OBJECTIVE: Despite availability of an array of antihypertensive drugs, malignant hypertension remains a life-threatening condition, and new therapeutic strategies for the treatment of malignant hypertension and malignant hypertension-associated organ damage are needed. The aim of the present study was to assess the effects of nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) stimulator on the course of malignant hypertension. The second aim was to investigate if the treatment with sodium-glucose cotransporter type 2 (SGLT2) inhibitor would augment the expected beneficial actions of the sGC stimulation on the course of malignant hypertension. METHODS: As a model of malignant hypertension, Ren-2 transgenic rats (TGR) treated with nonspecific NO synthase inhibitor (Nω-nitro- l -arginine methyl ester, l -NAME) was used. Blood pressure (BP) was monitored by radiotelemetry, and the treatment was started 3 days before administration of l -NAME. RESULTS: The treatment with sGC stimulator BAY 41-8543, alone or combined with SGLT2 inhibitor empagliflozin, abolished malignant hypertension-related mortality in TGR receiving l -NAME. These two treatment regimens also prevented BP increases after l -NAME administration in TGR, and even decreased BP below values observed in control TGR, and prevented cardiac dysfunction and malignant hypertension-related morbidity. The treatment with the SGLT2 inhibitor empagliflozin did not further augment the beneficial actions of sGC stimulator on the course of malignant hypertension-related mortality. CONCLUSION: The treatment with NO-independent sGC stimulator displayed marked protective actions on the course of malignant hypertension-related mortality and malignant hypertension-related cardiac damage. This suggests that application of sGC stimulator could be a promising therapeutic means for the treatment of malignant hypertension.

• Klíčová slova
• malignant hypertension, renin–angiotensin system, sodium-glucose cotransporter type 2 inhibitor, soluble guanylyl cyclase stimulator,
• MeSH
• benzhydrylové sloučeniny farmakologie   MeSH
• glifloziny MeSH
• glukosidy farmakologie   terapeutické užití   MeSH
• hypertenze maligní * prevence a kontrola   farmakoterapie   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• potkani transgenní MeSH
• pyrazoly * farmakologie   terapeutické užití   MeSH
• pyrimidiny * terapeutické užití   farmakologie   MeSH
• rozpustná guanylátcyklasa * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BAY 41-8543 MeSH Prohlížeč
• benzhydrylové sloučeniny MeSH
• empagliflozin MeSH Prohlížeč
• glifloziny MeSH
• glukosidy MeSH
• morfoliny MeSH
• NG-nitroargininmethylester MeSH
• pyrazoly * MeSH
• pyrimidiny * MeSH
• rozpustná guanylátcyklasa * MeSH

The aim of the study was to clarify the role of the interplay between hypertension and the renin-angiotensin system (RAS) in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. We hypothesized that in the late phase of hypertension with already developed signs of end-organ damage, inappropriate RAS activation could impair cardiac tolerance to I/R injury. Experiments were performed in male Cyp1a1-Ren-2 transgenic rats with inducible hypertension. The early phase of ANG II-dependent hypertension was induced by 5 days and the late phase by the 13 days dietary indole-3-carbinol (I3C) administration. Noninduced rats served as controls. Echocardiography and pressure-volume analysis were performed, angiotensins' levels were measured and cardiac tolerance to ischemia/reperfusion injury was studied. The infarct size was significantly reduced (by 50%) in 13 days I3C-induced hypertensive rats with marked cardiac hypertrophy, this reduction was abolished by losartan treatment. In the late phase of hypertension there are indications of a failing heart, mainly in reduced preload recruitable stroke work (PRSW), but only nonsignificant trends in worsening of some other parameters, showing that the myocardium is in a compensated phase. The influence of the RAS depends on the balance between the vasoconstrictive and the opposed vasodilatory axis. In the initial stage of hypertension, the vasodilatory axis of the RAS prevails, and with the development of hypertension the vasoconstrictive axis of the RAS becomes stronger. We observed a clear effect of AT1 receptor blockade on maximum pressure in left ventricle, cardiac hypertrophy and ANG II levels. In conclusion, we confirmed improved cardiac tolerance to I/R injury in hypertensive hypertrophied rats and showed that, in the late phase of hypertension, the myocardium is in a compensated phase.

• Klíčová slova
• ANG II-dependent hypertension, AT1 receptor antagonist, P-V analysis, ischemia/reperfusion injury, renin-angiotensin system,
• Publikační typ
• časopisecké články MeSH

Cardiovascular and heart diseases are leading causes of morbidity and mortality. Coronary artery endothelial and vascular dysfunction, inflammation, and mitochondrial dysfunction contribute to progression of heart diseases such as arrhythmias, congestive heart failure, and heart attacks. Classes of fatty acid epoxylipids and their enzymatic regulation by soluble epoxide hydrolase (sEH) have been implicated in coronary artery dysfunction, inflammation, and mitochondrial dysfunction in heart diseases. Likewise, genetic and pharmacological manipulations of epoxylipids have been demonstrated to have therapeutic benefits for heart diseases. Increasing epoxylipids reduce cardiac hypertrophy and fibrosis and improve cardiac function. Beneficial actions for epoxylipids have been demonstrated in cardiac ischemia reperfusion injury, electrical conductance abnormalities and arrhythmias, and ventricular tachycardia. This review discusses past and recent findings on the contribution of epoxylipids in heart diseases and the potential for their manipulation to treat heart attacks, arrhythmias, ventricular tachycardia, and heart failure.

• Klíčová slova
• Coronary artery, Cytochrome P450, Eicosanoids, Heart failure, Hypertension, Inflammation, Mitochondrial function, Myocardial infarction, Soluble epoxide hydrolase,
• MeSH
• epoxid hydrolasy antagonisté a inhibitory   metabolismus   MeSH
• epoxidové sloučeniny chemie   metabolismus   MeSH
• infarkt myokardu farmakoterapie   enzymologie   metabolismus   MeSH
• inhibitory enzymů terapeutické užití   MeSH
• komorová tachykardie farmakoterapie   enzymologie   metabolismus   MeSH
• lidé MeSH
• mastné kyseliny metabolismus   MeSH
• nemoci srdce farmakoterapie   enzymologie   metabolismus   MeSH
• rozpustnost MeSH
• srdeční arytmie farmakoterapie   enzymologie   metabolismus   MeSH
• srdeční selhání farmakoterapie   enzymologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• epoxid hydrolasy MeSH
• epoxidové sloučeniny MeSH
• inhibitory enzymů MeSH
• mastné kyseliny MeSH

This study evaluates the effects of chronic treatment with EET-A, an orally active epoxyeicosatrienoic acid (EETs) analog, on the course of aorto-caval fistula (ACF)-induced heart failure (HF) in Ren-2 transgenic rats (TGR), a model characterized by hypertension and augmented activity of the renin-angiotensin system (RAS). The results were compared with standard pharmacological blockade of the RAS using angiotensin-converting enzyme inhibitor (ACEi). The rationale for employing EET-A as a new treatment approach is based on our findings that apart from increased RAS activity, untreated ACF TGR also shows kidney and left ventricle (LV) tissue deficiency of EETs. Untreated ACF TGR began to die 17 days after creating ACF and were all dead by day 84. The treatment with EET-A alone or ACEi alone improved the survival rate: in 156 days after ACF creation, it was 45.5% and 59.4%, respectively. The combined treatment with EET-A and ACEi appeared to improve the final survival to 71%; however, the difference from either single treatment regimen did not reach significance. Nevertheless, our findings support the notion that targeting the cytochrome P-450-dependent epoxygenase pathway of arachidonic acid metabolism should be considered for the treatment of HF.

• Klíčová slova
• Ren-2 transgenic rats, angiotensin-converting enzyme inhibitor, aorto-caval fistula, congestive heart failure, cytochrome P-450, epoxyeicosatrienoic acids, hypertension, renin-angiotensin system, volume-overload heart failure,
• Publikační typ
• časopisecké články MeSH

The aim of the present study was to perform kidney messenger ribonucleic acid (mRNA) analysis in normotensive, Hannover Sprague-Dawley (HanSD) rats and hypertensive, Ren-2 renin transgenic rats (TGR) after doxorubicin-induced heart failure (HF) with specific focus on genes that are implicated in the pathophysiology of HF-associated cardiorenal syndrome. We found that in both strains renin and angiotensin-converting enzyme mRNA expressions were upregulated indicating that the vasoconstrictor axis of the renin-angiotensin system was activated. We found that pre-proendothelin-1, endothelin-converting enzyme type 1 and endothelin type A receptor mRNA expressions were upregulated in HanSD rats, but not in TGR, suggesting the activation of endothelin system in HanSD rats, but not in TGR. We found that mRNA expression of cytochrome P-450 subfamily 2C23 was downregulated in TGR and not in HanSD rats, suggesting the deficiency in the intrarenal cytochrome P450-dependent pathway of arachidonic acid metabolism in TGR. These results should be the basis for future studies evaluating the pathophysiology of cardiorenal syndrome secondary to chemotherapy-induced HF in order to potentially develop new therapeutic approaches.

• Klíčová slova
• chemotherapy-induced heart failure, cytochrome P-450, doxorubicin, endothelin system, hypertension, kidney, renal adrenergic system, renin-angiotensin-aldosterone system,
• MeSH
• doxorubicin škodlivé účinky   MeSH
• hypertenze komplikace   genetika   patofyziologie   MeSH
• krysa rodu Rattus MeSH
• ledviny účinky léků   patofyziologie   MeSH
• messenger RNA genetika   MeSH
• nemoci ledvin chemicky indukované   genetika   patofyziologie   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• protinádorová antibiotika škodlivé účinky   MeSH
• regulace genové exprese účinky léků   MeSH
• renin-angiotensin systém účinky léků   MeSH
• renin genetika   MeSH
• srdeční selhání chemicky indukované   genetika   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• doxorubicin MeSH
• messenger RNA MeSH
• protinádorová antibiotika MeSH
• Ren2 protein, rat MeSH Prohlížeč
• renin MeSH

We investigated the role of the interaction between hypertension and the renin-angiotensin system in the pathophysiology of myocardial ischemia/reperfusion injury. We hypothesized that in the early phase of angiotensin II (ANG II)-dependent hypertension with developed left ventricular hypertrophy, cardioprotective mechanism(s) are fully activated. The experiments were performed in transgenic rats with inducible hypertension, noninduced rats served as controls. The early phase of ANG II-dependent hypertension was induced by five-days (5 days) dietary indole-3-carbinol administration. Cardiac hypertrophy, ANG II and ANG 1-7 levels, protein expression of their receptors and enzymes were determined. Separate groups were subjected to acute myocardial ischemia/reperfusion injury, and infarct size and ventricular arrhythmias were assessed. Induced rats developed marked cardiac hypertrophy accompanied by elevated ANG levels. Ischemia/reperfusion mortality was significantly higher in induced than noninduced rats (52.1 and 25%, respectively). The blockade of AT1 receptors with losartan significantly increased survival rate in both groups. Myocardial infarct size was significantly reduced after 5 days induction (by 11%), without changes after losartan treatment. In conclusion, we confirmed improved cardiac tolerance to ischemia/reperfusion injury in hypertensive cardiohypertrophied rats and found that activation of AT1 receptors by locally produced ANG II in the heart was not the mechanism underlying infarct size reduction.

• Klíčová slova
• angiotensin II receptor antagonist, hypertension, infarct size, ischemia/reperfusion injury, renin-angiotensin system,
• Publikační typ
• časopisecké články MeSH

Cytochrome P450 (CYP-450) metabolites of arachidonic acid: epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) have established role in regulation of blood pressure (BP) and kidney function. EETs deficiency and increased renal formation of 20-HETE contribute to hypertension in spontaneously hypertensive rats (SHR). We explored the effects of 14,15-EET analog (EET-A) and of 20-HETE receptor blocker (AAA) on BP and kidney function in this model. In anesthetized SHR the responses were determined of mean arterial blood pressure (MABP), total renal (RBF), and cortical (CBF) and inner-medullary blood flows, glomerular filtration rate and renal excretion, to EET-A, 5 mg/kg, infused i.v. for 1 h to rats untreated or after blockade of endogenous EETs degradation with an inhibitor (c-AUCB) of soluble epoxide hydrolase. Also examined were the responses to AAA (10 mg/kg/h), given alone or together with EET-A. EET-A significantly increased RBF and CBF (+30% and 26%, respectively), seen already within first 30 min of infusion. The greatest increases in RBF and CBF (by about 40%) were seen after AAA, similar when given alone or combined with EET-A. MABP decreased after EET-A or AAA but not significantly after the combination thereof. In all groups, RBF, and CBF increases preceded the decrease in MABP. We found that in SHR both EET-A and AAA induced renal vasodilation but, unexpectedly, no additive effect was seen. We suggest that both agents have a definite therapeutic potential and deserve further experimental and clinical testing aimed at introduction of novel antihypertensive therapy.

• Klíčová slova
• 20-HETE antagonist, EET analog, epoxyeicosatrienoic acids, hypertension, soluble epoxide hydrolase,
• Publikační typ
• časopisecké články MeSH

Numerous studies indicate a significant role for cytochrome P-450-dependent arachidonic acid metabolites in blood pressure regulation, vascular tone, and control of renal function. Epoxyeicosatrienoic acids (EETs) exhibit a spectrum of beneficial effects, such as vasodilatory activity and anti-inflammatory, anti-fibrotic, and anti-apoptotic properties. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that inhibits sodium reabsorption in the kidney. In the present study, the efficiency of EET-A (a stable analog of 14,15-EET) alone and combined with AAA, a novel receptor antagonist of 20-HETE, was tested in spontaneously hypertensive rats (SHR). Adult SHR (16 weeks old) were treated with two doses of EET-A (10 or 40 mg/kg/day). In the following experiments, we also tested selected substances in the prevention of hypertension development in young SHR (6 weeks old). Young rats were treated with EET-A or the combination of EET-A and AAA (both at 10 mg/kg/day). The substances were administered in drinking water for 4 weeks. Blood pressure was measured by telemetry. Once-a-week observation in metabolic cages was performed; urine, blood, and tissue samples were collected for further analysis. The combined treatment with AAA + EET-A exhibited antihypertensive efficiency in young SHR, which remained normotensive until the end of the observation in comparison to a control group (systolic blood pressure, 134 ± 2 versus 156 ± 5 mmHg, respectively; p < 0.05). Moreover the combined treatment also increased the nitric oxide metabolite excretion. Considering the beneficial impact of the combined treatment with EET-A and AAA in young rats and our previous positive results in adult SHR, we suggest that it is a promising therapeutic strategy not only for the treatment but also for the prevention of hypertension.

• Klíčová slova
• 20-HETE antagonist, EET analog, epoxyeicosatrienoic acids, primary hypertension, spontaneously hypertensive rats,
• Publikační typ
• časopisecké články MeSH

While necroptosis has been shown to contribute to the pathogenesis of post-infarction heart failure (HF), the role of autophagy remains unclear. Likewise, linkage between these two cell death modalities has not been sufficiently investigated. HF was induced by 60-min left coronary occlusion in adult Wistar rats and heart function was assessed 6 weeks later followed by immunoblotting analysis of necroptotic and autophagic proteins in both the left (LV) and right ventricle (RV). HF had no effect on RIP1 and RIP3 expression. PhosphoSer229-RIP3, acting as a pro-necroptotic signal, was increased in LV while deceased in RV of failing hearts. Total MLKL was elevated in RV only. Decrease in pSer555-ULK1, increase in pSer473-Akt and no significant elevation in beclin-1 and LC3-II/I ratio indicated rather a lowered rate of autophagy in LV. No beclin-1 upregulation and decreased LC3 processing also suggested the inhibition of both autophagosome formation and maturation in RV of failing hearts. In contrast, p89 PARP1 fragment, a marker of executed apoptosis, was increased in RV only. This is the first study showing a different signaling in ventricles of the late phase of post-infarction HF, highlighting necroptosis itself rather than its linkage with autophagy in LV, and apoptosis in RV.

• Klíčová slova
• autophagy, cell death, heart failure, necroptosis,
• MeSH
• apoptóza * fyziologie   MeSH
• autofagie fyziologie   MeSH
• infarkt myokardu komplikace   patologie   MeSH
• nekroptóza fyziologie   MeSH
• potkani Sprague-Dawley MeSH
• potkani Wistar MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• serin-threoninkinasy interagující s receptory metabolismus   MeSH
• signální transdukce MeSH
• srdeční komory patologie   MeSH
• srdeční selhání etiologie   metabolismus   patologie   MeSH
• velikost orgánu MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• protein-serin-threoninkinasy MeSH
• RIPK1 protein, rat MeSH Prohlížeč
• Ripk3 protein, rat MeSH Prohlížeč
• serin-threoninkinasy interagující s receptory MeSH

Epoxyeicosatrienoic acids (EETs) are also known as epoxyeicosanoids that have renal and cardiovascular actions. These renal and cardiovascular actions can be regulated by soluble epoxide hydrolase (sEH) that degrades and inactivates EETs. Extensive animal hypertension studies have determined that vascular, epithelial transport, and anti-inflammatory actions of EETs lower blood pressure and decrease renal and cardiovascular disease progression. Human studies have also supported the notion that increasing EET levels in hypertension could be beneficial. Pharmacological and genetic approaches to increase epoxyeicosanoids in several animal models and humans have found improved endothelial vascular function, increased sodium excretion, and decreased inflammation to oppose hypertension and associated renal and cardiovascular complications. These compelling outcomes support the concept that increasing epoxyeicosanoids via sEH inhibitors or EET analogs could be a valuable hypertension treatment.

• MeSH
• antihypertenziva terapeutické užití   MeSH
• epoxid hydrolasy antagonisté a inhibitory   metabolismus   MeSH
• hypertenze farmakoterapie   metabolismus   patofyziologie   MeSH
• ikosanoidy metabolismus   terapeutické užití   MeSH
• inhibitory enzymů terapeutické užití   MeSH
• krevní tlak účinky léků   MeSH
• lidé MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antihypertenziva MeSH
• epoxid hydrolasy MeSH
• ikosanoidy MeSH
• inhibitory enzymů MeSH