Endothelin 1 (ET-1) seems essential in salt-dependent hypertension, and activation of ETA receptors causes renal vasoconstriction. However, the response in the renal medulla and the role of tissue NO availability has never been adequately explored in vivo. We examined effects of ETA and ETB receptor blockade (atrasentan and BQ788) on blood pressure (MAP), medullary blood flow (MBF) and medullary tissue NO. Effects of systemic and intramedullary blocker application were compared in anesthetized normotensive ET-1-pretreated Sprague-Dawley rats (S-D), in salt-dependent hypertension (HS/UNX) and in spontaneously hypertensive rats (SHR). Total renal blood flow (RBF) was measured using a Transonic renal artery probe, MBF as laser-Doppler flux, and tissue NO signal using selective electrodes. In normotensive rats ET-1 significantly increased MAP, decreased RBF (-20%) and renal medullary NO. In HS/UNX rats atrasentan decreased MAP and increased medullary NO, earlier and more profoundly with intravenous infusion. In SHR atrasentan decreased MAP, more effectively with intravenous infusion; the increase in tissue NO (∼10%) was similar with both routes; however, only intramedullary atrasentan increased MBF. No consistent responses to BQ788 were seen. We confirmed dominant role of ETA receptors in regulation of blood pressure and renal hemodynamics in normotensive and hypertensive rats and provided novel evidence for the role of ETA in control of intrarenal NO bioavailability in salt-dependent and spontaneous hypertension. Under conditions of activation of the endothelin system ETB stimulation preserved medullary perfusion.
- MeSH
- antagonisté endotelinového receptoru A farmakologie terapeutické užití MeSH
- antagonisté endotelinového receptoru B farmakologie terapeutické užití MeSH
- antihypertenziva farmakologie terapeutické užití MeSH
- atrasentan farmakologie terapeutické užití MeSH
- eliminace ledvinami účinky léků MeSH
- endotelin-1 farmakologie terapeutické užití MeSH
- hemodynamika účinky léků MeSH
- hypertenze farmakoterapie metabolismus MeSH
- krevní tlak účinky léků MeSH
- ledviny účinky léků metabolismus MeSH
- modely nemocí na zvířatech MeSH
- oligopeptidy farmakologie terapeutické užití MeSH
- oxid dusnatý metabolismus MeSH
- piperidiny farmakologie terapeutické užití MeSH
- potkani inbrední SHR MeSH
- potkani Sprague-Dawley MeSH
- receptor endotelinu A účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Endothelin-1 (ET-1) is a neuroactive protein produced in most brain cell types and participates in regulation of cerebral blood flow and blood pressure. In addition to its vascular effects, ET-1 affects synaptic and nonsynaptic neuronal and glial functions. Direct application of ET-1 to the hippocampus of immature rats results in cerebral ischemia, acute seizures, and epileptogenesis. Here, we investigated whether ET-1 itself modifies the excitability of hippocampal and cortical circuitry and whether acute seizures observed in vivo are due to nonvascular actions of ET-1. We used acute hippocampal and cortical slices that were preincubated with ET-1 (20 μM) for electrophysiological recordings. None of the slices preincubated with ET-1 exhibited spontaneous epileptic activity. The slope of the stimulus intensity-evoked response (input-output) curve and shape of the evoked response did not differ between ET-1-pretreated and control groups, suggesting no changes in excitability after ET-1 treatment. The threshold for eliciting an evoked response was not significantly increased in either hippocampal or cortical regions when pretreated with ET-1. Our data suggest that acute seizures after intrahippocampal application of ET-1 in rats are likely caused by ischemia rather than by a direct action of ET-1 on brain tissue.
- MeSH
- endotelin-1 farmakologie MeSH
- excitační postsynaptické potenciály fyziologie účinky léků MeSH
- hipokampus fyziologie účinky léků MeSH
- krysa rodu rattus MeSH
- nervový přenos fyziologie účinky léků MeSH
- potkani Wistar MeSH
- záchvaty chemicky indukované metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Plicní arteriální hypertenze (PAH) je primární onemocnění plicních arteriol, které vede k progredující prekapilární plicní hypertenzi a bez léčby relativně rychle k selhání pravé komory srdeční a k úmrtí nemocného. PAH vzniká buď z neznámé příčiny, nebo je asociována se známou vyvolávající příčinou (systémová onemocnění pojiva, jaterní onemocnění, vrozené zkratové srdeční vady, HIV infekce, abúzus některých anorektik). Současnou farmakoterapii PAH lze rozdělit na konvenční (léčba srdečního selhání, antikoagulační léčba, blokátory kalciových kanálů) a specifickou (prostanoidy, antagonisté endotelinových receptorů, inhibitory fosfodiesterázy 5). O způsobu léčby rozhoduje test akutní plicní vazodilatace. Pouze nemocní s pozitivním testem jsou indikováni k léčbě vysokými dávkami blokátorů kalciových kanálů. V případě negativního testu je vedle chronické antikoagulační léčby indikována specifická farmakoterapie jako monoterapie nebo jako kombinační léčba. K nově studovaným experimentálním léčebným možnostem u PAH patří agonisté receptorů pro prostacyklin, aktivátory a stimulátory solubilní guanylát cyklázy, statiny, antagonisté receptorů pro serotonin a blokátory serotoninového transportéru, inhibitory Rho-kinázy, vazoaktivní intestinální peptid nebo inhibitory tyrozin kinázy.
Pulmonary arterial hypertension (PAH) is a primary disease of pulmonary arterioles resulting in progressive precapillary pulmonary hypertension and, if untreated, it relatively rapidly leads to right ventricular failure and death. PAH either occurs due to unknown causes or is associated with a known cause (connective tissue disease, liver disease, congenital heart disease, HIV infection or abuse of some anorectic drugs). Current pharmacotherapy of PAH can be divided into conventional (treatment of heart failure, anticoagulation treatment, calcium channel blockers) and specific (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors). The method of treatment is determined by the use of acute pulmonary vasodilation testing. Treatment with high doses of calcium channel blockers is only indicated in patients with a positive test. Those who test negative receive, in addition to long-term anticoagulation treatment, a specific pharmacotherapy as monotherapy or combination therapy. Newly investigated experimental treatment options in PAH include prostacyclin receptor agonists, soluble guanylate cyclase activators and stimulators, statins, serotonin receptor antagonists and serotonin transporter blockers, Rho kinase inhibitors, vasoactive intestinal peptide or tyrosine kinase inhibitors.
- Klíčová slova
- Macientan,
- MeSH
- endotelin-1 antagonisté a inhibitory farmakologie fyziologie MeSH
- epoprostenol analogy a deriváty aplikace a dávkování farmakologie MeSH
- farmakoterapie metody MeSH
- inhibitory fosfodiesteras farmakologie terapeutické užití MeSH
- kombinovaná farmakoterapie MeSH
- léčivé přípravky MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- multicentrické studie jako téma MeSH
- plicní hypertenze farmakoterapie MeSH
- randomizované kontrolované studie jako téma MeSH
- zátěžový test MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
The aim of our study was to investigate mechanism of action of endothelins 1, 2 and 3 on spontaneous activity, tone and intraluminal pressure of human ureter. Both longitudinal tension and intraluminal pressure were recorded from the isolated segments of proximal human ureter. Endothelins 1, 2 and 3 (5.35x10-11 M - 5.05x10-8 M) produced concentration-dependent tonic contraction and sustained increase in intraluminal pressure of isolated preparations of human ureter. Endothelins 1 and 3 produced also concentration-dependent inhibition of spontaneous, phasic contractions of the isolated preparations. Selective antagonist of ETA receptors BQ123 and selective antagonist of ETB receptors BQ788 produced significant inhibition of endothelin-1-induced tonic contraction (pA2=8.80 and 6.55, respectively) and increase in intraluminal pressure (pA2=8.68 and 7.02, respectively), while they did not affect endothelin-1- induced inhibition of spontaneous activity. Endothelin 1 produces increase in tone and intraluminal pressure of isolated human ureter acting on both ETA and ETB receptors, the first one being functionally more important. Only endothelins 1 and 3 inhibit spontaneous, phasic activity of human ureter, but this effect was not blocked by selective antagonists of ETA and ETB receptors.
- MeSH
- endotelin-1 farmakologie fyziologie MeSH
- endotelin-2 farmakologie fyziologie MeSH
- endotelin-3 farmakologie fyziologie MeSH
- endoteliny farmakologie fyziologie MeSH
- hladké svalstvo fyziologie účinky léků MeSH
- lidé středního věku MeSH
- lidé MeSH
- receptory endotelinů antagonisté a inhibitory fyziologie MeSH
- senioři MeSH
- svalová kontrakce fyziologie účinky léků MeSH
- ureter fyziologie účinky léků MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
Plasma endothelin-1 (ET-1) levels are elevated in spinal cord injury (SCI), and ET-1 may be involved in the pathophysiology of this condition. However, its effects on contractile function of the heart of SCI rats are still unknown. To define more clearly the possiblel role of ET-1 following SCI, we investigated the effect of ET-1 on the contraction, calcium transients and L-type calcium current (ICa,L) in the cardiomyocytes of control and SCI rats. Sixteen Sprague-Dawley male rats aged 80-100 days and weighing 250-350 g were randomized into control and SCI groups. Fourteen days following compression injury to the spinal cord, effects of ET-1 on the contraction, calcium transients and ICa,L were studied in the cardiomyocytes of control and SCI rats by the technique of simultaneous measurement of intracellular Ca2+ and contraction and by whole-cell configuration of the patch-clamp technique. In myocytes from control rats, ET-1 significantly increased contraction, the magnitude of Ca2+ transients and the peak amplitude of ICa,L. However, ET-1 had little effect on the amplitude of contraction, calcium transients and ICa,L in myocytes from SCI rats. These results suggest that the positive inotropic effects of ET-1 on control myocardial contraction may be altered in pathological states such as SCI.
- MeSH
- endotelin-1 farmakologie fyziologie MeSH
- financování organizované MeSH
- kardiomyocyty cytologie fyziologie účinky léků MeSH
- kontrakce myokardu fyziologie účinky léků MeSH
- krysa rodu rattus MeSH
- metoda terčíkového zámku MeSH
- poranění míchy metabolismus patofyziologie MeSH
- potkani Sprague-Dawley MeSH
- vápník metabolismus MeSH
- vápníkové kanály - typ L fyziologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
Plicní arteriální hypertenze (PAH) je primární onemocnění plicních arteriol, které vede k progredující prekapilární plicní hypertenzi a bez léčby relativně rychle k selhání pravé komory srdeční a k úmrtí nemocného. PAH vzniká buď z neznámé příčiny, nebo je asociována se známou vyvolávající příčinou (systémová onemocnění pojiva, jaterní onemocnění, vrozené zkratové srdeční vady, HIV infekce, abúzus některých anorektik). Současnou farmakoterapii PAH lze rozdělit na konvenční (léčba srdečního selhání, antikoagulační léčba, blokátory kalciových kanálů) a specifickou (prostanoidy, antagonisté endotelinových receptorů, inhibitory fosfodiesterázy 5). O způsobu léčby rozhoduje test akutní plicní vazodilatace. Pouze nemocní s pozitivním testem jsou indikováni k léčbě vysokými dávkami blokátorů kalciových kanálů. V případě negativního testu je vedle chronické antikoagulační léčby indikována specifická farmakoterapie jako monoterapie nebo jako kombinační léčba. K nově studovaným experimentálním léčebným možnostem u PAH patří agonisté receptorů pro prostacyklin, aktivátory a stimulátory solubilní guanylát cyklázy, statiny, antagonisté receptorů pro serotonin a blokátory serotoninového transportéru, inhibitory Rho-kinázy, vazoaktivní intestinální peptid nebo inhibitory tyrozin kinázy.
Pulmonary arterial hypertension (PAH) is a primary disease of pulmonary arterioles resulting in progressive precapillary pulmonary hypertension and, if untreated, it relatively rapidly leads to right ventricular failure and death. PAH either occurs due to unknown causes or is associated with a known cause (connective tissue disease, liver disease, congenital heart disease, HIV infection or abuse of some anorectic drugs). Current pharmacotherapy of PAH can be divided into conventional (treatment of heart failure, anticoagulation treatment, calcium channel blockers) and specific (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors). The method of treatment is determined by the use of acute pulmonary vasodilation testing. Treatment with high doses of calcium channel blockers is only indicated in patients with a positive test. Those who test negative receive, in addition to long-term anticoagulation treatment, a specific pharmacotherapy as monotherapy or combination therapy. Newly investigated experimental treatment options in PAH include prostacyclin receptor agonists, soluble guanylate cyclase activators and stimulators, statins, serotonin receptor antagonists and serotonin transporter blockers, Rho kinase inhibitors, vasoactive intestinal peptide or tyrosine kinase inhibitors.
- Klíčová slova
- Macientan,
- MeSH
- endotelin-1 antagonisté a inhibitory farmakologie fyziologie MeSH
- epoprostenol analogy a deriváty aplikace a dávkování farmakologie MeSH
- farmakoterapie metody MeSH
- inhibitory fosfodiesteras farmakologie terapeutické užití MeSH
- kombinovaná farmakoterapie MeSH
- léčivé přípravky MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- multicentrické studie jako téma MeSH
- plicní hypertenze farmakoterapie MeSH
- randomizované kontrolované studie jako téma MeSH
- zátěžový test MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
We previously found that endothelin-1(1-31) (ET-1(1-31)) exhibited a pro-arrhythmogenic effect in isolated rat hearts. In this study, we further investigated the effects of ET-1(1-31) on a cell viability and observed [Ca(2+)](i) in cultured cardiomyocytes. Cultured neonatal rat cardiomyocytes were treated with 0.1, 1, and 10 nM ET-1(1-31) for 24h in the presence or absence of ET(A) receptor antagonist (BQ(123)) or phosphoramidon, a NEP/ECE inhibitor. Cell injury was evaluated by supernatant lactate dehydrogenase (LDH) assay, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) content. Cell viability was assessed by MTT assay. [Ca(2+)](i) was measured with Fluo-3/AM under a laser confocal microscope. 1) ET-1(1-31) dose-dependently increased LDH release and decreased cell viability. 2) LDH and MDA levels were significantly elevated and SOD activity decreased after administration of 1 nM ET-1(1-31) for 24h, and these changes were markedly attenuated by 1 uM BQ(123). 3) Exposure to 10 nM ET 1(1-31) caused a continuous increase in [Ca(2+)](i) to cultured beating cardiomyocytes and termination of [Ca(2+)](i) transient within 6 min, and this change was reversed by 1 uM BQ(123) and attenuated by 0.5 mM phosphoramidon. These results suggest that ET-1(1-31) could cause cell injury, and that the effect of ET-1(1-31) on [Ca(2+)](i) transients is mainly mediated by ET(A) receptor and partially attributed to the conversion of ET-1(1-31) to ET-1(1-21).
- MeSH
- aspartátové endopeptidasy antagonisté a inhibitory metabolismus MeSH
- časové faktory MeSH
- cyklické peptidy farmakologie MeSH
- endotelin-1 analogy a deriváty farmakologie MeSH
- financování organizované MeSH
- glykopeptidy farmakologie MeSH
- inhibitory proteas farmakologie MeSH
- kardiomyocyty enzymologie metabolismus účinky léků MeSH
- konfokální mikroskopie MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- L-laktátdehydrogenasa metabolismus MeSH
- malondialdehyd metabolismus MeSH
- metaloendopeptidasy antagonisté a inhibitory metabolismus MeSH
- novorozená zvířata MeSH
- peptidové fragmenty farmakologie MeSH
- potkani Sprague-Dawley MeSH
- receptor endotelinu A antagonisté a inhibitory metabolismus MeSH
- superoxiddismutasa metabolismus MeSH
- vápníková signalizace účinky léků MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
The goal of this study was to develop a new model of ischemia-induced seizures in immature rats using injection of vasoconstrictor Endothelin-1 (ET-1) into the brain. ET-1 (10, 20, or 40 pmol) was infused into the left dorsal hippocampus of freely moving Wistar rats 12 (P12) and 25 (P25) days old. Animals were then video/EEG-monitored for 100 min and monitoring was repeated 22 h later. Parameters of electrographic seizures (frequency and mean duration) as well as pattern of their behavioral correlates were evaluated. The pattern of behavioral seizures was used to develop model-specific scoring system. Cresyl violet and Fluoro Jade-B-staining were used to evaluate brain damage. Extension of the lesion was correlated with seizure severity. After ET-1-injection, seizures occurred in 83-100% animals of all age-and-dose groups and persisted for 24 h except P12 rats with 10 pmol. There were no differences in average seizure duration (18-40 s) or seizure frequency (3-7 seizures/100 min) among individual dose-groups. Between the 1st and 2nd observation period, total seizure duration decreased in 71% of P12 and 47% of P25 rats. Electrographic seizure activity was most frequently accompanied by clonus, incidence of more severe convulsions (barrel rolling or generalized clonic seizures) increased with dose of ET-1. Morphologic examination did not reveal any dose-related difference in damage severity, hippocampal damage was however more extensive in P12 compared to P25 animals. Seizure severity correlated positively with severity of the damage in both age groups. Our study presents focal injection of ET-1 into the brain as a new and practical model of ischemia-induced seizures in immature rats.
- MeSH
- elektroencefalografie statistika a číselné údaje MeSH
- endotelin-1 aplikace a dávkování farmakologie MeSH
- epilepsie chemicky indukované patofyziologie patologie MeSH
- financování organizované MeSH
- hipokampus patofyziologie patologie účinky léků MeSH
- injekce MeSH
- ischemie mozku chemicky indukované patofyziologie patologie MeSH
- krysa rodu rattus MeSH
- novorozená zvířata MeSH
- potkani Wistar MeSH
- videozáznam MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
