Acute excessive ethyl alcohol (ethanol) consumption alters cardiac electrophysiology and can evoke cardiac arrhythmias, e.g., in 'holiday heart syndrome'. Ethanol acutely modulates numerous targets in cardiomyocytes, including ion channels, Ca2+-handling proteins and gap junctions. However, the mechanisms underlying ethanol-induced arrhythmogenesis remain incompletely understood and difficult to study experimentally due to the multiple electrophysiological targets involved and their potential interactions with preexisting electrophysiological or structural substrates. Here, we employed cellular- and tissue-level in-silico analyses to characterize the acute effects of ethanol on cardiac electrophysiology and arrhythmogenesis. Acute electrophysiological effects of ethanol were incorporated into human atrial and ventricular cardiomyocyte computer models: reduced INa, ICa,L, Ito, IKr and IKur, dual effects on IK1 and IK,ACh (inhibition at low and augmentation at high concentrations), and increased INCX and SR Ca2+ leak. Multiscale simulations in the absence or presence of preexistent atrial fibrillation or heart-failure-related remodeling demonstrated that low ethanol concentrations prolonged atrial action-potential duration (APD) without effects on ventricular APD. Conversely, high ethanol concentrations abbreviated atrial APD and prolonged ventricular APD. High ethanol concentrations promoted reentry in tissue simulations, but the extent of reentry promotion was dependent on the presence of altered intercellular coupling, and the degree, type, and pattern of fibrosis. Taken together, these data provide novel mechanistic insight into the potential proarrhythmic interactions between a preexisting substrate and acute changes in cardiac electrophysiology. In particular, acute ethanol exposure has concentration-dependent electrophysiological effects that differ between atria and ventricles, and between healthy and diseased hearts. Low concentrations of ethanol can have anti-fibrillatory effects in atria, whereas high concentrations promote the inducibility and maintenance of reentrant atrial and ventricular arrhythmias, supporting a role for limiting alcohol intake as part of cardiac arrhythmia management.

• MeSH
• akční potenciály účinky léků   MeSH
• elektrofyziologické jevy účinky léků   MeSH
• ethanol škodlivé účinky   MeSH
• fibróza MeSH
• iontové kanály metabolismus   MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• lidé MeSH
• mezerový spoj účinky léků   metabolismus   MeSH
• počítačová simulace MeSH
• remodelace cév účinky léků   MeSH
• srdce účinky léků   patofyziologie   MeSH
• srdeční arytmie patologie   patofyziologie   MeSH
• srdeční síně účinky léků   patologie   patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Pulmonary arterial hypertension (PAH) remains a disease with limited therapeutic options and dismal prognosis. Despite its etiologic heterogeneity, the underlying unifying pathophysiology is characterized by increased vascular tone and adverse remodeling of the pulmonary circulation. Myeloperoxidase (MPO), an enzyme abundantly expressed in neutrophils, has potent vasoconstrictive and profibrotic properties, thus qualifying as a potential contributor to this disease. Here, we sought to investigate whether MPO is causally linked to the pathophysiology of PAH. Investigation of 2 independent clinical cohorts revealed that MPO plasma levels were elevated in subjects with PAH and predicted adverse outcome. Experimental analyses showed that, upon hypoxia, right ventricular pressure was less increased in Mpo-/- than in WT mice. The hypoxia-induced activation of the Rho-kinase pathway, a critical subcellular signaling pathway yielding vasoconstriction and structural vascular remodeling, was blunted in Mpo-/- mice. Mice subjected to i.v. infusion of MPO revealed activation of Rho-kinase and increased right ventricular pressure, which was prevented by coinfusion of the Rho-kinase inhibitor Y-27632. In the Sugen5416/hypoxia rat model, PAH was attenuated by the MPO inhibitor AZM198. The current data demonstrate a tight mechanistic link between MPO, the activation of Rho-kinase, and adverse pulmonary vascular function, thus pointing toward a potentially novel avenue of treatment.

• MeSH
• amidy aplikace a dávkování   MeSH
• arteria pulmonalis patologie   patofyziologie   MeSH
• dospělí MeSH
• hypoxie krev   etiologie   patologie   MeSH
• intravenózní infuze MeSH
• Kaplanův-Meierův odhad MeSH
• kinázy asociované s rho antagonisté a inhibitory   metabolismus   MeSH
• kohortové studie MeSH
• krysa rodu rattus MeSH
• lidé středního věku MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• peroxidasa aplikace a dávkování   krev   metabolismus   MeSH
• plíce patologie   MeSH
• plicní hypertenze krev   mortalita   patologie   patofyziologie   MeSH
• potkani Sprague-Dawley MeSH
• pyridiny aplikace a dávkování   MeSH
• rekombinantní proteiny aplikace a dávkování   krev   metabolismus   MeSH
• remodelace cév účinky léků   fyziologie   MeSH
• vazokonstrikce účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• krysa rodu rattus MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

We examined the upregulation of ET-1/ETBR/eNOS signaling in renoprotective effect of vitamin D in kidney fibrosis model in mice using unilateral ureteral obstruction (UUO). One group was treated with intraperitoneal injection of 0.125 mg/kg of Calcitriol (UUO+VD). Vascular remodeling was quantified based on lumen area and lumen/wall area ratio (LWAR) of intrarenal arteries using Sirius Red staining. ET-1, ETBR, eNOS, CD31 and VEGF mRNA expressions were quantified using qRT-PCR. Focusing on endothelin-1 (ET-1) signaling in endothelial cells (EC), siRNA of ET-1 was performed in human umbilical vein endothelial cells (HUVEC) for reducing ET-1 expression. Then HUVECs were treated with and without 100 nM Calcitriol treatment in hypoxic and normoxic conditions to elucidate ET-1/eNOS signaling. Our in vivo study revealed vascular remodeling and renal ischemia attenuation after Calcitriol treatment. Vascular remodeling was attenuated in the UUO+VD group as shown by increasing lumen areas and LWAR in intrarenal arteries. These findings were associated with significant higher CD31 and VEGF mRNA expression compared to the UUO group. Vitamin D treatment also increased ET-1, ETBR and eNOS mRNA expressions. Our in vitro study demonstrated Calcitriol induced ET-1 and eNOS mRNA expressions upregulation in HUVEC under normoxic and hypoxic condition. Meanwhile, siRNA for ET-1 inhibited the upregulation of eNOS mRNA expression after Calcitriol treatment. Vitamin D ameliorates kidney fibrosis through attenuating vascular remodeling and ischemia with upregulating ET-1/ETBR and eNOS expression.

• MeSH
• endoteliální buňky pupečníkové žíly (lidské) MeSH
• endotelin-1 biosyntéza   MeSH
• fibróza MeSH
• ischemie farmakoterapie   metabolismus   MeSH
• lidé MeSH
• messenger RNA biosyntéza   MeSH
• myši MeSH
• nemoci ledvin farmakoterapie   metabolismus   MeSH
• receptor endotelinu B biosyntéza   MeSH
• remodelace cév účinky léků   fyziologie   MeSH
• synthasa oxidu dusnatého, typ III biosyntéza   MeSH
• upregulace účinky léků   fyziologie   MeSH
• vitamin D farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Endothelin-1 (ET-1) induces pulmonary vascular remodeling and pulmonary hypertension secondary to pulmonary fibrosis. Given that endothelial cells are the main source of ET-1 and ET-1 from other cells may encounter difficulty penetrating vascular compartments, we hypothesize that endothelial-derived ET-1 promotes vascular remodeling secondary to pulmonary fibrosis. We used vascular endothelial ET-1 knock-out (VEETKO) and Wild type mice for this research. They were given intratracheal bleomycin and euthanized at day 28. We quantified pulmonary fibrosis, measured lung ET-1 and its receptors' expression, and assessed pulmonary vascular remodeling by calculating medial wall index, muscularization index, adventitial collagen and adventitial fibroblast and macrophage accumulation. Right ventricle remodeling was also assessed. Both VEETKO and Wild type mice developed comparable pulmonary fibrosis and similar fibrosis-related gene expression. Compared to Wild type mice, bleomycin-induced VEETKO mice had lower ET-1 peptide levels (15.4 pg/mg vs. 31.2 pg/mg, p<0.01). Expression of both ET-1 receptors mRNAs were increased in fibrosis models. Bleomycin-induced fibrosis VEETKO mice had significantly less muscularized arterioles, lower muscularization index and attenuated adventitial collagen, fibroblast and macrophage accumulation as compared to that of Wild type mice. Right ventricular pressure, hypertrophy and fibrosis did not increase both in VEETKO and Wild type mice despite the more enhanced vascular remodeling in Wild type. In conclusion, endothelial-derived endothelin-1 promotes pulmonary vascular remodeling secondary to bleomycin-induced pulmonary fibrosis.

• MeSH
• arteria pulmonalis účinky léků   metabolismus   patologie   MeSH
• bleomycin toxicita   MeSH
• cévní endotel metabolismus   patologie   MeSH
• endotelin-1 metabolismus   MeSH
• myši knockoutované MeSH
• myši transgenní MeSH
• myši MeSH
• plicní fibróza chemicky indukované   metabolismus   MeSH
• remodelace cév účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

AIM OF THE STUDY: Remodeling of pulmonary resistance arteries in rats due to 4-day hypoxia could be successfully suppressed by sodium cromoglycate. In this study, we tested the difference in the suppression between two distinct time patterns of cromoglycate administration during 21-day hypoxia. In the experiment, we focused on some details in both smooth muscle cells and extracellular matrix of pulmonary arterial walls. METHODS: During 21-day hypoxia, rats were treated with sodium cromoglycate either in the first four days or in the last four days. The first four days were chosen to test efficiency of an initial pulse of cromoglycate to suppress pulmonary vascular remodeling. The last four-day administration tested possibility to block remodeling post hoc. RESULTS: Initial pulse reduced and modified remodeling in all levels of pulmonary arteries, which comprises neomuscularization of prealveolar arteries, asymmetrical hypertrophy of tunica media in muscular pulmonary arteries and hypertrophy of tunica media and tunica adventitia in large conduit arteries. Terminal pulse had only negligible effect. CONCLUSIONS: Only the initial cromoglycate therapy led to significant morphological suppression of remodeling. We therefore assume important role of initial remodeling influencing during long time hypoxia experiment.

• MeSH
• arteria pulmonalis patologie   MeSH
• extracelulární matrix MeSH
• hypoxie farmakoterapie   MeSH
• kromoglykát dvojsodný farmakologie   MeSH
• krysa rodu rattus MeSH
• myocyty hladké svaloviny MeSH
• remodelace cév účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Acute dilation brought about by the dietary flavonoid quercetin in coronary arterioles has been described earlier, but no information is available on its chronic effects. Male Wistar rats (body weight about 190 g) were divided to two groups: the quercetin-treated group (n=22) had quercetin supplementation of approximately 30 mg/kg/day, whereas the control group (n=20) had none. After eight weeks of treatment, intramural coronary arterioles with identical passive diameters (178+/-14 microm and 171+/-9 microm) were prepared and their biomechanics and pharmacological reactivities were tested using pressure arteriography ex vivo. The spontaneous tone of quercetin-treated arteries was higher (16.5+/-1.9 % vs. 12.9+/-0.9 %), which resulted in a reduced lumen size (144+/-9 microm vs. 167+/-12 microm), thicker vascular wall (22.6+/-1.8 microm vs. 17.4+/-1.6 microm) and decreased tangential wall stress (16.8+/-1.1 kPa vs. 20.5+/-1.6 kPa) in supplemented animals (in spontaneous tone at 50 mm Hg, p<0.01 in all these comparisons). Elevated basal NO release resulted in increased endothelial dilation in quercetin-treated animals, especially at higher intraluminal pressures (10.8+/-2.5 % vs. 5.7+/-1.3 % at 70 mm Hg, p<0.01). We found remodeling of the geometry of coronary arterioles to ensure higher dilatory reserve and nitrogen monoxide production, as well as lowered elastic stress of the vessel wall.

• MeSH
• koronární cévy účinky léků   fyziologie   MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• quercetin aplikace a dávkování   MeSH
• remodelace cév účinky léků   fyziologie   MeSH
• rozvrh dávkování léků MeSH
• vazodilatace účinky léků   fyziologie   MeSH
• vazodilatancia aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

We evaluated the effects of N(G)-nitro-L-arginine methylester (L-NAME) (50 mg/kg/day) and 7-nitroindazole (7NI) (10 mg/kg/day) administered from 10th-16th week of age either individually or together on cardiovascular system of Wistar rats and SHR. Systolic blood pressure (sBP) was measured weekly by the plethysmographic method. For morphological studies, the animals (n=10) were perfused with a fixative (120 mm Hg), and thoracic aorta and carotid and coronary arteries were processed for electron microscopy. For functional investigation (n=10), aortic rings were used in an organ bath. In Wistar rats, L-NAME evoked an increase of sBP; hypertrophy of the heart and arterial walls; an increase in cross-sectional areas (CSA) of endothelial cells (EC), muscle cells (SMC), extracellular matrix (ECM), and a decrease in acetylcholine-induced endothelial-dependent relaxation (EDR). 7NI evoked sBP-independent hypotrophy of the heart and arterial walls, a decrease in CSA of EC and SMC without affecting the CSA of ECM, and a mild decrease in acetylcholine-induced EDR. 7NI and L-NAME administered together evoked lower effect on BP and trophicity of the heart and all arteries, and a similar decrease in acetylcholine-induced EDR compared to L-NAME alone. In SHR, 7NI did not evoke any effect on the studied parameters.

• MeSH
• aorta thoracica účinky léků   enzymologie   patofyziologie   ultrastruktura   MeSH
• arteriae carotides účinky léků   enzymologie   patofyziologie   ultrastruktura   MeSH
• hypertenze farmakoterapie   enzymologie   patologie   patofyziologie   MeSH
• indazoly farmakologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• kardiomegalie enzymologie   patologie   patofyziologie   prevence a kontrola   MeSH
• koronární cévy účinky léků   enzymologie   patofyziologie   ultrastruktura   MeSH
• krevní tlak účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• potkani inbrední SHR MeSH
• potkani Wistar MeSH
• remodelace cév účinky léků   MeSH
• remodelace komor účinky léků   MeSH
• srdeční komory účinky léků   enzymologie   patologie   patofyziologie   MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   metabolismus   MeSH
• vazodilatace účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH