OBJECTIVES: To evaluate the base excess response during acute in vivo carbon dioxide changes. DESIGN: Secondary analysis of individual participant data from experimental studies. SETTING: Three experimental studies investigating the effect of acute in vivo respiratory derangements on acid-base variables. SUBJECTS: Eighty-nine (canine and human) carbon dioxide exposures. INTERVENTIONS: Arterial carbon dioxide titration through environmental chambers or mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: For each subject, base excess was calculated using bicarbonate and pH using a fixed buffer power of 16.2. Analyses were performed using linear regression with arterial dioxide (predictor), base excess (outcome), and studies (interaction term). All studies show different baselines and slopes for base excess across carbon dioxide titrations methods. Individual subjects show substantial, and potentially clinically relevant, variations in base excess response across the hypercapnic range. Using a mathematical simulation of 10,000 buffer power coefficients we determined that a coefficient of 12.1 (95% CI, 9.1-15.1) instead of 16.2 facilitates a more conceptually appropriate in vivo base excess equation for general clinical application. CONCLUSIONS: In vivo changes in carbon dioxide leads to changes in base excess that may be clinically relevant for individual patients. A buffer power coefficient of 16.2 may not be appropriate in vivo and needs external validation in a range of clinical settings.

• MeSH
• acidobazická rovnováha * fyziologie   MeSH
• dospělí MeSH
• hyperkapnie patofyziologie   metabolismus   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• oxid uhličitý * metabolismus   MeSH
• poruchy acidobazické rovnováhy patofyziologie   metabolismus   MeSH
• psi MeSH
• umělé dýchání MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• psi MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Nitric oxide (NO)-stimulated cyclic guanosine monophosphate (cGMP) is a key regulator of cardiovascular health, as NO-cGMP signalling is impaired in diseases like pulmonary hypertension, heart failure and chronic kidney disease. The development of NO-independent sGC stimulators and activators provide a novel therapeutic option to restore altered NO signalling. sGC stimulators have been already approved for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and chronic heart failure (HFrEF), while sGC activators are currently in phase-2 clinical trials for CKD. The best characterized effect of increased cGMP via the NO-sGC-cGMP pathway is vasodilation. However, to date, none of the sGC agonists are in development for hypertension (HTN). According to WHO, the global prevalence of uncontrolled HTN continues to rise, contributing significantly to cardiovascular mortality. While there are effective antihypertensive treatments, many patients require multiple drugs, and some remain resistant to all therapies. Thus, in addition to improved diagnosis and lifestyle changes, new pharmacological strategies remain in high demand. In this review we explore the potential of sGC stimulators and activators as novel antihypertensive agents, starting with the overview of NO-sGC-cGMP signalling, followed by potential mechanisms by which the increase in cGMP may regulate vascular tone and BP. These effects may encompass not only acute vasodilation, but also mid-term and chronic effects, such as the regulation of salt and water balance, as well as mitigation of vascular ageing and remodelling. The main section summarizes the preclinical and clinical evidence supporting the BP-lowering efficacy of sGC agonists.

• MeSH
• agonisté guanylátcyklasy terapeutické užití   farmakologie   MeSH
• aktivátory enzymů terapeutické užití   farmakologie   MeSH
• antihypertenziva * terapeutické užití   farmakologie   MeSH
• guanosinmonofosfát cyklický * metabolismus   MeSH
• hypertenze * farmakoterapie   patofyziologie   MeSH
• lidé MeSH
• oxid dusnatý metabolismus   MeSH
• rozpustná guanylátcyklasa * metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Adverse events during the perinatal period are associated with an increased risk to develop cardiometabolic diseases later in life. We established a murine model to study long-term effects of perinatal hypoxia (PH) on the pulmonary circulation. We previously demonstrated that PH led to an impaired regulation of pulmonary vascular tone in adulthood, linked to alterations in K+ channels in males and in the nitric oxide (NO)/cyclic guanosine monophosphate pathway in females. Moreover, simultaneous administration of inhaled NO (iNO) during PH exposure prevented adverse effects of PH on adult pulmonary vasculature in females. The present study showed that PH induced a significant increase in right ventricular pressure in males and females, and an enhanced sensitivity to acute hypoxia in females. PH significantly reduced acetylcholine-induced relaxation in pulmonary artery, to a greater extent in females than in males. PH led to right ventricular hypertrophy in adulthood, appearing earlier in males than in females. Morphometric measurements showed a significant increase in the number of 25-75-μm pulmonary vessels in male lungs following PH, probably resulting in increased pulmonary vascular resistance. The effects of prolonged hypoxia in adulthood differed between males and females. Perinatal iNO during PH prevented PH-induced alterations in the cardiopulmonary system, whereas perinatal iNO alone could have some adverse effects. Therefore, PH led to long-lasting alterations in the regulation of adult pulmonary circulation, which vary between males and females. In males, the increased pulmonary vascular resistance was associated with morphological changes besides functional alterations, whereas females showed an important pulmonary vascular dysfunction. Keywords: Perinatal hypoxia, Pulmonary circulation, Endothelium-dependent relaxation, Phosphodiesterases, Sex differences.

• MeSH
• arteria pulmonalis metabolismus   patofyziologie   účinky léků   MeSH
• cévní rezistence fyziologie   MeSH
• hypoxie * patofyziologie   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• novorozená zvířata MeSH
• oxid dusnatý metabolismus   MeSH
• plicní oběh * fyziologie   MeSH
• pohlavní dimorfismus MeSH
• sexuální faktory MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease with unknown cause. It mainly affects joints and, without proper treatment, negatively impacts their movement, causes painful deformities, and reduces the patients' quality of life. Current treatment options consist of various types of disease-modifying antirheumatic drugs (DMARDs), however 20-30% of patients are partially resistant to them. Therefore, development of new drugs is necessary. Possible option are compounds exhibiting their action via endocannabinoid system, which plays an important role in pain and inflammation modulation. One such compound - cannabidiol (CBD) has already been shown to attenuate synovitis in animal model of RA in in vivo studies. However, it has low bioavailability due to its low water solubility and lipophilicity. This issue can be addressed by preparation of a lipid containing formulation targeting lymphatic system, another route of absorption in the body. Materials and Methods: CBD-containing emulsion was prepared by high-shear homogenization and its droplet size distribution was analysed by optical microscopy. The relative oral bioavailability compared to oil solution as well as total availability of CBD were assessed in a cross-over study in rats and absorption of CBD via lymphatic system was observed. The effect of CBD on the animal model of RA was determined. Results: Compared to oil solution, the emulsion exhibited higher absolute oral bioavailability. Significant lymphatic transport of CBD was observed in all formulations and the concentrations in lymph were calculated. The therapeutic effect of CBD on RA was confirmed as an improvement in clinical symptoms as well as morphological signs of disease activity were observed during the study. Conclusion: In this work, we prepared a simple stable emulsion formulation, determined the pharmacokinetic parameters of CBD and calculated its absolute bioavailability in rats. Moreover, we successfully tested the pharmaceutical application of such a formulation and demonstrated the positive effect of CBD in an animal model of RA.

• MeSH
• aplikace orální MeSH
• bolest farmakoterapie   MeSH
• emulze MeSH
• kanabidiol * farmakologie   chemie   MeSH
• klinické křížové studie MeSH
• krysa rodu rattus MeSH
• kvalita života MeSH
• revmatoidní artritida * farmakoterapie   MeSH
• voda MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In contrast to conventional diffusion magnetic resonance imaging (MRI), multi-b-value diffusion MRI methods are able to separate the signal from free water, pseudo-diffusion, and non-Gaussian components of water molecule diffusion. These approaches can then be utilised in so-called intravoxel incoherent motion imaging and diffusion kurtosis imaging. Various parameters provided by these methods can describe additional characteristics of the tissue microstructure and potentially help in the diagnosis and classification of various pathological processes. In this review, we present the basic principles and methods of analysing multi-b-value diffusion imaging data and specifically focus on the known possibilities for its use in the diagnosis of brain lesions. We also suggest possible directions for further research.

• MeSH
• difuzní magnetická rezonance * metody   MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• mozek diagnostické zobrazování   MeSH
• nemoci nervového systému * MeSH
• pohyb těles MeSH
• senzitivita a specificita MeSH
• voda MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• MeSH
• hodnocení rizik MeSH
• lidé MeSH
• oxid uhličitý * MeSH
• předoperační péče * metody   MeSH
• spotřeba kyslíku MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• dopisy MeSH
• komentáře MeSH
• úvodníky 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.

• 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

Viral infection may represent a stress condition to the host cell. Cells react to it by triggering the defence programme to restore homeostasis and these events may in turn impact the viral replication. The knowledge about tick-borne encephalitis virus (TBEV) infection-associated stress is limited. Here we investigated the interplay between TBEV infection and stress pathways in PMJ2-R mouse macrophage cell line, as macrophages are the target cells in early phases of TBEV infection. First, to determine how stress influences TBEV replication, the effect of stress inducers H2O2 and tunicamycin (TM) was tested. Viral multiplication was decreased in the presence of both stress inducers suggesting that the stress and cellular stress responses restrict the virus replication. Second, we investigated the induction of oxidative stress and endoplasmic reticulum (ER) stress upon TBEV infection. The level of oxidative stress was interrogated by measuring the reactive oxygen species (ROS). ROS were intermittently increased in infected cells at 12 hpi and at 72 hpi. As mitochondrial dysfunction may result in increased ROS level, we evaluated the mitochondrial homeostasis by measuring the mitochondrial membrane potential (MMP) and found that TBEV infection induced the hyperpolarization of MMP. Moreover, a transient increase of gene expression of stress-induced antioxidative enzymes, like p62, Gclm and Hmox1, was detected. Next, we evaluated the ER stress upon TBEV infection by analysing unfolded protein responses (UPR). We found that infection induced gene expression of two general sensors BiP and CHOP and activated the IRE1 pathway of UPR. Finally, since the natural transmission route of TBEV from its tick vector to the host is mediated via tick saliva, the impact of tick saliva from Ixodes ricinus on stress pathways in TBEV-infected cells was tested. We observed only marginal potentiation of UPR pathway. In conclusion, we found that TBEV infection of PMJ2-R cells elicits the changes in redox balance and triggers cellular stress defences, including antioxidant responses and the IRE1 pathway of UPR. Importantly, our results revealed the negative effect of stress-evoked events on TBEV replication and only marginal impact of tick saliva on stress cellular pathways.

• MeSH
• buněčné linie MeSH
• klíšťová encefalitida * MeSH
• myši MeSH
• peroxid vodíku metabolismus   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• replikace viru MeSH
• viry klíšťové encefalitidy * genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Pružnosť ciev je významným rizikovým faktorom kardiovaskulárnych ochorení (KVO), ktoré sú najčastejšou príčinou úmrtí v rozvinutých krajinách. Na základe merania pružnosti ciev obyvateľov zásobovaných mäkkou pitnou vodou (100 respondentov) a tvrdou pitnou vodou (100 respondentov) bol zistený výrazný rozdiel v rýchlosti pulznej vlny (PWVao), arteriálneho veku a v rozdieli medzi arteriálnym a skutočným vekom (∆ vek). U respondentov, ktorí konzumovali mäkkú pitnú vodu, bola PWVao o 1,9 m.s−1 vyššia, arteriálny vek o 23,2 rokov vyšší a ∆ vek o 14,5 roka vyšší. Respondentom pôvodne konzumujúcim mäkkú pitnú vodu bol obsah Ca a Mg v pitnej vode zvýšený o približne 10–15 mg.l−1. Po 18 mesiacoch konzumácie obohatenej pitnej vody so zvýšeným obsahom Ca a Mg sa respondentom pôvodne konzumujúcim mäkkú pitnú vodu PWVao znížila o 0,93 m.s−1, arteriálny vek sa znížil o 10,42 roka a ∆ vek sa znížil o 11,79 roka. Veľmi výrazne sa im tak znížilo riziko vzniku KVO.

Arterial stiffness is a significant risk factor for cardiovascular diseases (CVD), which are the most common cause of death in developed countries. Based on measurements of arterial stiffness in inhabitants supplied with soft drinking water (100 respondents) and hard drinking water (100 respondents), a significant difference in pulse wave velocity (PWVao), arterial age, and the difference between arterial and actual age (Δ age) was found. In the respondents consuming soft drinking water, PWVao was 1.9 m.s-1 higher, arterial age was 23 years higher, and Δ age was 14.5 years higher. The respondents originally consuming soft drinking water, had the content of Ca and Mg in their water increased by approximately 10-15 mg.l-1. After 18 months of consuming enriched drinking water with increased Ca and Mg content, PWVao in the respondents originally consuming soft drinking water decreased by 0.93 m.s-1, arterial age decreased by 10.42 years, and Δ age decreased by 11.79 years. Their risk of developing CVD thus decreased significantly.

• MeSH
• hořčík MeSH
• kardiovaskulární nemoci prevence a kontrola   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• pitná voda * analýza   MeSH
• tuhost cévní stěny MeSH
• vápník dietní MeSH
• Check Tag
• lidé MeSH
• Geografické názvy
• Slovenská republika MeSH

Long-term peritoneal dialysis is associated with the development of peritoneal membrane alterations, both in morphology and function. Impaired ultrafiltration (UF) is the most important functional change, and peritoneal fibrosis is the major morphological alteration. Both are caused by the continuous exposure to dialysis solutions that are different from plasma water with regard to the buffer substance and the extremely high-glucose concentrations. Glucose has been incriminated as the major cause of long-term peritoneal membrane changes, but the precise mechanism has not been identified. We argue that glucose causes the membrane alterations by peritoneal pseudohypoxia and by the formation of advanced glycosylation end products (AGEs). After a summary of UF kinetics including the role of glucose transporters (GLUT), and a discussion on morphologic alterations, relationships between function and morphology and a survey of the pathogenesis of UF failure (UFF), it will be argued that impaired UF is partly caused by a reduction in small pore fluid transport as a consequence of AGE-related vasculopathy and - more importantly - in diminished free water transport due to pseudohypoxia, caused by increased peritoneal cellular expression of GLUT-1. The metabolism of intracellular glucose will be reviewed. This occurs in the glycolysis and in the polyol/sorbitol pathway, the latter is activated in case of a large supply. In both pathways the ratio between the reduced and oxidised form of nicotinamide dinucleotide (NADH/NAD+ ratio) will increase, especially because normal compensatory mechanisms may be impaired, and activate expression of hypoxia-inducible factor-1 (HIF-1). The latter gene activates various profibrotic factors and GLUT-1. Besides replacement of glucose as an osmotic agent, medical treatment/prevention is currently limited to tamoxifen and possibly Renin/angiotensis/aldosteron (RAA) inhibitors.

• MeSH
• dialyzační roztoky škodlivé účinky   metabolismus   MeSH
• glukosa škodlivé účinky   metabolismus   MeSH
• glykosylace MeSH
• lidé MeSH
• peritoneální dialýza * škodlivé účinky   MeSH
• peritoneum metabolismus   MeSH
• ultrafiltrace MeSH
• voda metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH