RESUMO
There are three major types of sleep-disordered breathing (SDB) with respect to prevalence and health consequences, i.e. obstructive sleep apnoea syndrome (OSAS), Cheyne-Stokes respiration and central sleep apnoea (CSR-CSA) in chronic heart failure, and obesity hypoventilation syndrome (OHS). In all three conditions, hypoxia appears to affect body functioning in different ways. Most of the molecular and cellular mechanisms that occur in response to SDB-related hypoxia remain unknown. In OSAS, an inflammatory cascade mainly dependent upon intermittent hypoxia has been described. There is a strong interaction between haemodynamic and inflammatory changes in promoting vascular remodelling. Moreover, during OSAS, most organ, tissue or functional impairment is related to the severity of nocturnal hypoxia. CSR-CSA occurring during heart failure is primarily a consequence of cardiac impairment. CSR-CSA has deleterious consequences for cardiac prognosis and mortality since it favours sympathetic activation, ventricular ectopy and atrial fibrillation. Although correction of CSR-CSA seems to be critical, there is a need to establish therapy guidelines in large randomised controlled trials. Finally, OHS is a growing health concern, owing to the worldwide obesity epidemic and OHS morbidities. The pathophysiology of OHS remains largely unknown. However, resistance to leptin, obesity and severe nocturnal hypoxia lead to insulin resistance and endothelial dysfunction. In addition, several adipokines may be triggered by hypoxia and explain, at least in part, OHS morbidity and mortality. Overall, chronic intermittent hypoxia appears to have specific genomic effects that differ notably from continuous hypoxia. Further research is required to fully elucidate the molecular and cellular mechanisms.
Assuntos
Respiração de Cheyne-Stokes/diagnóstico , Respiração de Cheyne-Stokes/fisiopatologia , Hipóxia , Síndromes da Apneia do Sono/diagnóstico , Síndromes da Apneia do Sono/fisiopatologia , Idoso , Aterosclerose/terapia , Feminino , Insuficiência Cardíaca/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/terapia , Estresse Oxidativo , Polissonografia/métodos , Prevalência , PrognósticoRESUMO
Mechanisms underlying ectopic activity in the pulmonary vein (PV) which triggers paroxysmal atrial fibrillation are unknown. Although several studies have suggested that calcium signalling might be involved in these arrhythmias, little is known about calcium cycling in PV cardiomyocytes (CM). We found that individual PV CM showed a wide range of transverse tubular incidence and organization, going from their virtual absence, as described in atrial CM, to well transversally organised tubular systems, like in ventricular CM. These different types of CM were found in groups scattered throughout the tissue. The variability of the tubular system was associated with cell to cell heterogeneity of calcium channel (Cav1.2) localisation and, thereby, of Cav1.2-Ryanodine receptor coupling. This was responsible for multiple forms of PV CM calcium transient. Spontaneous calcium sparks and waves were not only more abundant in PV CM than in LA CM but also associated with a higher depolarising current. In conclusion, compared with either the atrium or the ventricle, PV myocardium presents marked structural and functional heterogeneity.
Assuntos
Sinalização do Cálcio , Átrios do Coração/citologia , Miócitos Cardíacos/fisiologia , Veias Pulmonares/citologia , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/análise , Miócitos Cardíacos/enzimologia , Veias Pulmonares/fisiologia , RatosRESUMO
Administration of recombinant human erythropoietin (rhEPO) is known to induce protection against cardiac ischaemia injury improving functional recovery and reducing apoptosis. But the underlying mechanisms are not elucidated. We determined the role of nitric oxide synthases (NOS) as well as ATP-dependent (K(ATP)) and calcium-activated (K(Ca)) potassium channels in the early cardioprotection induced by rhEPO. Wistar male rats were divided into two experimental groups treated by rhEPO (5,000 IU/kg, i.p.) or saline (control group). One hour later, rats were anaesthetized, hearts isolated, retrogradely perfused and submitted to a 30-min no-flow global ischaemia followed by 120 min of reperfusion sequence. Cardiac functional recovery (left ventricular developed pressure, LVDP) was significantly higher in the group treated by rhEPO (LVDP at 30 min reperfusion: 71.7 +/- 2.3 mmHg) compared with the control group (57.4 +/- 5.8 mmHg). We observed the same significant effect on its derivative (dP/dt). The rhEPO-induced improvement in ventricular function was abolished by perfusion prior to ischaemia with either N-nitro-l-arginine methyl ester (l-NAME, a nonspecific NOS inhibitor) or N-(3-(aminomethyl)benzyl)acetamidine (1,400W, a specific inducible NOS inhibitor) or 5-hydroxydecanoic acid (5HD, a mitochondrial K(ATP) channel blocker) but not with paxilline (a K(Ca) channel inhibitor). Thus, in vivo rhEPO administration provides early preconditioning against ischaemic injury in the isolated perfused rat heart that is dependent on iNOS and mitochondrial K(ATP) channels.
Assuntos
Eritropoetina/farmacologia , Precondicionamento Isquêmico Miocárdico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Amidinas/farmacologia , Animais , Benzilaminas/farmacologia , Ácidos Decanoicos/farmacologia , Inibidores Enzimáticos/farmacologia , Eritropoetina/administração & dosagem , Coração/efeitos dos fármacos , Hidroxiácidos/farmacologia , Injeções Intraperitoneais , Precondicionamento Isquêmico Miocárdico/métodos , Masculino , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/enzimologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Cálcio-Ativados/antagonistas & inibidores , Canais de Potássio Cálcio-Ativados/metabolismo , Ratos , Ratos Wistar , Proteínas Recombinantes , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
The delayed form of myocardial preconditioning is of particular interest because of its large window of protection. It involves many signalisation pathways who, along with transcription factors, activate cardioprotective genes. Amongst the latter, the hypoxia inducible factor 1 (HIF-1) whose a subunit is stabilized by hypoxia, appears to play a pivotal role in the delayed preconditioning induced by hypoxia. The stabilisation of HIF-1alpha by inhibitors of prolyl-4-hydroxylases, the enzymes responsible for its degradation in normoxia, reproduces the cardioprotective effects of hypoxia. These enzymes represent promising therapeutic targets for the treatment of various cardiovascular diseases.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Precondicionamento Isquêmico Miocárdico , Hipóxia Celular , Humanos , Precondicionamento Isquêmico Miocárdico/métodos , Fatores de TempoRESUMO
In this study, we investigated the influence of depth and duration of intermittent hypoxia (IH) on the infarct size development in isolated rat heart. The role of nitric oxide synthase (NOS) and ATP-sensitive K+ (K(ATP)) channel was also studied. Wistar male rats were exposed to IH [repetitive cycles of 1 min, 40 s with inspired oxygen fraction (FI(O2)), 5 or 10%, followed by 20-s normoxia], during 30 min or 4 h. Another group was exposed to 4 h of continuous hypoxia with 10% FI(O2). Twenty-four hours later, their hearts were isolated and subjected to a 30-min no-flow global ischemia-120-min reperfusion sequence. For some hearts, N(omega)-nitro-L-arginine methyl ester (L-NAME) (a nonselective inhibitor of NOS) or 5-hydroxydecanoic acid (5-HD) (a selective mitochondrial K(ATP) blocker) was infused before ischemia. Infarct size (in percentage of ventricles) was significantly reduced by prior IH for 4 h (10% FI(O2)) (21.8 +/- 3.1 vs. 33.5 +/- 2.5% in sham group). This effect was abolished by L-NAME or 5-HD. Infarct size was not different in groups subjected to either 30 min of IH or to continuous hypoxia compared with sham group. In contrast, IH for 4 h (5% FI(O2)) significantly increased infarct size (45.1 +/- 3.6 vs. 33.5 +/- 2.5% in sham group). Acute IH for 4 h with a minimal FI(O2) of 10% induced a delayed preconditioning against myocardial infarction in the rat, which was abolished by NOS inhibition and mitochondrial K(ATP) channel blockade. Depth, duration, and intermittence of hypoxia appeared to be critical for cardioprotection to occur.
Assuntos
Suscetibilidade a Doenças/fisiopatologia , Hipóxia/fisiopatologia , Precondicionamento Isquêmico Miocárdico/métodos , Infarto do Miocárdio/prevenção & controle , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia , Traumatismo por Reperfusão/terapia , Doença Aguda , Animais , Hipóxia/complicações , Masculino , Infarto do Miocárdio/etiologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/complicações , Resultado do TratamentoRESUMO
Coronary heart disease is frequently associated with obstructive sleep apnea syndrome and treating obstructive sleep apnea appears to significantly improve the outcome in coronary heart disease. Thus we have developed a rat model of chronic intermittent hypoxia (IH) to study the influence of this condition on myocardial ischemia-reperfusion tolerance and on functional vascular reactivity. Wistar male rats were divided in three experimental groups (n = 12 each) subjected to chronic IH (IH group), normoxia (N group), or control conditions (control group). IH consisted of repetitive cycles of 1 min (40 s with inspired O(2) fraction 5% followed by 20 s normoxia) and was applied for 8 h during daytime, for 35 days. Normoxic cycles were applied in the same conditions, inspired O(2) fraction remaining constant at 21%. On day 36, mean arterial blood pressure (MABP) was measured before isolated hearts were submitted to an ischemia-reperfusion protocol. The thoracic aorta and left carotid artery were also excised for functional reactivity studies. MABP was not significantly different between the three experimental groups. Infarct sizes (in percent of ventricles) were significantly higher in IH group (46.9 +/- 3.6%) compared with N (26.1 +/- 2.8%) and control (21.7 +/- 2.1%) groups. Vascular smooth muscle function was similar in aorta and carotid arteries from all groups. The endothelium-dependent relaxation in response to acetylcholine was also similar in aorta and carotid arteries from all groups. Chronic IH increased heart sensitivity to infarction, independently of a significant increase in MABP, and did not affect vascular reactivity of aorta and carotid arteries.
Assuntos
Coração/fisiologia , Hipóxia Encefálica/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Animais , Doença Crônica , Técnicas In Vitro , Masculino , Ratos , Ratos WistarRESUMO
Erythropoietin (EPO), the principal hematopoietic cytokine produced by the kidney and the liver in fetuses, regulates mammalian erythropoiesis and exhibits diverse cellular effects in non-hematopoietic tissues. The introduction of recombinant human EPO (rhEPO) has marked a significant advance in the management of anemia associated with chronic renal failure. At the same time, experimental studies have unveiled its potential cardioprotective actions. As with other preconditioning agents, administration of exogenous rhEPO can confer myocardial protection against ischemia-reperfusion injury, in terms of reduction in cellular apoptosis and necrosis as well as improvement in myocardial functional recovery. The purpose of this study is to review current information regarding the various protocols used to investigate the effects of rhEPO administration as well as its cardioprotective properties. We also address the potential mechanisms underlying the protective effects of EPO. A better understanding of these mechanisms is essential for the development of clinical applications and the design of novel therapeutical strategies.
Assuntos
Eritropoetina/uso terapêutico , Coração/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Eritropoetina/biossíntese , Humanos , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/fisiologia , Proteínas Recombinantes , Transdução de Sinais/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Interest in cannabinoid pharmacology developed rapidly since the discovery of cannabinoids receptors and endocannabinoids. Modulation of this system is becoming a hot topic in cardiovascular pharmacology mainly at the light of recent findings. Among them, cardiac effects of cannabinoids were described with respect to their probable participation to the well-studied preconditioning phenomenon. Beneficial effects of post-infarction cannabinoids administration against ischemia-reperfusion injury were also reported. Concerning their vascular effects the situation is more complex some studies reporting pressor effects while others depressor ones. It was also proposed that the endothelium-derived hyperpolarizing factor released by various vasodilators may be an endocannabinoid an hypothesis still discussed. Finally, pathological situations concerning the cardiovascular system and including brain ischemia, hemorrhagic and endotoxic shocks were reported to be linked with endocannabinoids. However, the clinical use of cannabinoid receptors agonists or antagonists will depend on the development of non psychoactive compounds.
Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Coração/efeitos dos fármacos , Precondicionamento Isquêmico Miocárdico , Animais , Isquemia Encefálica/tratamento farmacológico , Moduladores de Receptores de Canabinoides , Modelos Animais de Doenças , Cães , Hemodinâmica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Knockout , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Coelhos , Ratos , Ratos Sprague-Dawley , Receptores de Canabinoides/efeitos dos fármacos , Receptores de Droga , Choque Hemorrágico/tratamento farmacológico , Choque Séptico/tratamento farmacológicoRESUMO
OBJECTIVE: Protection conferred by heat stress (HS) against ischaemia-reperfusion injury, in term of mechanical function and myocardial necrosis, has been extensively studied. In contrast, the effects of disease states on this HS-induced cytoprotective response are less known. Therefore, we investigated the effects of prior heat stress on the infarct size in the isolated heart and on the myocardial heat stress protein (HSP) 72 synthesis, in a model of insulin-dependent diabetic rats. METHODS: Three groups of animals were studied: D rats were rendered diabetic by 55 mg/kg streptozotocin i.v. injection. DI rats received the same treatment plus a daily injection of insulin started 2 weeks after and V rats received the vehicle of streptozotocin plus a daily injection of saline. Eight weeks later, D, DI and V rats were either heat-stressed (42 degrees C for 15 min) or sham-anaesthetised. Twenty-four hours later, their hearts were isolated, perfused using the Langendorff technique, and subjected to a 30 min occlusion of the left coronary artery followed by 120 min of reperfusion. Myocardial HSP72 content was measured 24 h after HS or sham treatment using an electrophoresis coupled with a Western blot analysis. RESULTS: Infarct-to-risk ratio (I/R) was significantly reduced in hearts from heat-stressed (11.7 +/- 2.0%) compared to sham (30.0 +/- 3.2%) V rats. This cardioprotection was not observed in hearts from D (I/R: 31.4 +/- 3.3 vs. 34.3 +/- 3.5%) and DI (I/R: 28.7 +/- 1.6 vs. 30.3 +/- 1.6%) rats. Risk zones were similar between all experimental groups. The incidence of ventricular arrhythmias during ischaemia and reperfusion periods was not different between the six experimental groups. Western blot analysis of the myocardial HSP72 content showed a comparable heat stress-induced increase of this protein, in V, D and DI animals. CONCLUSION: These results demonstrate that myocardial protective effect induced by heat stress could not extend to a pathological animal model like the diabetic rat and seems to be unrelated to the HSP72 level. Further investigations are required to elucidate the precise role of the heat stress proteins in this adaptive response.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Temperatura Alta/uso terapêutico , Infarto do Miocárdio/prevenção & controle , Miocárdio/metabolismo , Análise de Variância , Animais , Western Blotting , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Eletroforese em Gel de Poliacrilamida , Proteínas de Choque Térmico HSP72 , Proteínas de Choque Térmico/análise , Proteínas de Choque Térmico/biossíntese , Insulina/uso terapêutico , Masculino , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Reperfusão Miocárdica , Ratos , Ratos WistarRESUMO
1. Heat stress (HS) is known to protect against myocardial ischaemia-reperfusion injury by improving mechanical dysfunction and decreasing necrosis. However, the mechanisms responsible for this form of cardioprotection remain to be elucidated. ATP-sensitive potassium (K(ATP)) channels have been shown to be involved in the delayed phase of protection following ischaemic preconditioning, a phenomenon closely resembling the HS-induced cardioprotection. The aim of this study was thus to investigate the role of K(ATP) channels in HS-induced protection of the isolated rat heart. 2. Twenty four hours after whole body heat stress (at 42 degrees C for 15 min) or sham anaesthesia, isolated perfused hearts were subjected to a 15 min stabilization period followed by a 15 min infusion of either 10 microM glibenclamide (Glib), 100 microM sodium 5-hydroxydecanoate (5HD) or vehicle (0.04% DMSO). Regional ischaemia (35 min) and reperfusion (120 min) were then performed. 3. Prior heat stress significantly reduced infarct-to-risk ratio (from 42.4+/-2.4% to 19.4+/-2.9, P<0.001). This resistance to myocardial infarction was abolished in both Glib-treated (40.1+/-1.8% vs 42.3+/-1.8%) and 5HD-treated (41.2+/-1.8% vs 41.8+/-1.2%) groups. 4. The results of this study suggest that K(ATP) channel activation contributes to the cytoprotective response induced by heat stress.
Assuntos
Coração/efeitos dos fármacos , Transtornos de Estresse por Calor/fisiopatologia , Infarto do Miocárdio/prevenção & controle , Bloqueadores dos Canais de Potássio , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio , Animais , Hemodinâmica , Técnicas In Vitro , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , RatosRESUMO
Endotoxin is known to confer a delayed protection against myocardial infarction. Lipopolysaccharide (LPS) treatment also induces the de novo synthesis of kinin B(1)-receptors that are not present in normal conditions. The aim of this study was to evaluate whether LPS-induced B(1)-receptors are implicated in the reduction of infarct size brought about by LPS. Rabbits were submitted to a 30-min coronary artery occlusion and 3-h reperfusion sequence. Six groups were studied: pretreated or not (control animals) with LPS (5 microgram kg(-1) i.v.) 24 h earlier and treated 15 min before and throughout ischaemia - reperfusion with either the B(1)-antagonist R-715 (1 mg kg(-1) h(-1)), the B(1)-agonist Sar-[D-Phe(8)]-des-Arg(9)-bradykinin (15 microgram kg(-1) h(-1)) or vehicle (saline). Infarct size and area at risk were assessed by differential staining and planimetric analysis. The presence of B(1)-receptors in LPS-pretreated animals was confirmed by a decrease in mean arterial pressure in response to B(1) stimulation. LPS-pretreatment significantly reduced infarct size (6.4+/-1.7%, of area at risk vs 24.1+/-2.5% in control animals, P<0.05). This protection was not modified by B(1)-receptor antagonism (7.4+/-2.2%, NS) or stimulation (5.2+/-1.2%, NS). Neither antagonist nor agonist modified infarct size in control animals. In conclusion, these data suggest that LPS-induced myocardial protection in the rabbit is not related to concomitant de novo B(1)-receptor induction.
Assuntos
Coração/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Receptores da Bradicinina/fisiologia , Animais , Hemodinâmica/efeitos dos fármacos , Lipídeo A/análogos & derivados , Lipídeo A/farmacologia , Masculino , Infarto do Miocárdio/tratamento farmacológico , Coelhos , Receptor B1 da BradicininaRESUMO
Nitric oxide (NO) donors are known to induce both delayed cardioprotection and myocardial heat stress protein (HSP) expression. Moreover, heat stress (HS), which also protects myocardium against ischaemic damages, is associated with a NO release. Therefore, we have investigated the implication of NO in HS-induced resistance to myocardial infarction, in the isolated rat heart model. Rats were divided in six groups (n=10 in each group), subjected or not to heat stress (42 degrees C internal temperature, 15 min) and treated or not with nitro-L-arginine-methylester (L-NAME) a non-selective inhibitor of NO synthase isoforms, or L-N(6)-(1-imino-ethyl)lysine (L-NIL), a selective inhibitor of the inducible NO synthase. Twenty-four hours after heat stress, their hearts were isolated, retrogradely perfused, and subjected to a 30-min occlusion of the left coronary artery followed by 120 min of reperfusion. Infarct-to-risk ratio was significantly reduced in HS (18.7+/-1.6%) compared to Sham (33.0+/-1.7%) hearts. This effect was abolished in L-NAME-treated (41.7+/-3.1% in HS+L-NAME vs 35.2+/-3.0% in Sham+L-NAME ) and L-NIL-treated (36.1+/-3.4% in HS+L-NIL vs 42.1+/-4.6% in Sham+L-NIL) groups. Immunohistochemical analysis of myocardial HSP 27 and 72 showed an HS-induced increase of these proteins, which was not modified by L-NAME pretreatment. We conclude that NO synthases, and in particular the inducible isoform, appear to play a role in the heat stress-induced cardioprotection, independently of HSP 27 and 72 levels. Further investigations are required to elucidate the precise role of HSPs in this adaptive response.
Assuntos
Transtornos de Estresse por Calor/patologia , Isoenzimas/fisiologia , Lisina/farmacologia , Infarto do Miocárdio/patologia , Óxido Nítrico Sintase/fisiologia , Animais , Inibidores Enzimáticos/farmacologia , Proteínas de Choque Térmico HSP72 , Transtornos de Estresse por Calor/enzimologia , Transtornos de Estresse por Calor/metabolismo , Proteínas de Choque Térmico/metabolismo , Hemodinâmica/efeitos dos fármacos , Imuno-Histoquímica , Técnicas In Vitro , Isoenzimas/antagonistas & inibidores , Lisina/análogos & derivados , Masculino , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II , Ratos , Ratos WistarRESUMO
The protection conferred by heat stress (HS) against myocardial ischaemia-reperfusion injury, in terms of mechanical function preservation and infarct size reduction, is well documented and mechanisms underlying these effects have been extensively explored. However, the effect of HS on coronary circulation is less known. The aim of this study was thus to investigate the role of ATP-sensitive potassium (K(ATP)) channels in the protection against ischaemic injury afforded by HS to the coronary endothelial function. Twenty-four hours after whole body hyperthermia (42 degrees C for 15 min, H groups) or sham anaesthesia (Sham groups), isolated perfused rat hearts were subjected to a 15 min stabilization period followed by a 30 min infusion of either 0.3 microM glibenclamide (Gli, a K(ATP) channel blocker) or its vehicle (V). Hearts were then exposed to a low-flow ischaemia (30 min)-reperfusion (20 min) (I/R) or normally perfused (50 min), after which coronaries were precontracted with 0.1 microM U-46619. Finally, the response to the endothelium-dependent vasodilator, 5-hydroxytryptamine (5-HT, 10 microM) was compared to that of the endothelium-independent vasodilator, sodium nitroprusside (SNP, 3 microM). In hearts from Sham-V and Sham-Gli groups, I/R selectively diminished 5-HT-induced vasodilatation without affecting the vasodilatation to SNP. In V-treated groups, prior HS preserved the vasodilatation produced by 5-HT. This HS-induced protection was abolished by Gli treatment. In conclusion, these results suggest that K(ATP) channel activation contributes to the preservation of coronary endothelial function conferred by heat stress against ischaemic insult.
Assuntos
Endotélio Vascular/fisiopatologia , Transtornos de Estresse por Calor , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Bloqueadores dos Canais de Potássio , Transportadores de Cassetes de Ligação de ATP , Animais , Pressão Sanguínea/efeitos dos fármacos , Glibureto/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Precondicionamento Isquêmico , Canais KATP , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Canais de Potássio/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização , Ratos , Ratos WistarRESUMO
1. Noradrenaline (NA), which is abundantly released during heat stress (HS), is known to induce both delayed cardioprotection and heat stress protein (HSP) 72 expression by the mediation of alpha, adrenoceptors. Therefore, we have investigated the implication of alpha1 adrenoceptors in HS-induced resistance to myocardial infarction, in the isolated rat heart model. 2. Rats were pretreated with prazosin (1 mg kg(-1), i.p., Praz) or 5-methylurapidil (3 mg kg(-1), i.v., 5MU) or chloroethylclonidine (3 mg kg(-1), i.v., CEC) or vehicle (V) in order to selectively antagonize alpha1, alpha1A and alpha1B adrenoceptors. They were then either heat stressed (42 degrees C for 15 min) or sham anaesthetized. Twenty-four hours later. their hearts were isolated, retrogradely perfused, and subjected to a 30 min occlusion of the left coronary artery followed by 120 min of reperfusion. 3. Infarct-to-risk ratio was significantly reduced in HS+V (15.4+/-1.8%) compared to Sham+V (35.7+/-1.3%) hearts. This effect was abolished in Praz-treated (29.1+/-1.6% in HS+Praz vs 34.1+/-4.0% in Sham+Praz), 5MU-treated (34.5+/-2.2% in HS+5MU vs 31.2+/-2.0% in Sham+5MU) and CEC-treated (33.4+/-3.0% in HS+CEC vs 32.4+/-1.3% in Sham+CEC) groups. Western blot analysis of myocardial HSP72 showed an HS-induced increase of this protein, which was not modified by Praz, 5MU and CEC pretreatments. 4. We conclude that both alpha1A and alpha1B adrenoceptor subtypes appear to play a role in the heat stress-induced cardioprotection, independently of the HSP72 level. Further investigations are required to elucidate the precise role of HSPs in this adaptative response.
Assuntos
Transtornos de Estresse por Calor/complicações , Proteínas de Choque Térmico/metabolismo , Infarto/prevenção & controle , Receptores Adrenérgicos alfa 1/fisiologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Clonidina/análogos & derivados , Clonidina/farmacologia , Proteínas de Choque Térmico HSP72 , Proteínas de Choque Térmico/análise , Masculino , Isquemia Miocárdica/prevenção & controle , Técnicas de Cultura de Órgãos , Piperazinas/farmacologia , Prazosina/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 1/classificação , Traumatismo por ReperfusãoRESUMO
1. This ex vivo study was performed to characterize B1 receptor induction in rats submitted to heat stress. Changes in aortic isometric tension were recorded after a 90 min in vitro incubation with [des-Arg9]-bradykinin. B1 receptor mRNA were detected in aorta and heart using RT-PCR technique. 2. Aortic rings from sham rats did not respond to [des-Arg9]-bradykinin. In contrast, this agonist induced a concentration-dependent relaxation of aortic rings from rats submitted to lipopolysaccharide (LPS) treatment or to heat stress 24 h earlier. 3. The concentration-dependent relaxation induced by [des-Arg9]-bradykinin on aortic rings from heat-stressed rats was abolished by [des-Arg10]-HOE 140, a selective B1 receptor antagonist. 4. In endothelium denuded aortic rings from heat-stress rats, [des-Arg9]-bradykinin induced a concentration-dependent constriction. 5. Pretreatment of intact aortic rings from heat-stress rats with the cyclo-oxygenase inhibitor, diclofenac (1 microM) did not prevent the concentration-dependent relaxation in response to [des-Arg9]-bradykinin. In contrast. NO synthase inhibition with N(omega)-nitro-L-arginine methyl ester (30 microM) totally prevented the vasorelaxant response. 6. B1 receptor mRNA were not detected in aorta and heart from sham animals but were present in tissue from heat-stressed and LPS-treated rats. 7. In conclusion, our results suggest that heat stress induces a transcriptional activation of the B1 receptor gene. The induction of B1 receptors leads to an endothelium- and NO-dependent vasorelaxant response to [des-Arg9]-bradykinin.
Assuntos
Aorta/metabolismo , Transtornos de Estresse por Calor/metabolismo , Relaxamento Muscular/efeitos dos fármacos , Miocárdio/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Animais , Pressão Sanguínea , Southern Blotting , DNA Complementar/síntese química , Endotélio Vascular/efeitos dos fármacos , Técnicas In Vitro , Lipopolissacarídeos/farmacologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Oligonucleotídeos/síntese química , Reação em Cadeia da Polimerase , RNA/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Transcrição Gênica/efeitos dos fármacosRESUMO
1. The aim of this study was to investigate whether histamine H3-receptor agonists could inhibit the effects of cardiac sympathetic nerve stimulation in the dog. 2. Catecholamine release by the heart and the associated variation of haemodynamic parameters were measured after electrical stimulation of the right cardiac sympathetic nerves (1-4 Hz, 10 V, 10 ms) in the anaesthetized dog treated with R-alpha-methyl-histamine (R-HA) and its prodrug BP 2.94 (BP). 3. Cardiac sympathetic stimulation induced a noradrenaline release into the coronary sinus along with a tachycardia and an increase in left ventricular pressure and contractility without changes in mean arterial pressure. Intravenous administration of H3-receptor agonists significantly decreased noradrenaline release by the heart (R-HA at 2 micromol kg(-1) h(-1): +77 +/- 25 vs +405 +/- 82; BP 2.94 at 1 mg kg(-1): +12 +/- 11 vs +330 +/- 100 pg ml(-1) in control conditions, P < or = 0.05), and increases in heart rate (R-HA at 2 micromol kg(-1) h(-1): +26 +/- 8 vs +65 +/- 10 and BP 2.94 at 1 mg kg(-1): +30 +/- 8 vs 75 +/- 6 beats min(-1), in control conditions P < or = 0.05), left ventricular pressure, and contractility. Treatment with SC 359 (1 mg kg(-1)) a selective H3-antagonist, reversed the effects of H3-receptor agonists. Treatment with R-HA at 2 micromol kg(-1) h(-1) and BP 2.94 at 1 mg kg(-1) tended to decrease, while that with SC 359 significantly increased basal heart rate (from 111 +/- 3 to 130 +/- 5 beats min(-1), P < or = 0.001). 4. Functional H3-receptors are present on sympathetic nerve endings in the dog heart. Their stimulation by R-alpha-methyl-histamine or BP 2.94 can inhibit noradrenaline release by the heart and its associated haemodynamic effects.
Assuntos
Coração/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Iminas/farmacologia , Metilistaminas/farmacologia , Fenóis/farmacologia , Pró-Fármacos/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Catecolaminas/metabolismo , Cães , Relação Dose-Resposta a Droga , Estimulação Elétrica , Coração/inervação , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacologia , Imidazóis/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
BACKGROUND: Pulmonary artery hypertension with right ventricular failure is a frequent complication that occurs immediately after heart transplantation in which the use of inhaled nitric oxide may be effective. METHODS: The effects of pulmonary artery hypertension and nitric oxide on myocardial function and on pulmonary and systemic hemodynamic parameters were evaluated in eight anesthetized dogs. Pulmonary artery hypertension was induced by successive microbead injections into the pulmonary circulation. RESULTS: Microbead injections resulted in overt pulmonary artery hypertension (pulmonary artery pressure, + 190%; pulmonary vascular resistance, + 389%; ratio of pulmonary vascular resistance to systemic vascular resistance, 0.41). RESULTS: The end-diastolic length of the right ventricular outflow tract increased significantly along with an increase in right ventricular contractility (peak first derivative of left ventricular pressure as a function of time, + 100%; outflow tract systolic shortening, + 19%). Despite this compensatory mechanism, the increased pulmonary barrier resulted in a decrease in stroke volume (-31%). Systemic effects were observed, such as an increase in heart rate that maintained the cardiac output despite a decrease in left ventricular end-diastolic length (end-diastolic length in region of left anterior descending artery, - 9%). Right myocardial and septal blood flows were also significantly increased. CONCLUSIONS: Nitric oxide administration restored the stroke volume with a decrease in pulmonary artery hypertension and an improvement of the pulmonary vascular resistance to systemic vascular resistance ratio. Systemic blood pressure and coronary perfusion remained unaffected. This selective effect on the pulmonary circulation should be considered a major advantage of nitric oxide inhalation in the treatment of right ventricular dysfunction in acute pulmonary hypertension.
Assuntos
Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Contração Miocárdica/efeitos dos fármacos , Óxido Nítrico/administração & dosagem , Circulação Pulmonar/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Doença Aguda , Administração por Inalação , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Óxido Nítrico/farmacologia , Vasodilatadores/farmacologiaRESUMO
The mechanism involved in the induction of kinin B1 receptors in pathological situations is not completely defined. In this study, we evaluated whether p42/p44 mitogen activated protein (MAP) and p38 stress activated protein (SAP) kinases were implicated in the activation of the gene encoding for the B1 receptor after heat stress in rat vascular smooth muscle cells (SMCs). Rat vascular SMCs were incubated with either vehicle, or 4(4-fluorophenyl)-2-(4 methylsulfinylphenyl)-5-(4pyridil)imidaz (SB 203580) (10 microM), a selective inhibitor of the p38 SAP kinase pathway or 2-(2amino-3-methoxyphenyl)4H-1-benzopyran-4-one (PD 98059) (25 microM), a selective inhibitor of the p42/p44 MAP kinase pathway and submitted or not to heat stress (42 degrees C, 20 min). Five hours later, B1 receptor mRNA was detected using a semi-quantitative RT-PCR technique. In the meantime, we characterised p42/p44 MAP kinase activation after heat stress by immunodetection. A basal expression of B1 receptor mRNA was detected in rat vascular SMCs. This expression was increased by heat stress. However, in cells previously incubated with either SB 203580 or PD 98059 and submitted to heat stress, this increase in B1 receptor mRNA was not detected. Moreover, we showed by immunodetection that heat stress was followed by a transient phosphorylation of p42/p44 MAP kinases. In conclusion, both p42/p44 and p38 kinases play a crucial role in the mechanism leading to B1 receptor mRNA induction after heat stress.
Assuntos
Proteínas Quinases Ativadas por Mitógeno/metabolismo , Músculo Liso Vascular/metabolismo , Receptores da Bradicinina/genética , Animais , Sequência de Bases , Primers do DNA/genética , Regulação da Expressão Gênica , Temperatura Alta , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptor B1 da Bradicinina , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Fisiológico/genética , Estresse Fisiológico/metabolismo , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
There has been increased interest in melatonin recently, since it was shown to be a potent scavenger of toxic free radicals. Melatonin has been found to be effective in protecting against pathological states due to reactive oxygen species release. The present study was performed in order to determine whether melatonin or 5-methoxy-carbonylamino-N-acetyl-tryptamine (5-MCA-NAT), a structurally related indole compound, protect against ischemia-reperfusion injury in the isolated rat heart. Wistar rats were treated in vivo with either melatonin (1 or 10 mg/kg, i.p.) or 5-MCA-NAT (10 mg/kg, i.p.) or their vehicle, 30 min before their hearts were excised and perfused according to the Langendorff technique. Two different protocols were then applied. In the first one, a regional ischemia (5 min)-reperfusion (30 min) sequence was performed in order to record incidence and duration of reperfusion arrhythmias. In the second one, infarct size was assessed after a regional ischemia (30 min)-reperfusion (120 min) sequence. Results show a spectacular protection against ischemia-reperfusion injuries (on arrhythmias as well as on infarct size) in rats pre-treated with 10 mg/kg of melatonin or 5-MCA-NAT. In conclusion, both melatonin and its structural analog, 5-MCA-NAT, appear to confer protection against ischemia-reperfusion injury in the isolated rat heart. This observation suggests that melatonin could have a potential clinical application in the treatment of myocardial ischemia, even if the mechanisms underlying this protection remain to be determined.
Assuntos
Melatonina/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Masculino , Infarto do Miocárdio/tratamento farmacológico , Ratos , Ratos WistarRESUMO
The aim of this study was to evaluate the ability of H3-histaminergic prejunctional receptors to modulate the noradrenaline release induced by myocardial ischaemia in the rat, and the effects of an eventual modulation on haemodynamic, biochemical and electrophysiological parameters. Isolated rat hearts were perfused according to the Langendorff technique. Control hearts (n = 13) were not treated; two groups were treated with the H3-agonist R-alpha-methyl-histamine at 0.3 microM (n = 14) and 1 microM (n = 11) and one group, used as positive control, was treated with the selective alpha 2-agonist Mivazerol at 0.5 microM (n = 14) added to the perfusion medium. Noradrenaline, lactate and transaminase output in the coronary effluent, as well as various haemodynamic and electrophysiological parameters, were measured during global and total ischaemia (30 min) and reperfusion (30 min). alpha 2-receptor stimulation increased ischaemia-induced noradrenaline release during reperfusion (195 +/- 13 vs. 145 +/- 12 pmol.g-1 in control group, P < 0.05). In contrast, R-alpha-methyl-histamine, at both doses, did not significantly modify these parameters. Both treatments did not affect ischaemia- and reperfusion-induced haemodynamic (decrease in heart rate or in left ventricular developed pressure), biochemical (lactate and GOT release) and electrophysiological (arrhythmias or increase in action potential duration) alterations. Unlike other species, the rat appears to be insensitive to H3-histaminergic receptor modulation of ischaemia-induced noradrenaline release, although a modulation can be seen with other prejunctional receptor agonists.