RÉSUMÉ
OBJECTIVES: The modulatory effect of deep inspiration (DI) on airway constriction is impaired in asthma. However, mechanisms underlying this impairment are not clear. Since there is evidence indicating that Rho-kinase activation mediates force maintenance under oscillatory strain, we investigated the impact of Rho-kinase inhibition on the bronchodilatory effect of DI in ovalbumin (OVA) sensitized guinea pigs. MATERIALS AND METHODS: forty-eight male Dunkin Hartley guinea pigs were divided into 8 groups including saline/ constant, saline/DI, OVA/constant, OVA/DI, Rho-I/OVA/constant, Rho-I/OVA/DI, OVA-Rho-I/MCh/constant, and OVA-Rho-I/MCh/DI. Animals were subjected to 12 inhalations of OVA or saline aerosol. Guinea pigs in Rho-I/OVA/constant or DI groups were treated with the Rho-kinase inhibitor (Rho-I) (Y-27632, 1 mM aerosols) prior to the last 8 allergen inhalations and OVA-Rho-I/MCh/constant or DI groups received Y-27632 at the end of allergen sensitization protocol before methacholine challenge. The bronchodilatory effect of DI in guinea pigs that were exposed to methacholine was assessed by using an animal ventilator. The bronchodilatory effect was assessed using several parameters: the airway pressure maintenance, airway pressure recovery, and decline of airway pressure. RESULTS: Results indicated that application of Y-27632 prior to methacholine challenge reduces the airway smooth muscle ability to maintain pressure and also causes further decline in airway pressure in OVA-sensitized animals undergone DI. However, the inhibition of Rho-kinase before OVA inhalations had minimal effect. CONCLUSION: We propose that alteration of Rho-kinase signaling pathway may be one of the mechanisms underlying the impairment of DI-induced bronchodilation in OVA-sensitized guinea pigs.
RÉSUMÉ
Asthma represents an episodic and fluctuating behavior characterized with decreased complexity of respiratory dynamics. Several evidence indicate that asthma severity or control is associated with alteration in variability of lung function. The pathophysiological basis of alteration in complexity of breathing pattern in asthma has remained poorly understood. Regarding the point that Rho-kinase is involved in pathophysiology of asthma, in present study we investigated the effect of Rho-kinase inhibition on complexity of respiratory dynamics in a guinea pig model of asthma. Male Dunkin Hartley guinea pigs were exposed to 12 series of inhalations with ovalbumin or saline. Animals were treated by the Rho-kinase inhibitor Y-27632 (1mM aerosols) prior to each allergen challenge. We recorded respiration of conscious animals using whole-body plethysmography. Exposure to ovalbumin induced lung inflammation, airway hyperresponsiveness and remodeling including goblet cell hyperplasia, increase in the thickness of airways smooth muscles and subepithelial collagen deposition. Complexity analysis of respiratory dynamics revealed a dramatic decrease in irregularity of respiratory rhythm representing less complexity in asthmatic guinea pigs. Inhibition of Rho-kinase reduced the airway remodeling and hyperreponsiveness, but had no significant effect on lung inflammation and complexity of respiratory dynamics in asthmatic animals. It seems that airway hyperresponsiveness and remodeling do not significantly affect the complexity of respiratory dynamics. Our results suggest that inflammation might be the probable cause of shift in the respiratory dynamics away from the normal fluctuation in asthma.
Sujet(s)
Asthme/physiopathologie , Respiration/effets des médicaments et des substances chimiques , rho-Associated Kinases/antagonistes et inhibiteurs , Amides/pharmacologie , Animaux , Asthme/traitement médicamenteux , Modèles animaux de maladie humaine , Cochons d'Inde , Mâle , Pléthysmographie du corps entier , Pyridines/pharmacologie , Phénomènes physiologiques respiratoires/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND: Several lines of evidence revealed that chronic treatment of anabolic androgenic steroids (AASs) is accompanied with some cardiovascular side effects and in addition they also negatively mask the beneficial effects of exercise training on cardiac performance. METHODS: The present study examined whether the nandrolone decanoate (ND)-induced cardiac effects were mediated by changing the cardiac uncoupling protein 2 (UCP2) and 3 (UCP3) expression. Five groups of male wistar-albino rats including sedentary control (SC), sedentary vehicle (SV), sedentary nandrolone decanoate (SND), exercise control (EC), and exercise nandrolone decanoate (END) were used. ND was injected (10 mg/kg/week, intramuscular) to the animals in the SND and END groups and endurance exercise training was performed on a treadmill five times per week. RESULTS: The protein expressions of cardiac UCP2 and UCP3 have significantly increased in both the SND and EC groups compared to the SC ones. In contrast to UCP3, no significant differences were found between UCP2 protein expressions of the END and SC groups. Compared with the SND group, the exercise training significantly decreased the UCP2 and UCP3 protein expressions in the END group. CONCLUSIONS: The study has indicated that endurance exercise in combination with ND can result in that the exercise effectively antagonizes the effects of ND treatment on UCP2 and UCP3 up-regulation.
Sujet(s)
Myocarde/métabolisme , Nandrolone/analogues et dérivés , Conditionnement physique d'animal , Protéine-2 de découplage/biosynthèse , Protéine-3 de découplage/biosynthèse , Régulation positive/effets des médicaments et des substances chimiques , Animaux , Poids/effets des médicaments et des substances chimiques , Coeur/effets des médicaments et des substances chimiques , Mâle , Nandrolone/antagonistes et inhibiteurs , Nandrolone/pharmacologie , Décanoate de nandrolone , Taille d'organe/effets des médicaments et des substances chimiques , RatsRÉSUMÉ
The impact of mechanical forces on pathogenesis of airway remodeling and the functional consequences in asthma remains to be fully established. In the present study, we investigated the effect of repeated bronchoconstriction induced by methacholine (MCh) on airway remodeling and airway hyperresponsiveness (AHR) in rats with or without sensitization to an external allergen. We provide evidence that repeated bronchoconstriction, using MCh, alone induces airway inflammation and remodeling as well as AHR in non-allergen-sensitized rats. Also, we found that the airways are structurally and functionally altered by bronchoconstriction induced by either allergen or MCh in allergen-sensitized animals. This finding provides a new animal model for the development of airway remodeling and AHR in mammals and can be used for studying the complex reciprocal relationship between bronchoconstriction and airway inflammation. Further studies on presented animal models are required to clarify the exact mechanisms underlying airway remodeling due to bronchoconstriction and the functional consequences.
Sujet(s)
Remodelage des voies aériennes/effets des médicaments et des substances chimiques , Bronchoconstriction/effets des médicaments et des substances chimiques , Bronchoconstricteurs/pharmacologie , Inflammation/anatomopathologie , Chlorure de méthacholine/pharmacologie , Hypersensibilité respiratoire/induit chimiquement , Actines/métabolisme , Allergènes/immunologie , Animaux , Granulocytes éosinophiles/anatomopathologie , Inflammation/induit chimiquement , Poumon/anatomopathologie , Mâle , Phénomènes mécaniques , Ovalbumine/immunologie , Rats , Rat Sprague-Dawley , Hypersensibilité respiratoire/immunologie , Hypersensibilité respiratoire/anatomopathologieRÉSUMÉ
Glutamatergic synapses are shown to mature during activity and development. In order to further explore how glutamate can change the excitability of noradrenergic neurons of locus coeruleus (LC) and to better understand the involvement of Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors complements across the LC, we investigated developmental changes in their activity during first postnatal weeks. Spontaneous and evoked excitatory postsynaptic currents (sEPSC and eEPSCs) were recorded in neurons of LC slices from 7, 14 and 21 days old rats using the whole cell patch clamp method. Also, the AMPA/NMDA current ratio (A/N) was measured. A pronounced AMPAR and NMDAR components mediated involvement in synaptic transmission were seen from the first postnatal week. Over this period of development, we have demonstrated that AMPA sEPSCs show an increase in frequency without major changes in their amplitude, while NMDA sEPSCs show an increase in frequency with a major change in amplitude. Neither the probability of release nor the AMPA/NMDA ratio was found to change significantly with age. It is concluded that NMDAR activity as well as AMPAR activity may be involved in coerulear excitability and modulatory effect during postnatal development.
Sujet(s)
Potentiels post-synaptiques excitateurs , Locus ceruleus/croissance et développement , Locus ceruleus/physiologie , Neurones/physiologie , Récepteur de l'AMPA/physiologie , Récepteurs du N-méthyl-D-aspartate/physiologie , Animaux , Mâle , Rats , Rat WistarRÉSUMÉ
ATP-sensitive potassium channels are supposed to have a substantial role in improvement of cardiac performance. This study was performed to evaluate whether nandrolone decanoate (ND) and (or) exercise training could affect the expression of cardiac K(ATP) channel subunits. Thirty-five male albino Wistar rats were randomly divided into 5 groups, including sedentary control (SC), sedentary vehicle (SV), sedentary ND (SND), exercise control (EC), and exercise and ND (E+ND). Exercise training was performed on a treadmill 5 times per week. ND was injected (10 mg/kg/week, i.m.) to the rats in the SND and E+ND groups. Following cardiac isolation, the expression of both sarcolemmal and mitochondrial subunits of K(ATP) channel was measured using Western blot method. The expression of sarcolemmal, but not mitochondrial, subunits of K(ATP) channel (Kir6.2 and SUR2) of EC group was significantly higher compared with SC group while ND administration (SND group) did not show any change in their expression. In the E+ND group, ND administration led to decrease of the over-expression of sarcolemmal Kir6.2 and SUR2 which was previously induced by exercise. There was no significant association between the mitochondrial expression of either Kir6.2 or SUR2 proteins and administration of ND or exercise. Supra-physiological dosage of ND negatively reverses the effects of exercise on the cardiac muscle expression of sarcolemmal, but not mitochondrial, K(ATP) channel subunits.
Sujet(s)
Canaux KATP/métabolisme , Mitochondries/effets des médicaments et des substances chimiques , Myocarde/métabolisme , Nandrolone/analogues et dérivés , Conditionnement physique d'animal/physiologie , Canaux potassiques/métabolisme , Sarcolemme/effets des médicaments et des substances chimiques , Transporteurs ABC/métabolisme , Adénosine triphosphate/métabolisme , Animaux , Coeur/effets des médicaments et des substances chimiques , Mâle , Mitochondries/métabolisme , Nandrolone/pharmacologie , Décanoate de nandrolone , Canaux potassiques rectifiants entrants/métabolisme , Rats , Rat Wistar , Sarcolemme/métabolismeRÉSUMÉ
Normal human breathing exhibits complex variability in both respiratory rhythm and volume. Analyzing such nonlinear fluctuations may provide clinically relevant information in patients with complex illnesses such as asthma. We compared the cycle-by-cycle fluctuations of inter-breath interval (IBI) and lung volume (LV) among healthy volunteers and patients with various types of asthma. Continuous respiratory datasets were collected from forty age-matched men including 10 healthy volunteers, 10 patients with controlled atopic asthma, 10 patients with uncontrolled atopic asthma, and 10 patients with uncontrolled non-atopic asthma during 60 min spontaneous breathing. Complexity of breathing pattern was quantified by calculating detrended fluctuation analysis, largest Lyapunov exponents, sample entropy, and cross-sample entropy. The IBI as well as LV fluctuations showed decreased long-range correlation, increased regularity and reduced sensitivity to initial conditions in patients with asthma, particularly in uncontrolled state. Our results also showed a strong synchronization between the IBI and LV in patients with uncontrolled asthma. Receiver operating characteristic (ROC) curve analysis showed that nonlinear analysis of breathing pattern has a diagnostic value in asthma and can be used in differentiating uncontrolled from controlled and non-atopic from atopic asthma. We suggest that complexity analysis of breathing dynamics may represent a novel physiologic marker to facilitate diagnosis and management of patients with asthma. However, future studies are needed to increase the validity of the study and to improve these novel methods for better patient management.
Sujet(s)
Asthme/diagnostic , Respiration , Fréquence respiratoire/physiologie , Volume courant/physiologie , Adulte , Asthme/physiopathologie , Études cas-témoins , Humains , Mâle , Dynamique non linéaire , Pléthysmographie , Courbe ROCRÉSUMÉ
Decreased heart rate variability (HRV) has both diagnostic and prognostic value in patients with sepsis. However, it is not known whether reduced HRV in sepsis reflects an altered input from the autonomic nervous system or a remodeling of the cardiac pacemaker cells by inflammatory mediators. The present study aimed to investigate the effect of endotoxin on the heart rate dynamics of a denervated isolated heart in rats. Saline or endotoxin was injected into rats and their hearts were isolated and perfused. Atrial electrical activity was recorded and memory length in the time-series was assessed using inverse statistical analysis. Memory was defined as a statistical feature that lasts for a period of time and distinguishes the time-series from a random process. Endotoxaemic hearts exhibited a prolonged memory compared to the controls with respect to observing rare events. This indicates that a sudden decelerating event could potentially affect the cardiac rhythm of an endotoxaemic heart for a longer time than the controls. The prolongation of memory is indirectly linked to a reduced controllability in a complex system; therefore our data may provide evidence for a reduced controllability in cardiac rhythm following endotoxaemia.
Sujet(s)
Agents cardiovasculaires/pharmacologie , Endotoxines/pharmacologie , Rythme cardiaque/effets des médicaments et des substances chimiques , Analyse de variance , Animaux , Endotoxémie/physiopathologie , Entropie , Coeur/effets des médicaments et des substances chimiques , Coeur/physiologie , Modèles linéaires , Mâle , Dynamique non linéaire , Probabilité , Rats , Rat Sprague-Dawley , Facteurs tempsRÉSUMÉ
BACKGROUND AND AIMS: The aim of this study was to investigate the early changes of cardiac uncoupling protein-2 (UCP2) expression following myocardial ischemia reperfusion in rats chronically treated with ramiprilat and losartan. METHODS: Male Wistar rats were assigned into seven groups (six in each): intact (control); sham-operated; nontreated rats subjected to ischemia and reperfusion (IR); ramiprilat-treated rats with (Ram+IR) and without ischemia (Ram); losartan treated with (Los+IR) and without ischemia (Los). Quantitative evaluation of UCP2 mRNA was carried out using real-time reverse transcription-polymerase chain reaction (RT-PCR). Mitochondria were isolated, and protein expression was quantified by Western blotting. RESULTS: In IR group: UCP2 protein but not mRNA level was increased in the ischemic area of the left ventricle (LV) (172% ± 26.7, p < 0.001 vs. LV of control). Following acute myocardial IR, UCP2 protein levels was increased in the ischemic area of the LV but not in RV, suggesting the local effect of ischemia on UCP2 expression. IR-induced overexpression of UCP2 was suppressed by ramiprilat and losartan. CONCLUSION: These findings suggest that losartan and ramiprilat can suppress UCP2 expression following myocardial IR, and by this mechanism may protect the myocardium against IR injury.
Sujet(s)
Analyse de profil d'expression de gènes , Canaux ioniques/génétique , Losartan/usage thérapeutique , Protéines mitochondriales/génétique , Lésion de reperfusion myocardique/traitement médicamenteux , Lésion de reperfusion myocardique/génétique , Ramipril/analogues et dérivés , Animaux , Pression sanguine/effets des médicaments et des substances chimiques , Rythme cardiaque/effets des médicaments et des substances chimiques , Hémodynamique/effets des médicaments et des substances chimiques , Canaux ioniques/métabolisme , Losartan/pharmacologie , Mâle , Protéines mitochondriales/métabolisme , Lésion de reperfusion myocardique/physiopathologie , ARN messager/génétique , ARN messager/métabolisme , Ramipril/pharmacologie , Ramipril/usage thérapeutique , Rat Wistar , Transcription génétique/effets des médicaments et des substances chimiques , Protéine-2 de découplageRÉSUMÉ
Previous reports have indicated that artificial stimulation of the vagus nerve reduces systemic inflammation in experimental models of sepsis. This phenomenon is a part of a broader cholinergic anti-inflammatory pathway which activates the vagus nerve to modulate inflammation through activation of alpha7 nicotinic acetylcholine receptors (α7nACHR). Heart rate variability represents the complex interplay between autonomic nervous system and cardiac pacemaker cells. Reduced heart rate variability and increased cardiac cycle regularity is a hallmark of clinical conditions that are associated with systemic inflammation (e.g. endotoxemia and sepsis). The present study was aimed to assess the role of α7nACHR in modulation of heart rate dynamics during systemic inflammation. Systemic inflammation was induced by injection of endotoxin (lipopolysaccharide) in rats. Electrocardiogram and body temperature were recorded in conscious animals using a telemetric system. Linear and non-linear indices of heart rate variability (e.g. sample entropy and fractal-like temporal structure) were assessed. RT-PCR and immunohistochemistry studies showed that α7nACHR is expressed in rat atrium and is mainly localized at the endothelial layer. Systemic administration of an α7nACHR antagonist (methyllycaconitine) did not show a significant effect on body temperature or heart rate dynamics in naïve rats. However, α7nACHR blockade could further reduce heart rate variability and elicit a febrile response in endotoxemic rats. Pre-treatment of endotoxemic animals with an α7nACHR agonist (PHA-543613) was unable to modulate heart rate dynamics in endotoxemic rats but could prevent the effect of endotoxin on body temperature within 24 h experiment. Neither methyllycaconitine nor PHA-543613 could affect cardiac beating variability of isolated perfused hearts taken from control or endotoxemic rats. Based on our observations we suggest a tonic role for nicotinic acetylcholine receptors in modulation of heart rate dynamics during systemic inflammation.
Sujet(s)
Composés hétérocycliques bicycliques/pharmacologie , Endotoxémie/métabolisme , Endotoxémie/physiopathologie , Rythme cardiaque/effets des médicaments et des substances chimiques , Myocarde/métabolisme , Quinuclidines/pharmacologie , Récepteur nicotinique de l'acétylcholine alpha7 , Animaux , Endotoxémie/induit chimiquement , Atrium du coeur/métabolisme , Atrium du coeur/anatomopathologie , Atrium du coeur/physiopathologie , Lipopolysaccharides/toxicité , Mâle , Myocarde/anatomopathologie , Rats , Rat Sprague-Dawley , Récepteur nicotinique de l'acétylcholine alpha7/agonistes , Récepteur nicotinique de l'acétylcholine alpha7/biosynthèseRÉSUMÉ
In a time-series, memory is a statistical feature that lasts for a period of time and distinguishes the time-series from a random, or memory-less, process. In the present study, the concept of "memory length" was used to define the time period, or scale over which rare events within a physiological time-series do not appear randomly. The method is based on inverse statistical analysis and provides empiric evidence that rare fluctuations in cardio-respiratory time-series are 'forgotten' quickly in healthy subjects while the memory for such events is significantly prolonged in pathological conditions such as asthma (respiratory time-series) and liver cirrhosis (heart-beat time-series). The memory length was significantly higher in patients with uncontrolled asthma compared to healthy volunteers. Likewise, it was significantly higher in patients with decompensated cirrhosis compared to those with compensated cirrhosis and healthy volunteers. We also observed that the cardio-respiratory system has simple low order dynamics and short memory around its average, and high order dynamics around rare fluctuations.
Sujet(s)
Mémoire/physiologie , Modèles biologiques , Adulte , Algorithmes , Asthme/physiopathologie , Volontaires sains , Rythme cardiaque , Humains , Cirrhose du foie/physiopathologie , Modèles statistiques , Probabilité , Respiration , Facteurs temps , Jeune adulteRÉSUMÉ
BACKGROUND AND OBJECTIVE: Respiratory inductive plethysmography is a non-invasive technique for measuring respiratory function. However, there are challenges associated with using linear methods for calibration of respiratory inductive plethysmography. In this study, we developed two nonlinear models, artificial neural network and adaptive neuro-fuzzy inference system, to estimate respiratory volume based on thoracoabdominal movements, and compared these models with routine linear approaches, including qualitative diagnostic calibration and multiple linear regression. METHODS: Recordings of spirometry volume and respiratory inductive plethysmography were obtained for 10 normal subjects and 10 asthmatic patients, during asynchronous breathing for 7 min. The first 5 min of recording were used to develop the models; the remaining data were used for subsequent validation of the results. RESULTS: The results from the nonlinear models fitted the spirometry volume curve significantly better than those obtained by linear methods, particularly during asynchrony (P < 0.05). On a breath-by-breath analysis, estimates of tidal volume, total cycle time and sigh values using the artificial neural network model were accurate by comparison with qualitative diagnostic calibration. In contrast to the artificial neural network model, there was a significant correlation between values for thoracoabdominal asynchrony and increased error of qualitative diagnostic calibration (P < 0.05). CONCLUSIONS: These results indicate that the nonlinear methods can be adapted to closely simulate variable conditions and used to study the patterns of volume changes during normal and asynchronous breathing.
Sujet(s)
Asthme/physiopathologie , Mesure des volumes pulmonaires/méthodes , Dynamique non linéaire , Pléthysmographie/méthodes , Mécanique respiratoire/physiologie , Adulte , Humains , Modèles linéaires , Mâle , Spirométrie , Jeune adulteRÉSUMÉ
Oxidative stress appears to have an important role in glucocorticoid insensitivity, as a crucial problem in asthma therapy. We studied the preventive effect of antioxidant N-acetylcysteine (NAC) on the airway hyper-responsiveness (AHR) and the accumulation of inflammatory cells in the airways in an animal model of steroid resistant acute exacerbation of asthma. Systemically sensitized Balb/C mice were exposed to Ovalbumin aerosol on days 13, 14, 15 and 16, followed by intratracheal lipopolysaccharide (LPS) to induce acute exacerbation. NAC (intraperitoneal, 320 mg/kg 30 min before and 12 hours after each challenge) reduced hyper-responsiveness with/out dexamethasone. LPS application caused neutrophilia in bronchoalveolar lavage fluid (BALF) and eosinophil count was higher than respective control in BALF as well as neutrophils after dexamethasone treatment. NAC significantly decreased neutrophil and eosinophil count in BALF as well as inflammatory cytokines (IL-13 and IL-5).We concluded that addition of NAC to asthma therapy has beneficial preventive effects in an animal model of steroid resistant acute exacerbation of asthma.
RÉSUMÉ
Endogenous hydrogen sulfide is produced by cystathionine-γ-lyase and cystathionine-ß-synthase in a variety of tissues and has recently been implicated in the regulation of cardiac functions. Acceleration of the heart rate in response to catecholamines is impaired in patients with cirrhosis. The present study was aimed to examine the role of endogenous hydrogen sulfide in the pathogenesis of chronotropic dysfunction in rats with cirrhosis. Cirrhosis was induced by surgical ligation of bile duct in rats. There was no significant difference in atrial cystathionine-γ-lyase and cystathionine-ß-synthase mRNA levels in control and cirrhotic rats as assessed by quantitative RT-PCR. Four weeks after bile duct ligation or sham surgery the atria were isolated and chronotropic responsiveness to adrenergic stimulation was assessed using standard organ bath. Incubation of the atria with propargylglycine (PAG, a cystathionine-γ-lyase inhibitor) and amino-oxyacetic acid (AOAA, a cystathionine-ß-synthase inhibitor) was associated with a significant desensitization of chronotropic response to adrenergic stimulation in controls rats. This indicates that endogenous hydrogen sulfide might be involved in modulation of adrenergic signaling in the atrium. Bile duct ligation was associated with impaired chronotropic responsiveness to adrenergic stimulation in comparison with sham-operated rats. In contrast to control group, incubation of the atria with PAG and AOAA was able to partially improve the chronotropic responsiveness to adrenergic stimulation in cirrhotic rats. Our data shows that local inhibition of endogenous hydrogen sulfide in atria has opposite effect in cirrhotic versus control rats and may play a role in physiological modulation of adrenergic signaling in the atrium.
Sujet(s)
Fibrose/physiopathologie , Cardiopathies/physiopathologie , Coeur/physiopathologie , Sulfure d'hydrogène/métabolisme , Alcynes/pharmacologie , Acide aminooxy-acétique/pharmacologie , Animaux , Cystathionine beta-synthase/antagonistes et inhibiteurs , Cystathionine beta-synthase/génétique , Cystathionine gamma-lyase/antagonistes et inhibiteurs , Cystathionine gamma-lyase/génétique , Fibrose/métabolisme , Glycine/analogues et dérivés , Glycine/pharmacologie , Coeur/effets des médicaments et des substances chimiques , Cardiopathies/métabolisme , Rythme cardiaque/effets des médicaments et des substances chimiques , Rythme cardiaque/physiologie , Mâle , Rats , Rat WistarRÉSUMÉ
Cardiac cycle is regulated by a complex interplay between autonomic nervous system and cardiac pacemaker cells. Decreased heart rate variability (HRV) and increased cardiac rhythm regularity are associated with poor prognosis in patients with systemic inflammation (e.g., sepsis). However, the underlying mechanism of decreased HRV in systemic inflammation is not understood. It is known that greater regularity in a complex system could indicate uncoupling of the system's components. The present study aimed to test the hypothesis that impaired responsiveness of cardiac pacemaker to autonomic nervous system may lead to uncoupling of the cardiovascular regulatory mechanisms during systemic inflammation. Systemic inflammation was induced by intraperitoneal injection of endotoxin (lipopolysaccharide, 1 mg/kg) in rats. Cardiovascular signals were recorded in conscious animals using a telemetric system. Heart rate dynamics was analyzed using Poincaré plot, and cardiac cycle regularity was assessed by sample entropy analysis. Spontaneously beating atria were isolated, and chronotropic responsiveness to adrenergic and cholinergic stimulation was assessed using standard organ bath. Sample entropy decreased significantly 4 h after endotoxin injection in conscious rats. Vagal modulation of cardiac cycle (as assessed by Poincaré plot) also exhibited a significant reduction in endotoxemic rats. Acute endotoxin challenge was associated with a significant hyporesponsiveness of isolated spontaneously beating atria to cholinergic stimulation. The chronotropic responsiveness to adrenergic stimulation was identical in controls and endotoxin-treated rats. These data propose that systemic inflammation is linked to reduced cardiac responsiveness to cholinergic stimulation. This may lead to partial uncoupling of cardiac pacemaker cells from autonomic neural control and can explain decreased HRV during systemic inflammation.
Sujet(s)
Agents cholinergiques/métabolisme , Endotoxémie/métabolisme , Neurones/métabolisme , Animaux , Électrocardiographie/méthodes , Coeur/physiologie , Atrium du coeur/anatomopathologie , Rythme cardiaque , Inflammation , Mâle , Pronostic , Rats , Rat Sprague-Dawley , Sepsie , Télémétrie/méthodes , Facteurs tempsRÉSUMÉ
Recent studies suggest that normobaric hyperoxia (HO) protects the rat brain from ischemia reperfusion (IR) injury. Protein kinase C (PKC) is a key signaling molecule involved in protection against IR injury but its role in protective effect of HO in brain injury in unknown. In this study we attempted to see if PKC is involved in the effect of HO. Rats were divided into four main experimental groups. The first two were exposed to 95 % oxygen (HO) in a chamber 4 h/day for 6 consecutive days. Each of these groups had a control group exposed to 21 % oxygen. To investigate the role of PKC during HO, chelerythrin chloride (CHEL, 1 mg/kg/day), a PKC inhibitor, or its vehicle was given to animals for 6 days. After 24 h, the rats were subjected to 60 min of right middle cerebral artery occlusion (MCAO). After 24 h reperfusion neurological deficit scores, infarct volume, brain edema and blood-brain Barrier (BBB) permeability were assessed. HO decreased the infarct volume and brain edema in comparison with controls. PKC inhibition was associated with a significant increase in infarct size in both HO and control animals. PKC inhibition was unable to change brain edema in the experimental groups. Both HO and PKC inhibition reduced the BBB permeability within 24 h post occlusion of middle cerebral artery. Although both HO and PKC inhibition were associated with inhibition of BBB permeability during ischemic brain injury in rats, the neuroprotective effect of HO was independent of PKC in the MCAO model.
RÉSUMÉ
Experimental studies show that detrimental effects of ischemia-reperfusion (I/R) injury can be attenuated by hyperoxic preconditioning in normal hearts, however, there are few studies about hyperoxia effects in diseased myocardium. The present study was designed to assess the cardioprotective effects of hyperoxia pretreatment (≥ 95 % O2) in acute diabetic rat hearts. Normal and one week acute diabetic rats were either exposed to 60 (H60) and 180 (H180) min of hyperoxia or exposed to normal atmospheric air (21 % O2). Then hearts were isolated immediately and subjected to 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size, cardiomyocyte apoptosis, enzymes release and ischemia induced arrhythmias were determined. Heart of diabetic control rats had less infarct size and decreased LDH and CK-MB release compared to normal hearts. 60 and 180 min of hyperoxia reduced myocardial infarct size and enzymes release in normal hearts. 180 min of hyperoxia also decreased cardiomyocytes apoptosis in normal state. On the other hand, protective values of hyperoxia were not significantly different in diabetic hearts. Moreover, hyperoxia reduced severity of ventricular arrhythmias in normal rat hearts whereas; it did not confer any additional antiarrhythmic protection in diabetic hearts. These findings suggest that diabetic hearts are less susceptible to ischemia-induced arrhythmias and infarction. Hyperoxia greatly protects rat hearts against I/R injury in normal hearts, however, it could not provide added cardioprotective effects in acute phase of diabetes.
RÉSUMÉ
UNLABELLED: HYPOTHESIS/INTRODUCTION: Our aim was to investigate whether a non-hypotensive dose of ramiprilat and losartan has myocardial protective effects during myocardial ischemia/reperfusion in vivo. MATERIALS AND METHODS: Three groups of rats were given 10 mg/kg per day of losartan for one (L-1W), four (L-4W) or 10 (L-10W) weeks. Another three groups were given 50 µg/kg per day of ramiprilat for one (R-1W), four (R-4W) or 10 (R-10W) weeks. The animals underwent 30 min of left anterior descending artery occlusion and subsequent reperfusion for 120 min. RESULTS: Myocardial infarct size (IS) was reduced in R-1W (28.4 ± 6.3%, p < 0.001), R-4W (27.8 ± 7.4, p < 0.001), L-4W (31.8 ± 6%, p < 0.05) and L-10W (25.3 ± 5.7, p < 0.001) groups compared with a saline group (48.3 ± 7.8%). A significant reduction in the number of ventricular ectopic beats (VEBs) was noted in groups R-1W (209 ± 41, p < 0.01), R-4W (176 ± 39, p < 0.01), L-4W (215 ± 52, p < 0.05) and L-10W (191 ± 61, p < 0.01 vs. saline 329 ± 48). The incidence of irreversible ventricular fibrillation (VF) and mortality were decreased significantly only in L-10W group. There were no significant decreases in episodes of VT, the incidence of irreversible VF and mortality in all of the groups treated with ramiprilat. CONCLUSION: These data indicate that losartan and ramiprilat protect the heart against ischemia/reperfusion injury independently of their hemodynamic effects but in a time-dependent manner.
Sujet(s)
Coeur/effets des médicaments et des substances chimiques , Losartan/pharmacologie , Losartan/usage thérapeutique , Lésion de reperfusion myocardique/traitement médicamenteux , Ramipril/analogues et dérivés , Animaux , Antihypertenseurs/pharmacologie , Antihypertenseurs/usage thérapeutique , Troubles du rythme cardiaque/complications , Troubles du rythme cardiaque/traitement médicamenteux , Troubles du rythme cardiaque/anatomopathologie , Troubles du rythme cardiaque/physiopathologie , Association de médicaments , Coeur/physiopathologie , Rythme cardiaque/effets des médicaments et des substances chimiques , Estimation de Kaplan-Meier , Mâle , Infarctus du myocarde/complications , Infarctus du myocarde/traitement médicamenteux , Infarctus du myocarde/anatomopathologie , Infarctus du myocarde/physiopathologie , Lésion de reperfusion myocardique/complications , Lésion de reperfusion myocardique/anatomopathologie , Lésion de reperfusion myocardique/physiopathologie , Ramipril/pharmacologie , Ramipril/usage thérapeutique , Rats , Rat WistarRÉSUMÉ
Insulin is a potent vasoactive hormone which induces vasodilatation at physiological concentrations. Aerobic exercise is known to improve insulin vasodilatory activity in humans and experimental animals. Since both insulin and physical training is known to activate K(ATP) and K(Ca2+) channels and increase nitric oxide (NO) synthesis, we hypothesized that insulin and exercise might use a common mechanism in mediating their vascular effect. The present study was carried out to investigate the role of NO, K(ATP) and K(Ca2+) channels in enhancement of insulin-induced cutaneous vasorelaxation by exercise in rats. Male Wistar rats were submitted to exercise training for 8weeks on a treadmill. Cutaneous microvascular response to insulin was recorded from soles skin using a laser Doppler flowmeter. Systemic arterial blood pressure and heart rate were measured using a tail-cuff during assessment of cutaneous blood flow. Subcutaneous injection of insulin induced a dose-dependent increase in skin blood flow in control rats which was significantly higher in exercised animals. Local inhibition of NO synthesis (l-NAME, 10(-4)M) was associated with a marked inhibitory effect on insulin-induced vasodilatation and this inhibition was significantly greater in exercised rats. Likewise, a selective K(Ca2+) channel blocker (iberiotoxin, 10(-9)M) inhibited insulin-induced vasodilatation and this inhibition was significantly exaggerated in exercised animals. Local K(ATP) blockade (glybenclamide, 10(-5)M) showed an identical response in sedentary and exercised animals. Insulin induced a marked vasodilatation in cutaneous microcirculation following aerobic exercise in rats. Both NO and K(Ca2+) channels might be involved in the genesis of this effect.