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
• morfoliny 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 cardioprotective effect of ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) in adult hearts is mediated by nitric oxide (NO). During the early developmental period, rat hearts exhibit higher resistance to ischemia-reperfusion (I/R) injury, contain higher levels of serum nitrates, and their resistance cannot be further increased by IPC or IPoC. NOS blocker (L-NAME) lowers their high resistance. Wistar rat hearts (postnatal Days 1 and 10) were perfused according to Langendorff and exposed to 40 min of global ischemia followed by reperfusion with or without IPoC. NO and reactive oxygen species donors (DEA-NONO, SIN-1) and L-NAME were administered. Tolerance to ischemia decreased between Days 1 and 10. DEA-NONO (low concentrations) significantly increased tolerance to I/R injury on both Days 1 and 10. SIN-1 increased tolerance to I/R injury on Day 10, but not on Day 1. L-NAME significantly reduced resistance to I/R injury on Day 1, but actually increased resistance to I/R injury on Day 10. Cardioprotection by IPoC on Day 10 was not affected by either NO donors or L-NAME. It can be concluded that resistance of the neonatal heart to I/R injury is NO dependent, but unlike in adult hearts, cardioprotective interventions, such as IPoC, are most likely NO independent.

• Klíčová slova
• DEA‐NONO, L‐NAME, SIN‐1, ischemic postconditioning, neonatal hearts, nitric oxide,
• MeSH
• donory oxidu dusnatého farmakologie   MeSH
• ischemické přivykání metody   MeSH
• ischemický postconditioning * metody   MeSH
• krysa rodu Rattus MeSH
• molsidomin farmakologie   analogy a deriváty   MeSH
• myokard metabolismus   MeSH
• NG-nitroargininmethylester * farmakologie   MeSH
• novorozená zvířata * MeSH
• oxid dusnatý * metabolismus   MeSH
• potkani Wistar * MeSH
• reperfuzní poškození myokardu * prevence a kontrola   metabolismus   MeSH
• srdce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• donory oxidu dusnatého MeSH
• molsidomin MeSH
• NG-nitroargininmethylester * MeSH
• oxid dusnatý * MeSH

Aspirin supplemented with quercetin was reported to enhance the therapeutic effects of aspirin in a rat model of preeclampsia. In this study, the underlying mechanisms were further explored. Preeclampsia was induced by L-NAME (50 mg/kg/day) via oral gavage from gestation day (GD)14 to GD19. Aspirin (1.5 mg/kg/day) administration was performed using aspirin mixed with rodent dough from GD0 to GD19. The administration of quercetin (2 mg/kg/day) was performed by intraperitoneal infusion from GD0 to GD19. Protein levels were evaluated using ELISA or Western blot, and microRNA (miRNA) level was evaluated by RT-PCR. Aspirin supplemented with quercetin ameliorated the increase of systolic blood pressure (SBP), proteinuria, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels, and improved the pregnancy outcomes in preeclampsia rats. Aspirin supplemented with quercetin inhibited miR-155 expression in preeclampsia rats. The decreased miR-155 level in placenta further increased the protein level of SOCS1 and inhibited the phosphorylation of p65. In this study, we demonstrated that aspirin supplemented with quercetin enhanced the effects of aspirin for the treatment of preeclampsia.

• MeSH
• Aspirin škodlivé účinky   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• mikro RNA * metabolismus   MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• placenta metabolismus   MeSH
• preeklampsie * chemicky indukované   farmakoterapie   prevence a kontrola   MeSH
• quercetin farmakologie   terapeutické užití   MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Aspirin MeSH
• mikro RNA * MeSH
• MIRN155 microRNA, rat MeSH Prohlížeč
• NG-nitroargininmethylester MeSH
• quercetin MeSH

The present study investigated the participation of the nitric oxide pathway in facilitating lordosis behavior induced by intrahypothalamic administration of apelin-13 in ovariectomized rats primed with estradiol benzoate (EB). The experiments involved the administration of a nitric oxide synthase inhibitor (L-NAME) or a nitric oxide-dependent, soluble guanylyl cyclase inhibitor (ODQ), and an inhibitor of protein kinase G (KT5823) to the ventromedial hypothalamus (VMH) of EB-primed rats 30 min before infusion of apelin-13 (0.75 μg/μl). This dose of apelin-13 consistently induces lordosis behavior at 30 min, 120 min, and 240 min following infusion. Results showed that injections of either L-NAME or KT5823 significantly reduced the lordosis induced by apelin at 120 and 240 min. However, VMH infusion of ODQ 30 min before apelin-13 infusion reduced but did not significantly inhibit, the lordosis elicited by this peptide at the same time points. We conclude that the nitric oxide pathway in the VMH plays an important role in lordosis induced by apelin-13 in EB-primed rats.

• Klíčová slova
• Apelin-13, Lordosis behavior, Nitric oxide,
• MeSH
• estradiol farmakologie   MeSH
• krysa rodu Rattus MeSH
• lordóza * chemicky indukované   MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• oxid dusnatý * metabolismus   MeSH
• sexuální chování zvířat fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• apelin-13 peptide MeSH Prohlížeč
• estradiol MeSH
• NG-nitroargininmethylester MeSH
• oxid dusnatý * MeSH

Hypertension is one of the most prevalent and powerful contributors of cardiovascular diseases. Malignant hypertension is a relatively rare but extremely severe form of hypertension accompanied with heart, brain, and renal impairment. Resveratrol, a recently described grape-derived, polyphenolic antioxidant molecule, has been proposed as an effective agent in the prevention of cardiovascular diseases. This study was designed to examine chronic resveratrol administration on blood pressure, oxidative stress, and inflammation, with special emphasis on cardiac structure and function in two models of experimental hypertension. The experiments were performed in spontaneously (SHRs) and malignantly hypertensive rats (MHRs). The chronic administration of resveratrol significantly decreased blood pressure in both spontaneously and malignant hypertensive animals. The resveratrol treatment ameliorated morphological changes in the heart tissue. The immunohistochemistry of the heart tissue after resveratrol treatment showed that both TGF-β and Bax were not present in the myocytes of SHRs and were present mainly in the myocytes of MHRs. Resveratrol suppressed lipid peroxidation and significantly improved oxidative status and release of NO. These results suggest that resveratrol prevents hypertrophic and apoptotic consequences induced by high blood pressure with more pronounced effects in malignant hypertension.

• Klíčová slova
• heart, resveratrol, spontaneously and malignant hypertension,
• MeSH
• antiflogistika farmakologie   terapeutické užití   MeSH
• antioxidancia terapeutické užití   MeSH
• apoptóza * účinky léků   MeSH
• hemodynamika účinky léků   MeSH
• hypertenze maligní farmakoterapie   enzymologie   patologie   patofyziologie   MeSH
• kardiotonika farmakologie   terapeutické užití   MeSH
• krysa rodu Rattus MeSH
• látky reagující s kyselinou thiobarbiturovou metabolismus   MeSH
• myokard patologie   MeSH
• NG-nitroargininmethylester chemie   farmakologie   MeSH
• oxidace-redukce MeSH
• potkani inbrední SHR MeSH
• protein X asociovaný s bcl-2 metabolismus   MeSH
• resveratrol chemie   farmakologie   terapeutické užití   MeSH
• srdeční komory účinky léků   patologie   patofyziologie   MeSH
• tělesná hmotnost účinky léků   MeSH
• velikost orgánu účinky léků   MeSH
• zánět komplikace   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antiflogistika MeSH
• antioxidancia MeSH
• kardiotonika MeSH
• látky reagující s kyselinou thiobarbiturovou MeSH
• NG-nitroargininmethylester MeSH
• protein X asociovaný s bcl-2 MeSH
• resveratrol MeSH

Reactive oxygen species (ROS) such as superoxide (O2-) generated by NAD(P)H oxidases have emerged as important molecules in blood pressure regulation. This study investigated the effect of apocynin and catalase on blood pressure and renal haemodynamic and excretory function in an L-NAME induced hypertension model. Forty Male Wistar-Kyoto (WKY) rats (n=8 per group) were treated with either: vehicle (WKY-C); L-NAME (WKY-L, 15 mg/kg/day in drinking fluid); WKY-L given apocynin to block NAD(P)H oxidase (WKY-LApo, 73 mg/kg/day in drinking water.); WKY-L given catalase to enhance ROS scavenging (WKY-LCat, 10000 U/kg/day i.p.); and WKY-L receiving apocynin plus catalase (WKY-LApoCat) daily for 14 days. L-NAME elevated systolic blood pressure (SBP), 116+/-1 to 181±4 mmHg, reduced creatinine clearance, 1.69+/-0.26 to 0.97+/-0.05 ml/min/kg and fractional sodium excretion, 0.84+/-0.09 to 0.55+/-0.09 % at day 14. Concomitantly, plasma malondialdehyde (MDA) increased six fold, while plasma total superoxide dismutase (T-SOD), plasma nitric oxide (NO) and plasma total antioxidant capacity (T-AOC) were decreased by 60-70 % and Nox 4 mRNA expression was increased 2-fold. Treatment with apocynin and catalase attenuated the increase in SBP and improved renal function, enhanced antioxidative stress capacity and reduced the magnitude of Nox4 mRNAs expression in the L-NAME treated rats. This study demonstrated that apocynin and catalase offset the development of L-NAME induced hypertension, renal dysfunction and reduced oxidative stress status, possibly contributed by a reduction in Nox4 expression during NOS inhibition. These findings would suggest that antioxidant compounds such as apocynin and catalase have potential in treating cardiovascular diseases.

• MeSH
• acetofenony farmakologie   MeSH
• antioxidancia farmakologie   MeSH
• hemodynamika MeSH
• hypertenze chemicky indukované   farmakoterapie   patofyziologie   MeSH
• inhibitory enzymů toxicita   MeSH
• katalasa farmakologie   MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech MeSH
• NADPH-oxidasa 4 metabolismus   MeSH
• NG-nitroargininmethylester toxicita   MeSH
• potkani inbrední WKY MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetofenony MeSH
• acetovanillone MeSH Prohlížeč
• antioxidancia MeSH
• inhibitory enzymů MeSH
• katalasa MeSH
• NADPH-oxidasa 4 MeSH
• NG-nitroargininmethylester MeSH
• Nox4 protein, rat MeSH Prohlížeč
• reaktivní formy kyslíku MeSH

Cardiovascular pathologies are frequently associated with anxiety and other behavioral disturbances. Ivabradine, an inhibitor of the hyperpolarization-activated cyclic nucleotide-gated channels in the sinoatrial node, decreases heart rate and provides cardiovascular protection. Although ivabradine is increasingly used in cardiovascular medicine, the data on its behavioral effects are lacking. The aim of this work was to show ivabradine's potential effect on behavior in healthy and hypertensive rats. After a four-week treatment period, systolic blood pressure was increased in the N(G)-nitro-L-arginine methyl ester (L-NAME)-group and ivabradine significantly reduced it. Furthermore, it reduced the heart rate in both the control and L-NAME-group. In the control group, ivabradine enhanced the time spent in and transition to the open arms of the elevated plus maze test (EPM). In the L-NAME-group, ivabradine does not show a significant effect on the time spent in the EPM open arms and the number of transitions into them. Furthermore, ivabradine has no impact on cognitive function in both control and L-NAME groups. We conclude that ivabradine showed no undesirable effects on anxiety, locomotion or learning; in fact, some of these parameters were even improved. For the first time it has been shown that ivabradine is a safe cardiovascular drug regarding its effect on psycho-behavioral manifestations.

• MeSH
• hypertenze chemicky indukované   farmakoterapie   patofyziologie   MeSH
• inhibitory enzymů farmakologie   terapeutické užití   MeSH
• ivabradin farmakologie   terapeutické užití   MeSH
• krevní tlak účinky léků   fyziologie   MeSH
• krysa rodu Rattus MeSH
• NG-nitroargininmethylester toxicita   MeSH
• paměť účinky léků   fyziologie   MeSH
• potkani Wistar MeSH
• srdeční frekvence účinky léků   fyziologie   MeSH
• úzkost * patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inhibitory enzymů MeSH
• ivabradin MeSH
• NG-nitroargininmethylester MeSH

Ivabradine, the selective inhibitor of the If current in the sinoatrial node, exerts cardiovascular protection by its bradycardic effect and potentially pleiotropic actions. However, there is a shortage of data regarding ivabradine's interaction with the renin-angiotensin-aldosterone system (RAAS). This study investigated whether ivabradine is able to protect a hypertensive heart in the model of L-NAME-induced hypertension and to interfere with the RAAS. Four groups (n = 10/group) of adult male Wistar rats were treated as follows for four weeks: control, ivabradine (10 mg/kg/day), L-NAME (40 mg/kg/day), and L-NAME plus ivabradine. L-NAME administration increased systolic blood pressure (SBP) and left ventricular (LV) weight, enhanced hydroxyproline concentration in the LV, and deteriorated the systolic and diastolic LV function. Ivabradine reduced heart rate (HR) and SBP, and improved the LV function. The serum concentrations of angiotensin Ang 1⁻8 (Ang II), Ang 1⁻5, Ang 1⁻7, Ang 1⁻10, Ang 2⁻8, and Ang 3⁻8 were decreased in the L-NAME group and ivabradine did not modify them. The serum concentration of aldosterone and the aldosterone/Ang II ratio were enhanced by L-NAME and ivabradine reduced these changes. We conclude that ivabradine improved the LV function of the hypertensive heart in L-NAME-induced hypertension. The protective effect of ivabradine might have been associated with the reduction of the aldosterone level.

• Klíčová slova
• L-NAME, aldosterone, angiotensin II, fibrosis, heart function, hypertension, ivabradine,
• MeSH
• aldosteron krev   MeSH
• angiotensiny krev   MeSH
• biologické markery MeSH
• echokardiografie MeSH
• funkce levé komory srdeční účinky léků   MeSH
• hydroxyprolin krev   metabolismus   MeSH
• hypertenze diagnóza   etiologie   metabolismus   patofyziologie   MeSH
• ivabradin farmakologie   MeSH
• kardiovaskulární látky farmakologie   MeSH
• kolagen metabolismus   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech MeSH
• NG-nitroargininmethylester škodlivé účinky   MeSH
• renin-angiotensin systém účinky léků   MeSH
• renin krev   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aldosteron MeSH
• angiotensiny MeSH
• biologické markery MeSH
• hydroxyprolin MeSH
• ivabradin MeSH
• kardiovaskulární látky MeSH
• kolagen MeSH
• NG-nitroargininmethylester MeSH
• renin MeSH

Electric stimulation (ES) could induce contraction of intestinal smooth muscle. The aim of this study was to analyze the effects of ES on esophageal motility and the underlying mechanism in vivo. Twenty-eight rabbits were equipped with a pair of subserosa electrodes (connected to an electrical stimulator) in the lower segment of the esophagus. The ES signal consisted of bipolar rectangular pulse trains, lasting for 3 s, with different amplitudes (1 mA, 3 mA, 5 mA and 10 mA), and frequencies (10 Hz, 20 Hz and 50 Hz). The amplitude of the contraction was recognized by high-resolution manometry. The effect of ES was tested under anesthesia and following administration of atropine, phentolamine or L-NAME. ES induced esophageal contraction at the stimulated site. A statistically significant increase in esophageal pressure was observed when the stimulation amplitude was above 3 mA. The increase in esophageal pressure was associated with the amplitude of stimulus as well as the frequency. During stimulation, atropine, phentolamine and L-NAME had no effect on the increase of esophageal pressure induced by ES. These findings implied that ES induced esophageal contraction were not mediated via the NANC, adrenergic or cholinergic pathway. The amplitude of esophageal contraction was current and frequency dependent.

• MeSH
• alfa blokátory farmakologie   MeSH
• antagonisté muskarinových receptorů farmakologie   MeSH
• atropin farmakologie   MeSH
• elektrická stimulace * MeSH
• ezofágus účinky léků   fyziologie   MeSH
• fentolamin farmakologie   MeSH
• gastrointestinální motilita účinky léků   fyziologie   MeSH
• králíci MeSH
• manometrie MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• poruchy motility jícnu patofyziologie   MeSH
• svalová kontrakce MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alfa blokátory MeSH
• antagonisté muskarinových receptorů MeSH
• atropin MeSH
• fentolamin MeSH
• NG-nitroargininmethylester MeSH

The renin-angiotensin-aldosterone system (RAAS) is a dominant player in several cardiovascular pathologies. This study investigated whether alterations induced by l-NAME, (NLG)-nitro-l-arginine methyl ester, a nitric oxide synthase inhibitor, and the protective effect of melatonin are associated with changes in the RAAS. Four groups of 3-month-old male Wistar rats (n = 10) were treated as follows for four weeks: untreated controls, rats treated with melatonin (10 mg/kg/day), rats treated with l-NAME (40 mg/kg/day), and rats treated with l-NAME + melatonin. l-NAME administration led to hypertension and left ventricular (LV) fibrosis in terms of enhancement of soluble, insoluble and total collagen concentration and content. Melatonin reduced systolic blood pressure enhancement and lowered the concentration and content of insoluble and total collagen in the LV. The serum concentration of angiotensin (Ang) 1-8 (Ang II) and its downstream metabolites were reduced in the l-NAME group and remained unaltered by melatonin. The serum aldosterone level and its ratio to Ang II (AA2-ratio) were increased in the l-NAME group without being modified by melatonin. We conclude that l-NAME-hypertension is associated with reduced level of Ang II and its downstream metabolites and increased aldosterone concentration and AA2-ratio. Melatonin exerts its protective effect in l-NAME-induced hypertension without affecting RAAS.

• Klíčová slova
• ">l-NAME, aldosterone, angiotensin 1–7, angiotensin II, fibrosis, melatonin,
• MeSH
• hypertenze * chemicky indukované   metabolismus   patofyziologie   prevence a kontrola   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• melatonin farmakologie   MeSH
• NG-nitroargininmethylester škodlivé účinky   farmakologie   MeSH
• potkani Wistar MeSH
• renin-angiotensin systém účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• melatonin MeSH
• NG-nitroargininmethylester MeSH