Substituted catechols include both natural and synthetic compounds found in the environment and foods. Some of them are flavonoid metabolites formed by the gut microbiota which are absorbed afterwards. Our previous findings showed that one of these metabolites, 4-methylcatechol, exerts potent vasorelaxant effects in rats. In the current study, we aimed at testing of its 22 structural congeners in order to find the most potent structure and to investigate the mechanism of action. 3-methoxycatechol (3-MOC), 4-ethylcatechol, 3,5-dichlorocatechol, 4-tert-butylcatechol, 4,5-dichlorocatechol, 3-fluorocatechol, 3-isopropylcatechol, 3-methylcatechol and the parent 4-methylcatechol exhibited high vasodilatory activities on isolated rat aortic rings with EC50s ranging from ∼10 to 24 μM. Some significant sex-differences were found. The most potent compound, 3-MOC, relaxed also resistant mesenteric artery but not porcine coronary artery, and decreased arterial blood pressure in both male and female spontaneously hypertensive rats in vivo without affecting heart rate. It potentiated the vasodilation mediated by cAMP and cGMP, but did not impact L-type Ca2+-channels. By using two inhibitors, activation of voltage-gated potassium channels (KV) was found to be involved in the mechanism of action. This was corroborated by docking analysis of 3-MOC with the KV7.4 channel. None of the most active catechols decreased the viability of the A-10 rat embryonic thoracic aorta smooth muscle cell line. Our findings showed that various catechols can relax vascular smooth muscles and hence could provide templates for developing new antihypertensive vasodilator agents without affecting coronary circulation.

• MeSH
• aorta thoracica účinky léků   metabolismus   MeSH
• arteriae mesentericae * účinky léků   metabolismus   MeSH
• arteriální tlak účinky léků   MeSH
• draslíkové kanály řízené napětím metabolismus   antagonisté a inhibitory   účinky léků   MeSH
• guanosinmonofosfát cyklický metabolismus   MeSH
• hypertenze farmakoterapie   patofyziologie   metabolismus   MeSH
• katecholy * farmakologie   chemie   MeSH
• koronární cévy účinky léků   metabolismus   MeSH
• krysa rodu rattus MeSH
• modely nemocí na zvířatech MeSH
• myocyty hladké svaloviny účinky léků   metabolismus   MeSH
• potkani inbrední SHR * MeSH
• prasata MeSH
• sexuální faktory MeSH
• simulace molekulového dockingu * MeSH
• svaly hladké cévní účinky léků   metabolismus   MeSH
• vazodilatace * účinky léků   MeSH
• vazodilatancia * farmakologie   chemie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Atherosclerosis is a major cause of ischemic stroke, and early detection of advanced atherosclerosis in the carotid artery is important for reducing morbidity and mortality. What is even more important is not only detection of atherosclerosis but early determination whether the patients are at high risk of an event with adverse effects as the size of the plaque does not necessarily reflect its potential to trigger such events. AIM: We studied whether plasma lipidomics profile can be used as a diagnostic tool for stratification of stable or unstable plaques without the need of removing the carotid plaque. METHODS: This study used liquid chromatography high-resolution tandem mass spectrometry lipidomics to characterize lipid profiles in patients' plasma and found that patients with significant and complicated (vulnerable) atherosclerotic plaque had distinct lipid profiles compared to those with insignificant plaques. RESULTS: The lipid classes that were most predictive of vulnerable plaque were lysophosphoethanolamines, fatty acyl esters of hydroxy fatty acids, free fatty acids, plasmalogens, and triacylglycerols. Most of these compounds were found decreased in plasma of patients with unstable plaques which enabled sufficient performance of a statistical model used for patient stratification. CONCLUSIONS: Plasma lipidomes measured by liquid chromatography-mass spectrometry show differences in patients with stable and unstable carotid plaques, therefore these compounds could potentially be used as biomarkers for unstable plaque in future clinical diagnosis.

• MeSH
• aterosklerotický plát * krev   MeSH
• biologické markery * krev   MeSH
• chromatografie kapalinová MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipidomika * MeSH
• lipidy * krev   MeSH
• nemoci arterie carotis * krev   diagnóza   MeSH
• prediktivní hodnota testů MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• spontánní ruptura MeSH
• studie případů a kontrol MeSH
• tandemová hmotnostní spektrometrie * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

BACKGROUND: The objective of this systematic review is to summarize the available animal models of ischemic limbs, and to provide an overview of the advantages and disadvantages of each animal model and individual method of limb ischemia creation. METHODS: A review of literature was conducted using the PubMed and Web of Science pages. Various types of experimental animals and surgical approaches used in creating ischemic limbs were evaluated. Other outcomes of interest were the specific characteristics of the individual experimental animals, and duration of tissue ischemia. RESULTS: The most commonly used experimental animals were mice, followed by rabbits, rats, pigs, miniature pigs, and sheep. Single or double arterial ligation and excision of the entire femoral artery was the most often used method of ischemic limb creation. Other methods comprised single or double arterial electrocoagulation, use of ameroid constrictors, photochemically induced thrombosis, and different types of endovascular methods. The shortest duration of tissue ischemia was 7 days, the longest 90 days. CONCLUSIONS: This review shows that mice are among the most commonly used animals in limb ischemia research. Simple ligation and excision of the femoral artery is the most common method of creating an ischemic limb; nevertheless, it can result in acute rather than chronic ischemia. A two-stage sequential approach and methods using ameroid constrictors or endovascular blinded stent grafts are more suitable for creating a gradual arterial occlusion typically seen in humans. Selecting the right mouse strain or animal with artificially produced diabetes or hyperlipidaemia is crucial in chronic ischemic limb research. Moreover, the observation period following the onset of ischemia should last at least 14 days, preferably 4 weeks.

• MeSH
• arteria femoralis * chirurgie   MeSH
• ischemie * MeSH
• králíci MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• modely u zvířat MeSH
• myši MeSH
• ovce MeSH
• prasata MeSH
• stenty MeSH
• teoretické modely MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• systematický přehled MeSH

SCOPE: The flavonoid quercetin reduces arterial blood pressure in animals and humans but the mechanisms remains elusive. The aim of this study was to test the activity of flavonoid microbial metabolites, which can participate on the final vasorelaxant effect. METHODS AND RESULTS: Both ex vivo (isolated rat thoracic aorta and mesenteric artery) and in vivo (normotensive and spontaneously hypertensive rats) approaches were used in this study. 4-methylcatechol and 3,4-dihydroxyphenylacetic acid (DHPA) had greater vasorelaxant effects on mesenteric artery than 3-(3-hydroxyphenyl)propionic acid, the previously reported metabolite with vasorelaxant effect. In vivo testing confirmed their blood pressure decreasing effect given both as bolus and slow infusion. Their mechanism at molecular level was different. CONCLUSIONS: This study is the first to show that flavonoid metabolites DHPA and 4-methylcatechol decrease arterial blood pressure and hence a mixture of microbial metabolites formed in the gastrointestinal tract may be responsible for or contribute to the effect of orally ingested quercetin.

• MeSH
• antihypertenziva farmakologie   MeSH
• aorta thoracica účinky léků   MeSH
• arteriae mesentericae účinky léků   MeSH
• arteriální tlak účinky léků   MeSH
• hypertenze farmakoterapie   patofyziologie   MeSH
• katecholy farmakologie   MeSH
• kyselina 3,4-dihydroxyfenyloctová farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• potkani inbrední SHR MeSH
• potkani Wistar MeSH
• techniky in vitro MeSH
• vazodilatace účinky léků   MeSH
• vazodilatancia farmakologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Apelin is a peptide known to have a vital role in cardiovascular diseases. It has been proven to induce proliferation and tube formation in endothelial cells, stabilise contacts between endothelial cells, and mediate pericyte recruitment. Since apelin level is reduced early after myocardial infarction, a supportive therapy with apelin is being investigated for its beneficial effect on blood vessel formation. It is becoming apparent, however, that the final effect of apelin often depends on stimuli the cell receives and the cross-talk with other molecules inside the cell. Hence, understanding the apelin pathway potentially can help us to improve angiogenic therapy. This review summarises recent knowledge regarding molecules involved in apelin signalling while focusing on their roles in angiogenesis within the ischemic environment after myocardial infarction.

• MeSH
• endoteliální buňky metabolismus   MeSH
• fyziologická neovaskularizace fyziologie   MeSH
• infarkt myokardu metabolismus   MeSH
• intracelulární signální peptidy a proteiny metabolismus   MeSH
• ischemická choroba srdeční metabolismus   MeSH
• lidé MeSH
• patologická angiogeneze metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

This study examined the effects of a novel orally active 14,15-epoxyeicosatrienoic acid analog (EET-A) on blood pressure (BP) and myocardial infarct size (IS) in two-kidney, one-clip (2K1C) Goldblatt hypertensive rats during sustained phase of hypertension. Between days 31 and 35 after clip placement the rats were treated with EET-A and BP was monitored by radiotelemetry; sham-operated normotensive rats were used as controls. Tissue concentrations of epoxyeicosatrienoic acids served as a marker of production of epoxygenase metabolites. The rats were subjected to acute myocardial ischemia/reperfusion (I/R) injury and IS was determined. We found that EET-A treatment did not lower BP in 2K1C rats and did not alter availability of biologically active epoxygenase metabolites in 2K1C or in sham-operated rats. The myocardial IS was significantly smaller in untreated 2K1C rats as compared with normotensive controls and EET-A reduced it in controls but not in 2K1C rats. Our findings suggest that during the phase of sustained hypertension 2K1C Goldblatt hypertensive rats exhibit increased cardiac tolerance to I/R injury as compared with normotensive controls, and that in this animal model of human renovascular hypertension short-term treatment with EET-A does not induce any antihypertensive and cardioprotective actions.

• MeSH
• ambulantní monitorování krevního tlaku metody   MeSH
• aplikace orální MeSH
• časové faktory MeSH
• infarkt myokardu metabolismus   patologie   prevence a kontrola   MeSH
• kinasa 3 glykogensynthasy metabolismus   MeSH
• krevní tlak účinky léků   MeSH
• kyselina 8,11,14-eikosatrienová aplikace a dávkování   analogy a deriváty   MeSH
• kyseliny hydroxyeikosatetraenové metabolismus   MeSH
• ledviny účinky léků   metabolismus   patologie   MeSH
• modely nemocí na zvířatech MeSH
• myokard metabolismus   patologie   MeSH
• potkani Sprague-Dawley MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• renin-angiotensin systém účinky léků   MeSH
• renovaskulární hypertenze farmakoterapie   metabolismus   patofyziologie   MeSH
• reperfuzní poškození myokardu metabolismus   patologie   prevence a kontrola   MeSH
• signální transdukce účinky léků   MeSH
• telemetrie MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Pulmonary hypertension (PH), associated with imbalance in vasoactive mediators and massive remodeling of pulmonary vasculature, represents a serious health complication. Despite the progress in treatment, PH patients typically have poor prognoses with severely affected quality of life. Asymmetric dimethyl arginine (ADMA), endogenous inhibitor of endothelial nitric oxide synthase (eNOS), also represents one of the critical regulators of pulmonary vascular functions. The present study describes a novel mechanism of ADMA-induced dysfunction in human pulmonary endothelial and smooth muscle cells. The effect of ADMA was compared with well-established model of hypoxia-induced pulmonary vascular dysfunction. It was discovered for the first time that ADMA induced the activation of signal transducer and activator of transcription 3 (STAT3) and stabilization of hypoxia inducible factor 1α (HIF-1α) in both types of cells, associated with drastic alternations in normal cellular functions (e.g., nitric oxide production, cell proliferation/Ca(2+) concentration, production of pro-inflammatory mediators, and expression of eNOS, DDAH1, and ICAM-1). Additionally, ADMA significantly enhanced the hypoxia-mediated increase in the signaling cascades. In summary, increased ADMA may lead to manifestation of PH phenotype in human endothelial and smooth muscle cells via the STAT3/HIF-1α cascade. Therefore this signaling pathway represents the potential pathway for future clinical interventions in PH.

• MeSH
• amidohydrolasy metabolismus   MeSH
• arginin analogy a deriváty   farmakologie   MeSH
• arteria pulmonalis účinky léků   metabolismus   patofyziologie   MeSH
• endoteliální buňky účinky léků   metabolismus   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• hypoxie buňky MeSH
• kultivované buňky MeSH
• lidé MeSH
• mediátory zánětu metabolismus   MeSH
• mezibuněčná adhezivní molekula-1 metabolismus   MeSH
• myocyty hladké svaloviny účinky léků   metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• plicní hypertenze etiologie   metabolismus   patofyziologie   MeSH
• proliferace buněk účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• svaly hladké cévní účinky léků   metabolismus   patofyziologie   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• vápník metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Results of our previous studies have suggested that enhanced generation of superoxide (O2(-)) may contribute to the pathophysiology of hypertension in Ren-2 transgenic rats (TGR). The present study was performed to evaluate in TGR the effects of chronic treatment with the O2(-) scavenger tempol and the antioxidant apocynin on the development of hypertension. Systolic blood pressure (SBP) was monitored from 30 to 99 days of age in TGR and in normotensive Hannover Sprague-Dawley (HanSD) rats. At the end of the experiment, urinary protein and 8-isoprostane excretion were determined and angiotensin II (ANG II) and malondialdehyde (MDA) levels were measured in kidney and cardiac tissues. Cardiac hypertrophy was assessed as the ratio of left heart ventricle weight to tibia length (LVW/TL). Although tempol and apocynin treatment in TGR significantly decreased 8-isoprostane excretion and MAD tissue concentrations as compared with untreated TGR, it did not alter the course of SBP, LVW/TL ratio, proteinuria or ANG II levels that were enhanced as compared with HanSD rats. Our data suggest that the development of hypertension in TGR is clearly ANG II-dependent but the contribution of oxidative stress to the development of hypertension in this model appears to be negligible.

• MeSH
• acetofenony farmakologie   MeSH
• analýza rozptylu MeSH
• angiotensin II analýza   fyziologie   krev   moč   MeSH
• antioxidancia farmakologie   MeSH
• časové faktory MeSH
• cyklické N-oxidy farmakologie   MeSH
• dinoprost analogy a deriváty   moč   MeSH
• hypertenze komplikace   patofyziologie   prevence a kontrola   MeSH
• kardiomegalie komplikace   prevence a kontrola   MeSH
• krevní tlak MeSH
• krysa rodu rattus MeSH
• ledviny chemie   MeSH
• malondialdehyd analýza   MeSH
• modely nemocí na zvířatech MeSH
• myokard chemie   MeSH
• náhodné rozdělení MeSH
• nemoci ledvin komplikace   prevence a kontrola   MeSH
• oxidační stres fyziologie   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• proteinurie MeSH
• renin genetika   MeSH
• scavengery volných radikálů farmakologie   MeSH
• spinové značení MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

We found previously that selective blockade of endothelin ETA receptors is superior to nonselective ET(A)/ET(B) in attenuating hypertension and survival rate in Ren-2 transgenic rats (TGR). In the present pilot study, we were interested in whether similar effects will be found in TGR with inducible malignant hypertension (iTGR; official strain name Cyp1A1-Ren-2rats), which were derived from the original Ren-2 transgenic rat strain. Studies were performed in three-month old male iTGR. Treatment with either bosentan, a non-selective ET(A)/ET(B), or with atrasentan, a selective ET(A) receptor blocker, was started on day 2 of the experiment. Feeding with indole-3-carbinole (13C; 03% in rat chow), a natural xenobiotic which activates the Cyplal promoter of the mouse Ren-2 gene, began on day 3 and lasted for 4 days until day 6. Systolic BP, body weight, plasma ANG II and tissue ANG II and ET-1 concentrations were determined daily. Severe hypertension developed as early as 1 day after beginning of 13C feeding which was accompanied by a significant reduction in body weight and by increases in plasma and tissue ANG II and left ventricle ET-1 concentrations. Atrasentan or bosentan had no effects on the rise in BP or plasma and tissue ANG II concentrations but prevented the rise in heart ventricle ET-1 concentration. Our data show that blockade of the ET system does not prevent or attenuate the rapid development of severe hypertension in iTGR; a long-term protective effect of ET blockade on cardiac (and renal) damage, however, cannot be excluded and awaits further investigations.

• MeSH
• angiotensin II krev   metabolismus   MeSH
• antagonisté endotelinového receptoru MeSH
• antihypertenziva farmakologie   MeSH
• cytochrom P-450 CYP1A1 genetika   účinky léků   MeSH
• endotelin-1 MeSH
• hypertenze farmakoterapie   chemicky indukované   MeSH
• indoly škodlivé účinky   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• ledviny metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• potkani transgenní MeSH
• pyrrolidiny farmakologie   MeSH
• receptory endotelinů MeSH
• renin genetika   MeSH
• srdeční komory metabolismus   MeSH
• sulfonamidy farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

Our previous studies in heterozygous Ren-2 transgenic rats (TGR) have shown that early treatment with selective endothelin (ET)(A) receptor blockade is superior to nonselective ET(A/B) receptor blockade. The aim of this study was to evaluate the role of the ET system in male heterozygous TGR with established hypertension (late-onset treatment). TGR and control Hannover Sprague-Dawley (HanSD) rats were fed a high-salt diet and were treated concomitantly with the nonselective ET(A/B) receptor blocker bosentan or the selective ET(A) receptor blocker atrasentan from day 52 of age on. Survival rate was partly increased by bosentan and fully normalized with atrasentan. Bosentan transiently decreased blood pressure (BP), whereas atrasentan significantly reduced BP as early as one week after the start of the treatment. This effect persisted for the whole experimental period. Atrasentan also substantially reduced cardiac hypertrophy, proteinuria, glomerulosclerosis and left ventricle ET-1 content. Bosentan improved and atrasentan almost restored podocyte architecture and reversed changes in podocyte phenotype represented by the expression of CD 10, desmin and vimentin. Our results demonstrate that selective ET(A) receptor blockade has more favorable effects than nonselective ET(A/B) receptor blockade and, unlike observed in homozygous TGR, ET(A) receptor blockade has similar effects in heterozygous rats with established hypertension as in young animals with developing hypertension.

• MeSH
• angiotensin II fyziologie   MeSH
• antagonisté endotelinového receptoru MeSH
• elektronová mikroskopie MeSH
• endotelin-1 metabolismus   MeSH
• financování organizované MeSH
• fokálně segmentální glomeruloskleróza patologie   MeSH
• geneticky modifikovaná zvířata MeSH
• heterozygot MeSH
• hypertenze maligní farmakoterapie   genetika   patologie   MeSH
• imunohistochemie MeSH
• krevní tlak genetika   účinky léků   MeSH
• krysa rodu rattus MeSH
• ledviny patologie   MeSH
• míra přežití MeSH
• potkani Sprague-Dawley MeSH
• proteinurie genetika   MeSH
• receptory endotelinů MeSH
• renin fyziologie   genetika   MeSH
• sodík dietní farmakologie   MeSH
• tělesná hmotnost genetika   MeSH
• velikost orgánu genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH