at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53%, p < 0.05). After 2 weeks post-ACF, untreated TGR group showed lower mean arterial pressure (MAP) (124 ± 3 vs. 146 ± 4 mmHg, p < 0.05), renal blood flow (7.6 ± 0.3 vs. 10.5 ± 0.3 mL.min -1 .g -1 , p < 0.05) and absolute sodium excretion (0.18 ± 0.06 vs. 1.09 ± 0.19 μmol.min -1 .g -1 , p<0.05) than sham-operated TGR group, respectively. The treatment with ACEi alone or combination treatment with sEHi did not prevent the changes in renal hemodynamics and sodium excretion. Conclusion: We found that addition of sEHi to ACEi treatment did not provide better protection against CHF progression and the survival rate, indeed, decreased significantly. Thus, increasing bioavailability of tissue EETs in individuals with pharmacologically-induced suppression of the RAS is not a promising approach to further attenuate renal dysfunction and progression of CHF.

P3513Sex-related differences in the outcome of congestive heart failure: study on rats treated with ACEi alone or combined with soluble epoxide hydrolase inhibitor

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
P Kala ◽  
L Cervenka ◽  
M Taborsky ◽  
J Sadowski ◽  
P Skaroupkova ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Survival Rate ◽  
Epoxide Hydrolase ◽  
Combined Treatment ◽  
Heart Association ◽  
Soluble Epoxide Hydrolase ◽  
Sham Operation ◽  
Male And Female ◽  
Therapeutic Measures

Abstract Introduction In search for new therapeutic measures of congestive heart failure (CHF) attention focused on the role of epoxyeicosatrienoic acids (EETs), cytochrome P450-dependent epoxygenase pathway metabolites of arachidonic acid, with antihypertensive and organ-protective actions. The EETs are rapidly broken-down by soluble epoxide hydrolase (sEH). Blocking sEH and increasing tissue EETs bioavailability had antihypertensive and cardio- and renoprotective effects. The studies of the biological mechanisms underlying the sex-related differences in the CHF and in the responses to new pharmacological measures are missing. The rat model in which CHF is induced by volume overload by creation of the aorto-caval fistula (ACF) is recommended for preclinical studies by American Heart Association. It has been noticed that the hypertensive rat transgenic for the mouse Ren-2 renin gene (TGR) presents a unique angiotensin II-dependent model of hypertension. We found that male ACF TGR displayed tissue deficiency of EETs, and increasing intrarenal EETs levels by pharmacological blockade of sEH attenuated the progression of CHF in male ACF TGR. However, we did not examine if this effect occurs also in female ACF TGR. Purpose The aim was to establish if sex-related differences, if present, are demonstrable with standard treatment with ACEi alone and with the combined treatment with ACEi and sEHi. Methods Male and female TGR rats were randomly assigned either to ACF procedure or to sham-operation. One week after the procedure rats were divided into the 8 experimental groups (sham-operated male TGR + placebo, ACF male TGR + placebo, ACF male TGR + ACEi, ACF male TGR + ACEi + sEHi, sham-operated female TGR + placebo, ACF female TGR + placebo, ACF female TGR + ACEi, ACF female TGR + ACEi + sEHi). C-AUCB was used as an sEHi and trandolapril as ACEi, both in drinking water in doses previously tested. The follow-up period was 50 weeks and the primary end-point was death from any cause. Results All sham-operated male and female TGR survived until the end of experiment. All untreated male ACF TGR animals died by week 20. In contrast, untreated female ACF survived in the rate of 32%. The treatment with ACEi improved survival rate similary in male as well as female ACF TGR (74% and 65%). The combined treatment with ACEi and sEHi worsened the survival in male ACF TGR as compared with ACF TGR + ACEi (38%). In contrast, the combined treatment with ACEi and sEHi in female ACF TGR significantly improved the course and the final survival rate (84%) as compared with female ACF TGR + ACEi alone. Picture 1 Conclusions The study suggests that in CHF individuals in whom hypertension and increased RAS activity run in parallel, the patients' sex is the co-determinant of CHF progression. In particular it can influence the effectiveness of the therapeutic measures applied to slow it down. Therefore, in pre- and clinical studies the sex-related differences should be seriously considered. Acknowledgement/Funding Ministry of Health of the Czech Republic grant no. 17- 28220A; Grant Agency of Charles University, project number 32218

scholarly journals 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

2015 ◽  
pp. 857-873 ◽  
Author(s):  
L. ČERVENKA ◽  
V. MELENOVSKÝ ◽  
Z. HUSKOVÁ ◽  
A. SPORKOVÁ ◽  
M. BÜRGELOVÁ ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Drinking Water ◽  
Renal Dysfunction ◽  
Epoxide Hydrolase ◽  
Renin Angiotensin System ◽  
Volume Overload ◽  
Soluble Epoxide Hydrolase ◽  
Angiotensin System ◽  
Renin Angiotensin

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.

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