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.
- 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
To provide novel insights into the pathogenesis of heart failure-induced renal dysfunction, we compared the effects of ACE inhibitor (ACEi) and AT1 receptor blocker (ARB) on systemic and kidney hemodynamics during heart failure in normotensive HanSD and hypertensive transgenic (TGR) rats. High-output heart failure was induced by creating an aorto-caval fistula (ACF). After five weeks, rats were either left untreated or treatment with ACEi or ARB was started for 15 weeks. Subsequently, echocardiographic, renal hemodynamic and biochemical measurements were assessed. Untreated ACF rats with ACF displayed significantly reduced renal blood flow (RBF) (HanSD: 8.9 ± 1.0 vs. 4.7 ± 1.6; TGR: 10.2 ± 1.9 vs. 5.9 ± 1.2 ml/min, both P < .001), ACEi had no major RBF effect, whereas ARB completely restored RBF (HanSD: 5.6 ± 1.1 vs. 9.0 ± 1.5; TGR: 7.0 ± 1.2 vs. 10.9 ± 1.9 ml/min, both P < .001). RBF reduction in untreated and ACEi-treated rats was accompanied by renal hypoxia as measured by renal lactate dehydrogenase activity, which was ameliorated with ARB treatment (HanSD: 40 ± 4 vs. 42 ± 3 vs. 29 ± 5; TGR: 88 ± 4 vs. 76 ± 4 vs. 58 ± 4 milliunits/mL, all P < .01). Unlike improvement seen in ARB-treated rats, ACE inhibition didn't affect urinary nitrates compared to untreated ACF TGR rats (50 ± 14 vs. 22 ± 13 vs. 30 ± 13 μmol/mmol Cr, both P < .05). ARB was more effective than ACEi in reducing elevated renal oxidative stress following ACF placement. A marker of ACEi efficacy, the angiotensin I/angiotensin II ratio, was more than ten times lower in renal tissue than in plasma. Our study shows that ARB treatment, in contrast to ACEi administration, prevents renal hypoperfusion and hypoxia in ACF rats with concomitant improvement in NO bioavailability and oxidative stress reduction. The inability of ACE inhibition to improve renal hypoperfusion in ACF rats may result from incomplete intrarenal RAS suppression in the face of depleted compensatory mechanisms.
- MeSH
- biologické markery MeSH
- blokátory receptoru 1 pro angiotenzin II farmakologie MeSH
- hemodynamika účinky léků MeSH
- hypertenze komplikace MeSH
- inhibitory ACE farmakologie MeSH
- krevní tlak MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- náchylnost k nemoci MeSH
- receptor angiotensinu typ 1 metabolismus MeSH
- renální insuficience etiologie metabolismus prevence a kontrola MeSH
- renální oběh účinky léků MeSH
- srdeční selhání komplikace etiologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We aimed to study the impact of altered thyroid status on myocardial expression of electrical coupling protein connexin-43 (Cx43), the susceptibility of rats to ventricular fibrillation (VF) and the effects of antioxidant-rich red palm oil (RPO). Adult male and female euthyroid, hyperthyroid (treated with T3/T4), hypothyroid (treated with methimazole) Wistar rats supplemented or not with RPO for 6 weeks were used. Function of isolated perfused heart and VF threshold were determined. Left ventricular tissue was used for assessment of mRNA and protein levels of Cx43, its phosphorylated forms and topology. Protein kinase C signaling (PKC) and gene transcripts of some proteins related to cardiac arrhythmias were assessed. Hyperthyroid state resulted in decrease of total and phosphorylated forms of Cx43 and suppression of PKC-ε expression in males and females, decrease of Cx43 mRNA in females, decrease of VF threshold and increase of functional parameters in male rat hearts. In contrast, hypothyroid status resulted in the increase of total and phosphorylated forms of Cx43, enhancement PKC-ε expression in males and females, increase of Cx43 mRNA in females, increase of VF threshold and decrease of functional parameters in male rat hearts. Function of the heart was partially normalized by RPO intake, which also enhanced myocardial Cx43 and PKC-ε expression as well as increased VF threshold in hyperthyroid male rats. We conclude that there is an inverse relationship between myocardial expression of Cx43, including its functional phosphorylated forms, and susceptibility of male rat hearts to VF in condition of altered thyroid status. RPO intake partly ameliorated adverse changes caused by excess of thyroid hormones.
- MeSH
- aplikace orální MeSH
- konexin 43 antagonisté a inhibitory genetika metabolismus MeSH
- krysa rodu rattus MeSH
- messenger RNA antagonisté a inhibitory genetika metabolismus MeSH
- myokard metabolismus MeSH
- oleje rostlin aplikace a dávkování farmakologie MeSH
- potkani Wistar MeSH
- srdce účinky léků MeSH
- srdeční arytmie farmakoterapie metabolismus MeSH
- štítná žláza účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
