Coronary artery vasospasm (constriction) caused by reduced nitric oxide bioavailability leads to myocardial infarction. Reduced endothelial release of nitric oxide by the neurotransmitter acetylcholine, leads to paradoxical vasoconstriction as it binds to smooth muscle cell M3 receptors. Thus, inhibition of coronary artery vasospasm will improve clinical outcomes. Inhibition of insulin regulated aminopeptidase has been shown to improve vessel function, thus we tested the hypothesis that HFI419, an inhibitor of insulin regulated aminopeptidase, could reduce blood vessel constriction to acetylcholine. The abdominal aorta was excised from New Zealand white rabbits (n=15) and incubated with 3mM Hcy to induce vascular dysfunction in vitro for 1h. HFI419 was added 5min prior to assessment of vascular function by cumulative doses of acetylcholine. In some rings, vasoconstriction to acetylcholine was observed in aortic rings after pre-incubation with 3mM homocysteine. Incubation with HFI419 inhibited the vasoconstrictive response to acetylcholine, thus improving, but not normalizing, vascular function (11.5±8.9% relaxation vs 79.2±37% constriction, p<0.05). Similarly, in another group with mild vasoconstriction, HFI419 inhibited this effect (34.9±4.6% relaxation vs 11.1±5.2%, constriction, p<0.05). HFI419 had no effect on control aorta or aorta with mild aortic dysfunction. The present study shows that HFI419 prevents acetylcholine mediated vasoconstriction in dysfunctional blood vessels. HFI419 had no effect on normal vasodilation. Our results indicate a therapeutic potential of HFI419 in reducing coronary artery vasospasm.

• MeSH
• acetylcholin toxicita   MeSH
• aorta abdominalis účinky léků   enzymologie   MeSH
• cévní endotel účinky léků   enzymologie   MeSH
• cystinylaminopeptidasa antagonisté a inhibitory   metabolismus   MeSH
• inhibitory enzymů farmakologie   MeSH
• králíci MeSH
• orgánové kultury - kultivační techniky MeSH
• vazokonstrikce účinky léků   fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Hyperhomocysteinemia (HHcy) impairs nitric oxide endothelium-dependent vasodilation, consequently leading to atherosclerosis, a risk factor for cardiovascular disease. Novel treatments for HHcy are necessary. AIM: We tested the hypothesis that alamandine, a vasoactive peptide of the renin-angiotensin system (RAS), could reverse HHcy-induced vascular dysfunction through the MrgD receptor and that this is mediated by the protein kinase A (PKA) pathway. Furthermore, we sought to determine a putative binding model of alamandine to the MrgD receptor through docking and molecular dynamics simulations. METHOD: The abdominal aorta was excised from New Zealand white rabbits (n = 15) and incubated with 3 mmol/L Hcy (to mimic HHcy) to induce vascular dysfunction in vitro. Vascular function was assessed by vasodilatory responses to cumulative doses of acetylcholine. RESULT: Vasodilation was significantly impaired in HHcy-incubated aortic rings while alamandine reversed this effect (control, 74.2 ± 5.0%; Hcy, 30.3 ± 9.8%; alamandine + Hcy, 59.7 ± 4.8%, P < .0001). KT5720 (PKA inhibitor) significantly inhibited the ability of alamandine to attenuate the impaired vasodilation caused by HHcy (KT5720 + Hcy + alamandine, 27.1 ± 24.1, P < .01). Following immunohistochemistry analysis, the MrgD receptor was highly expressed within the media and endothelial layer of aortic rings in HHcy compared to control (media: 0.23 ± 0.003 vs control 0.16 ± 0.01, P < .05 and endothelium: 0.68 ± 0.07 vs control 0.13 ± 0.02, P < .01, in PA/I (A.U) units). Computational studies also propose certain interactions of alamandine within the MrgD transmembrane domain. CONCLUSION: This study shows that alamandine is effective in reversing HHcy-induced vascular dysfunction, possibly through the PKA signaling pathway via MrgD. Our results indicate a therapeutic potential of alamandine in reversing the detrimental effects of HHcy.

• MeSH
• aorta abdominalis účinky léků   MeSH
• hyperhomocysteinemie komplikace   farmakoterapie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• karbazoly farmakologie   MeSH
• králíci MeSH
• nemoci cév farmakoterapie   etiologie   MeSH
• oligopeptidy terapeutické užití   MeSH
• proteinkinasy závislé na cyklickém AMP metabolismus   MeSH
• pyrroly farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• simulace molekulového dockingu MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Antioxidants have not reduced the burden of cardiovascular disease, and current evidence suggests a beneficial role of oxidative stress, via NADPH oxidase (Nox) upregulation, in endothelial function. Homocysteine thiolactone (HcyT) induces blood vessel dysfunction and this correlates with increased vascular oxidative stress. This study aimed to determine if pharmacological inhibition of Nox could impair HcyT induced blood vessel dysfunction. Abdominal aorta were excised from New Zealand White rabbits (n = 6), cut into rings and sequentially mounted in organ baths. Rings were preincubated with 0.55 μmol/L homocysteine thiolactone for 1 h, or combinations of putative Nox inhibitors (plumbagin for Nox4, gp91ds-tat for Nox2, and ML090 for Nox1), 30 min prior to the addition of HcyT, followed by a dose response curve to acetylcholine on phenylephrine preconstricted rings. Plumbagin, ML090 + gp91ds-tat and HcyT reduced responses to acetylcholine, and Plumbagin + Hcyt caused constriction to acetylcholine, which was normalised to plumbagin by ML090. Plumbagin + ML090 or plumbagin + gp91ds-tat completely impaired the effect of acetylcholine. ML090 inhibited the effect of HcyT on reduced response to acetylcholine, whereas gp91ds-tat had no effect. This study concludes that inhibition of Nox1 prevents, whereas inhibition of Nox4 worsens, acetylcholine induced blood vessel relaxation caused by HcyT, while Nox2 inhibition has no effect. However combinations of Nox inhibitors worsen acetylcholine induced blood vessel relaxation. These results suggest that there is cross-talk between Nox isoforms during physiological and pathophysiological processes.

• MeSH
• aorta abdominalis účinky léků   patofyziologie   MeSH
• chinoxaliny farmakologie   MeSH
• glykoproteiny farmakologie   MeSH
• homocystein analogy a deriváty   farmakologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• králíci MeSH
• NADPH-oxidasy antagonisté a inhibitory   MeSH
• naftochinony farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Akutní uzávěr abdominální aorty představuje život ohrožující příhodu, která může navzdory urgentnímu chirurgickému řešení končit fatálně. Heparinem indukovaná trombocytopenie se objevuje u 1–3 % nemocných léčených heparinem i nízkomolekulárním, závažnější je její II. typ (dále HIT). HIT se může kromě trombocytopenie projevit také trombózou v žilním nebo tepenném řečišti. Základem léčby je ukončení léčby heparinem a změna antikoagulační léčby. HIT nezpůsobují antikoagulancia argatroban, bivalirudin a danaparoid, pravděpodobnost vzniku HIT je nízká při terapii fondaparinem. Autoři dokumentují případ 67letého muže přijatého k hospitalizaci na interní oddělení pro ileofemorální flebotrombózu pravé dolní končetiny. Nemocný před 2 lety prodělal resekci rekta pro karcinom, 15 dnů před přijetím prodělal hemihepatektomii pro metastázu karcinomu, perioperačně byl nemocnému preventivně podáván enoxaparin. Nemocný byl vzhledem k flebotrombóze léčen ode dne přijetí terapeutickou dávkou nadroparinu. Šestý den hospitalizace se u nemocného rychle rozvinula paraparéza dolních končetin, echografický nález svědčil pro akutní uzávěr abdominální aorty a pravděpodobně i pánevních tepen oboustranně, ileofemorální flebotrombóza byla nalezena i v levé dolní končetině. Stav byl urgentně řešen trombektomií Fogartyho katétrem z obou femorálních tepen. Vzhledem k trombotickým příhodám a poklesu počtu trombocytů až na 59 × 109/l byla vyslovena suspekce na heparinem indukovanou trombocytopenii, nemocný byl proto převeden na fondaparinux. Při této léčbě se hodnota trombocytů v krevním obraze normalizovala. Diagnóza HIT byla potvrzena laboratorním vyšetřením (průkaz specifických protilátek, pozitivita funkčního testu). Tato raritní kazuistika dokládá možnost i akutně život ohrožující trombózy abdominální aorty v důsledku HIT.

Acute occlusion of the abdominal aorta is a life-threatening event with possible fatal outcomes in spite of urgent surgical management. Heparin-induced thrombocytopenia (HIT) occurs in 1 to 3% of patients treated with heparin including low-molecular-weight heparin. Rare type II HIT is also manifested by ischemia due to peripheral arterial thrombosis. The mainstay of therapy is termination of heparin treatment and change of anticoagulant medication. Fondaparinux or hirudin-type anticoagulants do not cause HIT. The authors present a case history of a 67-year-old male patient admitted to hospitalization at the department of internal medicine because of right ileofemoral phlebothrombosis. The patient underwent rectal resection due to carcinoma two years ago and hemihepatectomy because of metastasis 15 days before admission to the department of internal medicine. He received enoxaparin sodium preventatively in the pre-surgical management. The patient was treated with a curative dose of nadroparin calcium. On the 6th day of hospitalization, the patient suffered from a rapidly developing paraparesis of the lower extremities; echography showed an acute occlusion of the abdominal aorta and probably of iliac arteries on both sides, too. Ileofemoral phlebothrombosis was found in the left lower extremity. The condition was urgently managed by Fogarty catheter thrombectomy from both femoral arteries. Given the thrombocytopenia of 85 × 109/l and thrombotic episodes in spite of treatment with low-molecular-weight heparin, the diagnosis of HIT was suspected and the patient was switched to fondaparinux. The value of thrombocytes became normal during this treatment. The diagnosis of type II HIT was confirmed by laboratory examination. This rare case report documents the possibility of comorbidity of an acutely life-threatening thrombosis of the abdominal aorta as a consequence of type II HIT.

• Klíčová slova
• akutní uzávěr abdominální aorty, heparinem indukovaná trombocytopenie,
• MeSH
• aorta abdominalis * patofyziologie   patologie   účinky léků   MeSH
• heparin * škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• polysacharidy škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• statistika jako téma MeSH
• trombocytopenie * diagnóza   etiologie   komplikace   MeSH
• žilní trombóza MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• kazuistiky MeSH

AIM: Observational studies in human patients and animal experiments suggested that statins have a potential in slowing the growth of small abdominal aortic aneurysms (AAA). Our aim was to quantify histological postoperative changes of AAA in porcine experimental model of AAA with and without administration of atorvastatin. METHODS: The AAA was induced by intraaortic infusion of porcine pancreatic elastase and subrenal application of plastic cuff. The AAA statin group (N.=14) received atorvastatin 1 mg/kg daily for 28 days, the other AAA group (N.=13) did not. The aortic diameter was measured by ultrasonography. Aortic samples were described using eleven quantitative histological parameters and compared with healthy aortae. RESULTS: There was no difference in aortic diameter between the AAA with statin when compared to AAA without statin. Administration of atorvastatin led to a better postoperative histological condition of the aortic elastin network, preservation of contractile phenotype of vascular smooth muscle, a higher density of vasa vasorum, it prevented thickening of intima and media. The increase in wall thickness in AAA without atorvastatin has not been accompanied by a proportional increase in number of vasa vasorum. CONCLUSION: The effects of atorvastatin seem to prevent the histopathological progression of AAA.

• MeSH
• aneurysma břišní aorty chemicky indukované   patologie   prevence a kontrola   ultrasonografie   MeSH
• aorta abdominalis účinky léků   patologie   ultrasonografie   MeSH
• časové faktory MeSH
• kyseliny heptylové farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• pankreatická elastasa MeSH
• progrese nemoci MeSH
• pyrroly farmakologie   MeSH
• statiny farmakologie   MeSH
• Sus scrofa MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Příspěvek shrnuje současný stav poznání etiopatogeneze aneuryzmatu abdominální aorty. Vychází z morfologie normální aorty a ze změn, které postihují její jednotlivé vrstvy. Sumarizuje známé rizikové faktory a s ohledem na úlohu a postižení významných složek cévní stěny se blíže věnuje vlivům hemodynamickým a genetickým. Zvláštní pozornost věnuje zánětlivým procesům ve stěně aneuryzmatu včetně cytokinů a matrix-degradujících proteáz s prokázaným vztahem k rozvoji aneuryzmatu. Rozebírá i vliv trombu a současné výsledky hledání možných biomarkerů rizika a progrese onemocnění. V závěru shrnuje dosavadní zkušenosti s farmakomodulací aneuryzmatu s využitím antihypertenziv, statinů, antibiotik a nesteroidních antiflogistik.

The paper summarizes the latest research on the abdominal aorta aneurysm etiopathogenesis and compares normal aorta morphology with changes in the aortic aneurysm wall. The role of risk factors, especially hemodynamic and genetic, is discussed in detail. Special attention is paid to inflammatory processes including cytokines and matrix degrading proteases that contribute to the development of aneurysm. The role of thrombus and the current results of research into biomarkers indicating the risks and progression of the disease are analysed. Finally, a review of pharmacomodulation of the aortic aneurysm using statins, antibiotics, antihypertensive and nonsteroidal antiinflammatory drugs is presented.

• Klíčová slova
• etipatogeneze, biomarkery, farmakomodulace,
• MeSH
• aneurysma břišní aorty genetika   imunologie   patofyziologie   MeSH
• antiflogistika nesteroidní MeSH
• aorta abdominalis anatomie a histologie   účinky léků   MeSH
• beta blokátory farmakologie   MeSH
• biologické markery MeSH
• elastin MeSH
• hemodynamika MeSH
• histologie MeSH
• inhibitory proteas MeSH
• lidé MeSH
• makrolidy MeSH
• matrixové metaloproteinasy MeSH
• progrese nemoci MeSH
• rizikové faktory MeSH
• statiny farmakologie   MeSH
• tetracykliny farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

The changes of the composition of blood lipoproteins caused by menopause could also change the effect of hypolipidemic therapy. Using an experimental model we studied the changes of serum lipids and the effect of immediate or delayed treatment with simvastatin on atherosclerosis after surgical menopause. Female golden Syrian hamster aged 6 months were fed hypercholesterolemic diet during the whole study. Atherosclerotic changes in thoracic and abdominal aortas were assessed by stereomicroscopic method after 12 weeks. Four experimental groups were studied: sham-operated animals (n=5), ovariectomized animals (n=9), ovariectomized animals treated for 12 weeks (n=10), and ovariectomized animals treated 4 weeks after ovariectomy for 8 weeks (n=9). The dose of simvastatin was 10 mg/kg of body weight. After 12 weeks, ovariectomized animals had tenfold higher concentration of triglycerides in LDL fraction and significantly higher prevalence of atherosclerosis than animals without ovariectomy. Treatment with simvastatin substantially decreased the prevalence of atherosclerotic changes, but otherwise did not change individual serum lipids including LDL cholesterol. However, it improved proportions of pro- and antiatherogenic serum lipids mainly by the increase of HDL cholesterol. The timing of simvastatin treatment had no significant effect on atherosclerotic changes or lipid parameters. Simvastatin treatment partly prevented atherosclerotic changes induced by ovariectomy. This effect was not mediated by decrease of LDL cholesterol, but by increase in HDL cholesterol.

• MeSH
• aorta abdominalis patologie   účinky léků   MeSH
• aorta thoracica patologie   účinky léků   MeSH
• ateroskleróza krev   patologie   prevence a kontrola   MeSH
• biologické markery krev   MeSH
• časové faktory MeSH
• financování organizované MeSH
• HDL-cholesterol krev   MeSH
• křečci praví MeSH
• křeček rodu Mesocricetus MeSH
• LDL-cholesterol krev   MeSH
• lipoproteiny LDL krev   MeSH
• modely nemocí na zvířatech MeSH
• nemoci aorty krev   patologie   prevence a kontrola   MeSH
• ovarektomie MeSH
• rozvrh dávkování léků MeSH
• simvastatin aplikace a dávkování   farmakologie   MeSH
• statiny aplikace a dávkování   farmakologie   MeSH
• triglyceridy krev   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• ženské pohlaví MeSH
• zvířata MeSH

OBJECTIVE: To prospectively compare contrast properties of extracelullar (gadobutrol) and hepatospecific (gadoxetic acid) contrast agents in upper abdominal MRI studies. MATERIALS AND METHODS: Standardized (0.1 ml/kg) dose of gadobutrol (56 subjects) and gadoxetic acid (51 subjects) was administered intravenously by MRI-compatible injector at 2 ml/s, followed by 20 ml saline flush. MR signal intensity changes (SIC) between precontrast scans and arterial phase, portal venous phase, equilibrium, and delayed scans at 10 and 20 min were measured in abdominal aorta, portal vein, common bile duct, liver, and spleen. Mean SIC values for gadobutrol and gadoxetic acid were compared by a two-sample t-test with p-value <0.05 considered significant. RESULTS: In abdominal aorta, the mean SIC in the arterial phase did not significantly differ between gadobutrol (330%) and gadoxetic acid (295%). In portal vein, the mean SIC in the portal venous phase significantly differed between gadobutrol (267%) and gadoxetic acid (176%). Liver parenchyma enhancement was significantly higher for gadobutrol than for gadoxetic acid in both arterial phase (28 versus 13%) and portal venous phase (81 versus 46%). On the contrary, gadobutrol reached significantly lower mean SIC in the liver on delayed scans at 10 min (47 versus 59%) and 20 min (40 versus 67%), as well as in common bile duct at 10 min (54 versus 133%) and 20 min (57 versus 457%), respectively. In the spleen, mean SIC for gadobutrol was significantly higher at all phases. CONCLUSION: Gadobutrol showed superior enhancement of upper abdominal structures in the dynamic phases whereas gadoxetic acid showed better enhancement of the hepatobiliary structures on delayed scans.

• MeSH
• aorta abdominalis účinky léků   MeSH
• břicho patologie   MeSH
• diethylentriaminpentaacetát gadolinia diagnostické užití   MeSH
• dospělí MeSH
• ductus choledochus účinky léků   MeSH
• financování organizované MeSH
• injekce intravenózní MeSH
• interpretace obrazu počítačem MeSH
• játra účinky léků   MeSH
• kontrastní látky MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• mladiství MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vylepšení obrazu MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• srovnávací studie MeSH

• MeSH
• angiografie metody   využití   MeSH
• antitumorózní látky terapeutické užití   MeSH
• aorta abdominalis účinky léků   MeSH
• arteria hepatica účinky léků   MeSH
• arteria renalis účinky léků   MeSH
• lékařská onkologie metody   trendy   MeSH
• lidé MeSH
• nádory ledvin chirurgie   terapie   MeSH
• nefrektomie metody   využití   MeSH
• paliativní péče metody   využití   MeSH
• terapeutická embolizace metody   trendy   využití   MeSH
• urologické chirurgické výkony metody   trendy   využití   MeSH
• Check Tag
• lidé MeSH

• MeSH
• aorta abdominalis fyziologie   účinky léků   MeSH
• elektrická stimulace MeSH
• endotel fyziologie   MeSH
• hladké svalstvo fyziologie   účinky léků   MeSH
• králíci MeSH
• noradrenalin MeSH
• svalová kontrakce MeSH
• sympatický nervový systém fyziologie   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH