Heart failure (HF) has been declared as global pandemic and current therapies are still ineffective, especially in patients that develop concurrent cardio-renal syndrome. Considerable attention has been focused on the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway. In the current study, we aimed to investigate the effectiveness of sGC stimulator (BAY41-8543) with the same mode of action as vericiguat, for the treatment of heart failure (HF) with cardio-renal syndrome. As a model, we chose heterozygous Ren-2 transgenic rats (TGR), with high-output heart failure, induced by aorto-caval fistula (ACF). The rats were subjected into three experimental protocols to evaluate short-term effects of the treatment, impact on blood pressure, and finally the long-term survival lasting 210 days. As control groups, we used hypertensive sham TGR and normotensive sham HanSD rats. We have shown that the sGC stimulator effectively increased the survival of rats with HF in comparison to untreated animals. After 60 days of sGC stimulator treatment, the survival was still 50% compared to 8% in the untreated rats. One-week treatment with sGC stimulator increased the excretion of cGMP in ACF TGR (109 ± 28 nnmol/12 h), but the ACE inhibitor decreased it (-63 ± 21 nnmol/12 h). Moreover, sGC stimulator caused a decrease in SBP, but this effect was only temporary (day 0: 117 ± 3; day 2: 108 ± 1; day 14: 124 ± 2 mmHg). These results support the concept that sGC stimulators might represent a valuable class of drugs to battle heart failure especially with cardio-renal syndrome, but further studies are necessary.

• Klíčová slova
• ACF, BAY41-8543, Heart failure, Vericiguat, cGMP, sGC stimulator,
• MeSH
• guanosinmonofosfát cyklický metabolismus   MeSH
• guanylátcyklasa MeSH
• hypertenze * farmakoterapie   MeSH
• kardiorenální syndrom * MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• oxid dusnatý metabolismus   MeSH
• píštěle * MeSH
• potkani transgenní MeSH
• rozpustná guanylátcyklasa metabolismus   MeSH
• srdeční selhání * farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• guanosinmonofosfát cyklický MeSH
• guanylátcyklasa MeSH
• oxid dusnatý MeSH
• rozpustná guanylátcyklasa MeSH

OBJECTIVE: We evaluated the therapeutic effectiveness of a new, orally active epoxyeicosatrienoic acid analog (EET-A) in rats with angiotensin II (ANG II)-dependent malignant hypertension. METHODS: Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. EET-A treatment was started either simultaneously with I3C induction process (early treatment) or 10 days later during established hypertension (late treatment). Blood pressure (BP) (radiotelemetry), indices of renal and cardiac injury, and plasma and kidney levels of the components of the renin-angiotensin system (RAS) were determined. RESULTS: In I3C-induced hypertensive rats, early EET-A treatment attenuated BP increase (to 175 ± 3 versus 193 ± 4 mmHg, P < 0.05, on day 13), reduced albuminuria (15 ± 1 versus 28 ± 2 mg/24 h, P < 0.05), and cardiac hypertrophy as compared with untreated I3C-induced rats. This was associated with suppression of plasma and kidney ANG II levels (48 ± 6 versus 106 ± 9 and 122 ± 19 versus 346 ± 11 fmol ml or g, respectively, P < 0.05) and increases in plasma and kidney angiotensin (1-7) concentrations (84 ± 9 versus 37 ± 6 and 199 ± 12 versus 68 ± 9 fmol/ml or g, respectively, P < 0.05). Remarkably, late EET-A treatment did not lower BP or improve renal and cardiac injury; indices of RAS activity were not affected. CONCLUSION: The new, orally active EET-A attenuated the development of experimental ANG II-dependent malignant hypertension, likely via suppression of the hypertensiogenic axis and augmentation of the vasodilatory/natriuretic axis of RAS.

• MeSH
• albuminurie farmakoterapie   MeSH
• angiotensin I metabolismus   MeSH
• angiotensin II metabolismus   MeSH
• časové faktory MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• hypertenze maligní chemicky indukované   patofyziologie   prevence a kontrola   MeSH
• indoly MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• kyselina 8,11,14-eikosatrienová analogy a deriváty   terapeutické užití   MeSH
• ledviny metabolismus   MeSH
• peptidové fragmenty metabolismus   MeSH
• potkani transgenní MeSH
• renin-angiotensin systém účinky léků   MeSH
• renin genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• angiotensin I (1-7) MeSH Prohlížeč
• angiotensin I MeSH
• angiotensin II MeSH
• cytochrom P-450 CYP1A1 MeSH
• indole-3-carbinol MeSH Prohlížeč
• indoly MeSH
• kyselina 8,11,14-eikosatrienová MeSH
• peptidové fragmenty MeSH
• Ren2 protein, rat MeSH Prohlížeč
• renin MeSH

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.

• MeSH
• angiotensin I krev   MeSH
• angiotensin II krev   MeSH
• benzoáty farmakologie   terapeutické užití   MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• epoxidové sloučeniny metabolismus   MeSH
• inhibitory ACE MeSH
• krysa rodu Rattus MeSH
• kyselina 8,11,14-eikosatrienová analogy a deriváty   krev   metabolismus   MeSH
• ledviny metabolismus   MeSH
• močovina analogy a deriváty   farmakologie   terapeutické užití   MeSH
• modely nemocí na zvířatech MeSH
• myokard metabolismus   MeSH
• náhodné rozdělení MeSH
• peptidové fragmenty krev   MeSH
• preklinické hodnocení léčiv MeSH
• renální insuficience krev   etiologie   prevence a kontrola   MeSH
• renin-angiotensin systém účinky léků   MeSH
• srdeční selhání krev   komplikace   diagnostické zobrazování   farmakoterapie   MeSH
• ultrasonografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid MeSH Prohlížeč
• angiotensin I (1-7) MeSH Prohlížeč
• angiotensin I MeSH
• angiotensin II MeSH
• benzoáty MeSH
• epoxid hydrolasy MeSH
• epoxidové sloučeniny MeSH
• inhibitory ACE MeSH
• kyselina 8,11,14-eikosatrienová MeSH
• močovina MeSH
• peptidové fragmenty MeSH