RESUMO
The purpose of the present study is to determine the effects of early decrease in the lesion size on late brain tissue loss, synaptogenesis and functionality after a focal brain lesion in rats. The lesion was induced either to the cortex using the photothrombotic ischemic stroke or to the striatum using the malonate poisoning model. The cortical and striatal lesions amounted to 66-80 mm(3) at day 1 post-lesion and were reduced by 50% after the acute administration of dipyridyl (a liposoluble iron chelator) and aminoguanidine (an inhibitor of the inducible nitric oxide synthase), respectively. Loss of histologically intact tissue and synaptophysin expression as an indicator of synaptogenesis were examined at day 35 post-lesion. Both types of lesion resulted in synaptophysin upregulation in contralateral and ipsilateral cortical areas. On the contrary, brain tissue loss was greater after the striatal (-17%) than the cortical lesion (-5%). Synaptophysin expression and tissue loss were not different between drug- and vehicle-treated rats. Moreover, a set of standard neurological tests revealed a difference in deficit between the both types of lesion, yet only in the acute post-lesion stage. However, it did not distinguish between vehicle- and drug-treated rats whatever the lesion location. Our results indicate that late histological endpoints measurements are not recommended to probe the potential neuroprotective properties of a drug administered within the acute post-lesion stage. They also suggest that inhibition of cytotoxic mechanisms involved in lesion growth is of no clinical interest when it cannot lead to a long-term histological protection and/or increased synaptogenesis.
Assuntos
Encéfalo/patologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Sinaptofisina/biossíntese , 2,2'-Dipiridil/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Isquemia Encefálica/complicações , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Córtex Cerebral/patologia , Guanidinas/farmacologia , Imuno-Histoquímica , Masculino , Atividade Motora/fisiologia , Neostriado/patologia , Estimulação Física , Ratos , Ratos Wistar , Acidente Vascular Cerebral/etiologia , Sinaptofisina/genética , Vibrissas/inervação , Vibrissas/fisiologiaRESUMO
STUDY OBJECTIVE: The clinical application of doxorubicin, a potent cytotoxic agent, is limited by a dose dependent cardiotoxicity and by the acquired resistance of the neoplastic cells. Recently, the sensitivity of resistant cancer cells to doxorubicin has been enhanced by the acute administration of amiodarone. The aim of this study was to investigate whether or not this potentiates the cardiotoxicity of doxorubicin. DESIGN: Hearts from rats pretreated or not with amiodarone 50 mg.kg-1.d-1 for 5 d were perfused via the left atrium with a Krebs-Henseleit solution containing, or not, doxorubicin 6 mg.litre-1. After 40 min of perfusion, the left main coronary artery was ligated and the ligature was maintained for 10 min. It was then cut and reperfusion continued for 10 min. The cardiac output, heart rate, and mean fibrillation duration induced by the reperfusion were measured by timed collections and ECG recordings. SUBJECTS: 32 adult male Sprague-Dawley rats (250-300 g) were used throughout the study. MEASUREMENTS AND RESULTS: After 40 min of perfusion, the cardiac output in the control and amiodarone groups was constant, but significant decreases of 25.5 and 30.4% were noted in both doxorubicin groups. The mean fibrillation durations observed during reperfusion were 331(73), 66(22), 444(86), and 22(9) s for the control, amiodarone, doxorubicin and amiodarone-doxorubicin groups respectively. CONCLUSION: Amiodarone, while maintaining its antiarrhythmic effect, did not potentiate the negative inotropic effect of doxorubicin. These results suggest that the cardiotoxicity produced by the clinically acute administration of amiodarone with doxorubicin is not greater than that caused by doxorubicin given alone.
Assuntos
Amiodarona/toxicidade , Débito Cardíaco/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Doxorrubicina/toxicidade , Fibrilação Ventricular/tratamento farmacológico , Amiodarona/uso terapêutico , Animais , Interações Medicamentosas , Masculino , Miocárdio/metabolismo , Técnicas de Cultura de Órgãos , Ratos , Ratos EndogâmicosRESUMO
OBJECTIVE: Two hormonal systems with opposite effects are activated in congestive heart failure: the renin-angiotensin system that promotes vasoconstriction, cardiac hypertrophy and salt retention, and the atrial natriuretic factor (ANF), which has vasorelaxant and natriuretic effects. It could be of therapeutic interest to associate prevention of angiotensin II formation, by inhibition of angiotensin I-converting enzyme (ACE), with potentiation of the ANF effects, by inhibition of neprilysin (NEP). METHODS: The effects of long-term therapy with fasidotril, a mixed NEP/ACE inhibitor, were assessed in rats submitted to coronary artery ligation. Twenty-four hours after ligation, 172 rats were assigned to either placebo or fasidotril therapy (180 mg/kg/day, orally) for 40 weeks. The date of spontaneous death was recorded, myocardial infarct size was determined and rats were classified as having small, moderate or large infarcts. RESULTS: In rats with moderate infarcts, fasidotril prolonged survival, 50% of the control rats dying during the 40-week observation period compared with 30% of treated rats (P = 0.04, log-rank test)). In rats with large infarcts, mortality was significantly reduced during the initial 25 weeks of therapy, during which 23.5% of animals died compared to 53.8% in untreated rats (P = 0.015). Cardiac hypertrophy was significantly attenuated by fasidotril for the three infarct sizes. Plasma renin activity was not increased by therapy, which presumably reflected the inhibition of renal renin secretion by endogenous ANF. Fasidotril therapy had no significant effects on arterial blood pressure and heart rate. CONCLUSION: In addition to its beneficial effects on survival and cardiac hypertrophy, the lack of hypotensive effect of fasidotril is of interest by reducing the risk of renal hypoperfusion and differentiates the mixed inhibitor from selective ACE inhibitors.
Assuntos
Alanina/análogos & derivados , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/mortalidade , Inibidores de Proteases/uso terapêutico , Alanina/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Distribuição de Qui-Quadrado , Frequência Cardíaca/efeitos dos fármacos , Masculino , Infarto do Miocárdio/sangue , Neprilisina/sangue , Peptidil Dipeptidase A/sangue , Ratos , Ratos Wistar , Renina/sangue , Taxa de Sobrevida , Fatores de TempoRESUMO
Rat atrial natriuretic factor (125I-rANF, 99-128) is hydrolysed by pure enkephalinase (EC 3.4.24.11) in vitro at a rate similar to that of 125I-hANF. Trichloroacetic precipitated radioactivity was significantly elevated in the kidneys of rats pretreated with acetorphan, an enkephalinase inhibitor, and receiving 125I-rANF, indicating that the exogenous hormone was protected against degradation. A single oral administration of acetorphan elicited diuretic and natriuretic effects in conscious normotensive rats and natriuretic effects in spontaneously hypertensive rats, effects which were not accompanied by significant changes in kaliuresis. The diuretic and natriuretic effects were still observed in conscious normotensive rats after three days of repeated administration of the drug. In conscious or anesthetized rats in which volume expansion was elicited by hydroelectrolytic loads, the initial rate of urinary elimination of water and sodium was nearly doubled by treatment with enkephalinase inhibitors. This effect was prevented by coadministration of an ANF antiserum, which suggests that the effect was mediated by endogenous ANF. These various observations suggest that enkephalinase inhibitors protect endogenous ANF from degradation and thereby enhance the typical renal effects of the hormone.
Assuntos
Fator Natriurético Atrial/metabolismo , Diurese/efeitos dos fármacos , Natriurese/efeitos dos fármacos , Neprilisina/antagonistas & inibidores , Potássio/urina , Tiorfano/farmacologia , Animais , Fator Natriurético Atrial/administração & dosagem , Fator Natriurético Atrial/sangue , Cromatografia Líquida de Alta Pressão , Injeções Intravenosas , Masculino , Neprilisina/sangue , Pró-Fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos , Tiorfano/administração & dosagem , Tiorfano/análogos & derivados , Fatores de TempoRESUMO
Rats fed with low (0.015%), normal (0.08%) or high (0.32%) magnesium (Mg) diet for 5-6 weeks were subjected to photothrombosis-induced infarction. As compared to normal diet, Mg deprivation increased by 45% infarct volume at 24 h after photothrombosis but did not modify the lesion at 4 h after photothrombosis. Mg supplementation did not protect from infarction whatever the time point examined. No differences in pre-ischemic systolic blood pressure and glycemia as well as in post-ischemic kaliemia, calcemia and plasma antioxidant activity were observed between groups. However, plasma total Mg level correlated with plasma antioxidant activity at 4 h after photothrombosis. These results demonstrate that brains from Mg deficient rats are more susceptible to permanent focal ischemia than rats fed with normal or high Mg diet.
Assuntos
Isquemia Encefálica/sangue , Deficiência de Magnésio/sangue , Magnésio/sangue , Acidente Vascular Cerebral/sangue , Animais , Isquemia Encefálica/dietoterapia , Magnésio/farmacologia , Magnésio/uso terapêutico , Masculino , Ratos , Ratos Wistar , Acidente Vascular Cerebral/dietoterapiaRESUMO
Inducible nitric oxide synthase (iNOS) protects heart against ischemia/reperfusion injury. However, it is unknown whether the beneficial effects of iNOS are mediated by the interaction of NO with radical oxygen species (ROS). To address this issue, we examined the effects of liposoluble iron-induced ROS generation in isolated perfused hearts from rats treated with lipopolysaccharide (LPS). LPS administration (10 mg/kg, i.p., 6 h before heart removal) induced iNOS expression and increased NO production as indicated by a 3-fold elevation of nitrite level in coronary effluents relative to control hearts. An enhanced expression of hemeoxygenase 1 protein was also observed in septic hearts compared to control. Iron-induced perfusion and contractile deficits were ameliorated by LPS with more important coronary than myocardial benefits. In iron-loaded hearts, oxidative stress as measured by the 2,3 dihydroxybenzoic acid/salicylic acid concentration ratio in cardiac tissue was 23% lower in septic than in control heart although the difference did not reach significance. In addition, the presence of the NO synthase inhibitor N-nitro-L-arginine in the perfusion medium totally blocked NO production but did not reverse the protective effects of LPS. The results indicate that LPS protects from iron-induced cardiac dysfunction by mechanisms independent on ex vivo NO production and suggest that NO acts as a trigger rather than a direct mediator of the cardioprotective effects of LPS in heart exposed to iron.
Assuntos
Coração/efeitos dos fármacos , Ferro/metabolismo , Miocárdio/enzimologia , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/metabolismo , Animais , Arginina/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Hidroxibenzoatos/metabolismo , Radical Hidroxila , Immunoblotting , Lipopolissacarídeos/metabolismo , Contração Miocárdica/efeitos dos fármacos , Óxido Nítrico/química , Óxido Nítrico Sintase Tipo II , Nitritos/metabolismo , Nitroarginina/química , Estresse Oxidativo , Perfusão , Ratos , Ratos Wistar , Traumatismo por Reperfusão/prevenção & controle , Ácido Salicílico/metabolismo , Fatores de TempoRESUMO
We examined clinical recovery from repeated brain ischemic insults that have been reported to affect cytologic outcome. Brain ischemia was induced in the rat by four-vessel occlusion. A 30-min ischemia was given as a single insult or induced in animals made ischemic 24 h earlier by a 10-min insult but exempt both of brain hypoperfusion and neurologic deficit in spite of a partial necrosis of the CA1 sector of hippocampus. Repeated ischemia was associated with a significantly poorer clinical outcome as indicated by an increase in percentage of rats that exhibited postischemic seizure activity combined with the percentage of unconvulsive rats exhibiting neurologic deficits after 72 h of reperfusion (81% vs. 50% after a single 30-min ischemia). Examination of hippocampal damage showed that neurons surviving the first ischemia did not acquire resistance to the second ischemia. Pentobarbital given from start of overt seizures (30 to 60 mg/kg, IP, thrice daily) was able to stop convulsions and to antagonize processes involved in ischemia-induced neuronal death of CA1 hippocampus.
Assuntos
Encéfalo/patologia , Encéfalo/fisiopatologia , Ataque Isquêmico Transitório/fisiopatologia , Pentobarbital/farmacologia , Animais , Glicemia/metabolismo , Temperatura Corporal , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular , Hipocampo/patologia , Ataque Isquêmico Transitório/patologia , Masculino , Necrose , Células Piramidais/patologia , Ratos , Ratos Wistar , Convulsões/patologia , Convulsões/fisiopatologia , Fatores de TempoRESUMO
Stroke is a leading cause of death and disability in industrialized countries. Although surviving patients exhibit a certain degree of restoration of function attributable to brain plasticity, the majority of stroke survivors has to struggle with persisting deficits. In order to potentiate post-stroke recovery, several rehabilitation therapies have been undertaken and many experimental studies have reported that brain-derived neurotrophic factor (BDNF) is central to many facets of neuroplastic processes. However, although BDNF role in brain plasticity is well characterized through strategies that manipulate its content, the involvement of this neurotrophin in spontaneous post-stroke recovery remains to be clarified. Besides, while the neuroplastic role of BDNF is restricted to its mature form, most studies investigating the proper effect of ischemia on post-stroke BDNF metabolism focused on mRNA or total protein expressions. In addition, these studies are mainly performed in brain regions collected either at or around the lesion site. Therefore, the objective of the present study was to investigate in both hemispheres, the long-term expression (up to one month) of both pro- and mature BDNF forms in rats subjected to photothrombotic ischemia. These assessments were performed in the cortex and in the hippocampus, two regions known to subserve functional recovery after stroke and were coupled to the study of synaptophysin expression, a marker of synaptogenesis. Our study reports that stroke induces an early and transient increase (4h) in mature BDNF expression in the cortex of both hemispheres that was associated with a delayed rise (30d) in synaptophysin levels ipsilateraly. In both hippocampal territories, the pattern of mature BDNF expression shows a more delayed increase (from 8 to 30d), which coincides with the evolution of synaptophysin expression. Interestingly, in these hippocampal territories, pro-BDNF levels evolve differently suggesting a differential gene regulation between the two hemispheres. While highlighting the complexity of changes in BDNF metabolism after stroke, our data suggest that BDNF involvement in spontaneous post-stroke plasticity is region-dependent.
Assuntos
Isquemia Encefálica/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Plasticidade Neuronal/fisiologia , Acidente Vascular Cerebral/metabolismo , Animais , Encéfalo/fisiopatologia , Isquemia Encefálica/fisiopatologia , Masculino , Ratos , Ratos Wistar , Acidente Vascular Cerebral/fisiopatologia , Sinaptofisina/metabolismo , Fatores de TempoRESUMO
Rats were treated with alpha-methyl-para-tyrosine (AMT, 250 mg/kg, i.p), an hydroxylase inhibitor, in order to decrease brain levels of catecholamines. Six hours later, when cerebral dopamine (DA) and norepinephrine were reduced by about 80%, a transient forebrain ischemia of 30 min duration was induced by four-vessel occlusion technique. Evaluation of brain damage 72 hours after ischemia showed that AMT treatment significantly decreased neuronal necrosis in the striatum but had no cytoprotective effect in the CA1 sector of the hippocampus and in the neocortex. AMT treatment reduced mortality within the ischemic period but did not affect either the mortality within the recirculation period or the postischemic neurologic deficit. These results suggest that the striatal cytoprotective effect of AMT is linked to cerebral DA depletion and that excessive release of DA during ischemia or dopaminergic hyperactivity during recirculation play a detrimental role in the development of ischemic cell damage in the striatum.
Assuntos
Corpo Estriado/efeitos dos fármacos , Ataque Isquêmico Transitório/tratamento farmacológico , Metiltirosinas/farmacologia , Neurônios/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Animais , Encéfalo/metabolismo , Catecolaminas/metabolismo , Morte Celular/efeitos dos fármacos , Corpo Estriado/citologia , Ataque Isquêmico Transitório/metabolismo , Ataque Isquêmico Transitório/patologia , Masculino , Neurônios/citologia , Prosencéfalo/irrigação sanguínea , Ratos , Ratos Endogâmicos , Fatores de Tempo , alfa-MetiltirosinaRESUMO
The left coronary artery in rats was ligated for a period of 15 days to induce hypertrophy of the non-infarcted myocardium. Left ventricular performances were evaluated in the working heart model. In addition, cardiac hypertrophic indices and noradrenaline content were measured. Variables were determined in the absence or presence of the angiotensin-converting enzyme inhibitor, perindopril. A 35 and 60% decrease in the coronary and cardiac output, respectively, and a 57% decrease in the noradrenaline content of the non-infarcted left ventricular free wall were seen. Furthermore, a 15% increase in the heart/body weight ratio was observed in the infarcted group. After chronic treatment of the animals with perindopril (2 mg.kg-1 body weight, per os), coronary and cardiac output were impaired to a lesser extent: 8 and 35% respectively, with only a 15% decrease in the noradrenaline content of the non-infarcted left ventricular free wall. Furthermore, the increase in heart/body weight ratio was significantly less than in the nontreated infarct group (7%). We conclude that the beneficial effects of converting enzyme inhibition, during the development of myocardial infarction, on left ventricular performances are associated with a decrease in the hypertrophic indices and a normalization of sympathetic activity.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Indóis/farmacologia , Miocárdio/metabolismo , Norepinefrina/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Débito Cardíaco/efeitos dos fármacos , Cardiomegalia/fisiopatologia , Circulação Coronária/efeitos dos fármacos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Masculino , Tamanho do Órgão/efeitos dos fármacos , Perindopril , Ratos , Ratos EndogâmicosRESUMO
Thiorphan, a potent inhibitor of enkephalinase (membrane metalloendopeptidase, atriopeptidase, EC 3.4.24.11) enhanced markedly (+214%) and prolonged the rise in plasma atrial natriuretic factor (ANF) immunoreactivity in anesthetized rats submitted to acute extracellular volume expansion obtained through i.v. injection of a Ringer's solution. These changes were accompanied by marked potentiations of the natriuretic and diuretic responses to the ANF-releasing stimulus, whereas kaliuresis was only slightly affected. Thiorphan also enhanced markedly the biphasic rise in urinary cyclic GMP excretion elicited by volume expansion. All these renal responses to volume expansion in thiorphan-treated rats were significantly reduced by pretreatment with anti-ANF antibodies, suggesting an involvement of the endogenous natriuretic hormone protected against degradation. However, pretreatment with antibradykinin antibodies led to qualitatively similar results, suggesting that the endogenous kinin-generating system in kidney may also participate in the responses to endogenous ANF and their potentiation by the peptidase inhibitor.
Assuntos
Fator Natriurético Atrial/fisiologia , Cininas/fisiologia , Natriurese/efeitos dos fármacos , Tiorfano/farmacologia , Animais , Anticorpos/farmacologia , Função Atrial , Fator Natriurético Atrial/sangue , Fator Natriurético Atrial/imunologia , Bradicinina/imunologia , Bradicinina/fisiologia , Volume Cardíaco/fisiologia , GMP Cíclico/urina , Rim/efeitos dos fármacos , Rim/fisiologia , Masculino , Neprilisina/antagonistas & inibidores , Neprilisina/fisiologia , Ratos , Ratos EndogâmicosRESUMO
The acute diuretic and natriuretic effects of fasidotrilat, a mixed inhibitor of neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE) were evaluated in control and myocardial-infarcted rats. Fasidotrilat injection (10 mg/kg i.v.) had no significant effect on arterial blood pressure and led to significant elevations in urine volume (+57% in control rats and +114% in infarcted rats) and of urinary sodium excretion (+81% in control rats and +225% in infarcted rats). Comparison between control and infarcted rats showed that fasidotrilat-induced changes in diuresis and natriuresis were higher in infarcted rats (2.4-fold for diuresis and 4.7-fold for natriuresis, p < 0.05), despite a lower perfusion pressure (-10 mm Hg) in infarcted rats. These data show the potential therapeutic interest of mixed NEP/ACE inhibitors in congestive heart failure.
Assuntos
Alanina/análogos & derivados , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores Enzimáticos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Natriurese/efeitos dos fármacos , Neprilisina/antagonistas & inibidores , Peptidil Dipeptidase A/efeitos dos fármacos , Alanina/farmacologia , Alanina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Diurese/efeitos dos fármacos , Diurese/fisiologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/fisiopatologia , Ligadura , Masculino , Infarto do Miocárdio/fisiopatologia , Natriurese/fisiologia , Ratos , Ratos WistarRESUMO
Elevation of cell iron content was produced by use of a lipophilic iron ligand, 8-hydroxyquinoline (HQ), capable of transferring catalytically active iron into cells. The Fe(3+)-HQ complex labeled with 59Fe was avidly taken up by isolated perfused hearts contrary to the hydrophilic complex Fe(3+)-citrate. Hearts perfused in aerobic conditions with Krebs-Henseleit buffer were exposed for 15 min to the iron complexes, Fe(3+)-HQ (5 microM/10 microM and 10 microM/20 microM), or Fe(3+)-citrate (10 microM), and then perfused for 30 min with normal buffer. Exposure to the high dose of Fe(3+)-HQ (10 microM/20 microM) resulted in early and irreversible decreases in coronary flow and heart rate (-48% and -33%, respectively), initial increases followed by decreases in left ventricular systolic pressure and +dP/dt, and increase in left ventricular end-diastolic pressure (+80%). The low dose of Fe(3+)-HQ (5 microM/10 microM) mimicked with a lower magnitude the effects of the high dose, whereas Fe(3+)-citrate had no effects on cardiac parameters. Only hearts exposed to the high dose of Fe(3+)-HQ exhibited a significant increase (+60%) in thiobarbituric acid-reactive substance level, an index of lipid peroxidation. The production of hydroxyl radicals was investigated by measuring 2,3-dihydroxybenzoic acid level in the coronary effluent after addition of salicylic acid (1 mM) in the perfusate. An immediate and high increase (x6) was seen during heart exposure to Fe(3+)-HQ (10 microM/20 microM) and to Fe(3+)-citrate (10 microM). Considering Fe(3+)-citrate had no effect on cardiac function and lipid peroxidation it was concluded that this hydroxyl radical formation occurring in the extracellular space was not implicated in Fe(3+)-HQ-induced cardiac dysfunction. These results demonstrate the deleterious effect of increasing intracellular reactive iron level in non-ischemic hearts.
Assuntos
Circulação Coronária/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Ferro/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Radicais Livres , Radical Hidroxila , Técnicas In Vitro , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Miocárdio/citologia , Oxiquinolina/farmacologia , Perfusão , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
The aim of the study was to compare, in a rat model of congestive heart failure, the effect of captopril, a selective angiotensin-converting enzyme (ACE; EC 3.4.15.1) inhibitor, to that of alatriopril, a mixed inhibitor of ACE and atriopeptidase (EC 3.4.24.11), an enzyme implicated in the degradation of atrial natriuretic factor (ANF). Myocardial infarction was induced by ligation of the left coronary artery. Groups of rats received orally twice daily captopril (10 mg/kg), alatriopril (100 mg/kg) or vehicle. Treatments were started 18 to 20 h after ligation and continued for 4 weeks. Hypertrophic and hormonal changes reflecting congestive heart failure were assessed in rats with large infarcts by measuring the relative weight of cardiac tissues as well as by assaying ANF in heart and plasma and by measuring renin activity in plasma. Both treatments significantly reduced cardiac hypertrophy, but alatriopril showed a greater efficacy than captopril--the increase in relative heart weight reaching 38% with captopril and only 22% with alatriopril (P < .05). The hypertrophy of right ventricle was reduced by 47% with alatriopril and by 35% with captopril (N.S.), whereas the corresponding reductions for atria were 47% vs. 21% (P < .05). Both treatments prevented the ligation-induced increase of ANF level in the right ventricle. In contrast, plasma ANF level was significantly reduced after captopril but not after alatriopril treatment, a difference that probably reflects the protection of endogenous ANF in circulation resulting from atriopeptidase inhibition. Plasma renin was increased by 36-fold after captopril but only by 1.6-fold after alatriopril, a difference that presumably reflects the inhibition of renal renin secretion by endogenous ANF after alatriopril. These data suggest that enhancement of ANF levels in circulation via atriopeptidase inhibition magnifies the capacity of ACE inhibitors to prevent cardiac hypertrophy, and they show the potential therapeutic value of mixed ACE-atriopeptidase inhibitors in congestive heart failure.
Assuntos
Alanina/análogos & derivados , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Cardiomegalia/tratamento farmacológico , Dioxóis/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Hormônios/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Alanina/farmacologia , Sequência de Aminoácidos , Angiotensina I/antagonistas & inibidores , Angiotensina I/farmacologia , Animais , Fator Natriurético Atrial/sangue , Fator Natriurético Atrial/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Bradicinina/antagonistas & inibidores , Bradicinina/farmacologia , Cardiomegalia/enzimologia , Modelos Animais de Doenças , Insuficiência Cardíaca/enzimologia , Hormônios/sangue , Masculino , Dados de Sequência Molecular , Infarto do Miocárdio/enzimologia , Miocárdio/enzimologia , Miocárdio/metabolismo , Neprilisina/sangue , Peptidil Dipeptidase A/sangue , Ratos , Ratos Wistar , Renina/sangueRESUMO
Cyclosporin A (CsA) is widely used as the immunosuppressant of choice for preventing graft rejection. However, its clinical use is hampered by certain side effects, especially its nephrotoxicity and other cardiovascular side effects. CsA for intravenous infusion contains cremophor (Cre) and this vehicle has significant adverse effects on endothelial function and vascular muscle. The present study was aimed at investigating the direct effects of CsA and Cre on isolated and perfused rat hearts in the dosage that closely approximates the peak level achieved for the prevention of graft rejection in the rat. Transplantation is a clinical setting in which the myocardium may be exposed to transient ischemia. In this study, we have shown that the vehicle of CsA, namely Cre, has significant adverse effects on cardiac function. We observed a reduction in coronary flow and aortic output. Addition of CsA appeared to induce a further reduction of aortic flow. We have also shown that a significant increase of thiobarbituric acid reactive substances, considered as an index of lipid peroxidation, occurred in the reperfused heart in the presence of Cre+CsA. Our experimental study shows that Cre turned out to be toxic to myocardium by itself. In the heart, potential Cre-CsA interactions possibly potentiating CsA toxicity could not be excluded. The increase of lipid peroxidation in the heart perfused with CsA suggests that reactive oxygen species may be involved in the detrimental effects of this substance on the heart.
Assuntos
Ciclosporina/farmacologia , Coração/efeitos dos fármacos , Imunossupressores/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Veículos Farmacêuticos/toxicidade , Polietilenoglicóis/toxicidade , 3,4-Metilenodioxianfetamina/metabolismo , Análise de Variância , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Circulação Coronária/efeitos dos fármacos , Ciclosporina/toxicidade , Sinergismo Farmacológico , Transplante de Coração , Masculino , Isquemia Miocárdica/induzido quimicamente , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Taquicardia/induzido quimicamente , Fibrilação Ventricular/induzido quimicamenteRESUMO
To evaluate the contribution of cellular dysfunction and neuronal loss to brain N-acetylaspartate (NAA) depletion, NAA was measured in brain tissue by HPLC and UV detection in rats subjected to cerebral injury, associated or not with cell death. When lesion was induced by intracarotid injection of microspheres, the fall in NAA was related to the degree of embolization and to the severity of brain oedema. When striatal lesion was induced by local injection of malonate, the larger the lesion volume, the higher the NAA depletion. However, reduction of brain oedema and striatal lesion by treatment with the lipophilic iron chelator dipyridyl (20 mg/kg, 1 h before and every 8 h after embolization) and the inducible nitric oxide synthase inhibitor aminoguanidine (100 mg/kg given 1 h before malonate and then every 9 h), respectively, failed to ameliorate the fall in NAA. Moreover, after systemic administration of 3-nitropropionic acid, a marked reversible fall in NAA striatal content was observed despite the lack of tissue necrosis. Overall results show that cellular dysfunction can cause higher reductions in NAA level than neuronal loss, thus making of NAA quantification a potential tool for visualizing the penumbra area in stroke patients.
Assuntos
Ácido Aspártico/análogos & derivados , Ácido Aspártico/análise , Química Encefálica , Edema Encefálico/metabolismo , Isquemia Encefálica/metabolismo , 2,2'-Dipiridil/administração & dosagem , 2,2'-Dipiridil/farmacologia , 2,2'-Dipiridil/uso terapêutico , Doença Aguda , Animais , Biomarcadores , Edema Encefálico/etiologia , Edema Encefálico/patologia , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Artérias Carótidas , Morte Celular , Cromatografia Líquida de Alta Pressão , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Guanidinas/administração & dosagem , Guanidinas/farmacologia , Guanidinas/uso terapêutico , Injeções Intra-Arteriais , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Masculino , Malonatos/toxicidade , Microesferas , Mitocôndrias/efeitos dos fármacos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Nitrocompostos , Estresse Oxidativo , Pré-Medicação , Propionatos/toxicidade , Ratos , Ratos Wistar , Espectrofotometria Ultravioleta , Succinato Desidrogenase/antagonistas & inibidoresRESUMO
The aim of the present study was to determine, in rats with myocardial infarction, the systemic and cardiac hemodynamic effects of aladotrilat and of its prodrug, aladotril, both of which display inhibitory activity toward both neutral endopeptidase (NEP, EC. 3.4.24.11) and angiotensin I-converting enzyme (ACE). The effects of acute intravenous injection of aladotrilat (30 mg/kg bolus injection plus 30 mg/kg/hr infusion) were measured for 1 hr in conscious infarcted rats and compared with the effects of SQ 28,603, a selective NEP inhibitor (30 mg/kg bolus injection plus 30 mg/kg/hr infusion), and captopril, a selective ACE inhibitor (10 mg/kg bolus injection plus 10 mg/kg/hr infusion). Unlike SQ 28,603, aladotrilat and captopril produced a slight fall in mean arterial blood pressure. The three treatments had no significant effect on heart rate and rate of increase of left ventricular pressure (LV + dP/dt) but caused significant decreases in left ventricular end-diastolic pressure (LVEDP). The effect of aladotrilat on decreasing LVEDP was faster than those of captopril or SQ 28,603. In chronic experiments, groups of rats received orally, twice daily, captopril (10 mg/kg), aladotril (100 mg/kg) or vehicle. Treatments were started 18 to 20 hr after coronary artery ligation and continued for 4 weeks. Hemodynamic parameters and cardiac hypertrophy were measured at the end of therapy. Unlike aladotril, captopril treatment resulted in significant decreases in mean arterial blood pressure and left ventricular systolic pressure (approximately 15 mm Hg) and produced renal vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Alanina/análogos & derivados , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Infarto do Miocárdio/fisiopatologia , Neprilisina/antagonistas & inibidores , Peptidil Dipeptidase A/metabolismo , Inibidores de Proteases/farmacologia , Alanina/farmacologia , Animais , Captopril/farmacologia , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Masculino , Infarto do Miocárdio/enzimologia , Ratos , Ratos WistarRESUMO
Myocardial infarction was induced by rats by ligation of the left coronary artery. Treatment with TM1, a prodrug of SQ 28,603, an inhibitor of neutral endopeptidase (NEP, EC 3.4.24.11), was started 18-20 hours after ligation and was continued for 4 weeks (100 mg/kg, orally, twice daily). Morphological and biochemical parameters were assessed at the endo of therapy. The treatment resulted in a significant reduction of heart hypertrophy, which was restricted to the parts of myocardium hemodynamically upstream of the infarcted left ventricle. The weights of the right ventricle and atria were reduced by 15-20%, whereas the treatment had no effect on the left ventricle and septum weights. Treatment led to an almost complete inhibition of plasma NEP activity and to a slight decrease (-14%, p < 0.05) in plasma ACE activity. Plasma ANF level increased 3.8-fold after ligation, and treatment resulted in a slight ( + 29%) and nonsignificant additional increase in the ANF level. The amount of hydroxyproline in the right ventricle was enhanced by + 207% in control ligated rats and by +140% (NS) in treated rats. These data indicated that prolonged NEP inhibition exerts a favorable effect in heart failure by reducing the development of right ventricular and atrial hypertrophy. These effects may result from an improvement in hemodynamic conditions, leading to a reduction in cardiac preload.
Assuntos
Alanina/análogos & derivados , Cardiomegalia/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Alanina/uso terapêutico , Animais , Fator Natriurético Atrial/sangue , Ligadura , Masculino , Neprilisina/sangue , Ratos , Ratos WistarRESUMO
We examined the efficacy of the liposoluble iron chelator 2,2'-dipyridyl (DP) in reducing histological damage in rats submitted to cerebral ischemia and the mechanisms involved in the potential cytoprotection. For this purpose, DP (20 mg/kg, i.p.) was administered 15 min before and 1 h after induction of cortical photothrombotic vascular occlusion in rat. Histological studies were performed to assess infarct volume (at days 1 and 3 postischemia) and astromicroglial activation (at day 3 postischemia). Damage to endothelial and neuronal cells was evaluated at day 1 postischemia by quantitative measurements of Evans Blue extravasation and N-acetylaspartate levels, respectively. Cerebral blood flow was recorded in the ischemic core by laser-Doppler flowmetry within the 15 min to 2 h period after photothrombosis. At 4-h postischemia, radical oxygen species (ROS) production was evaluated by measuring brain glutathione concentrations. The cortical expression of the proteins heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1alpha (HIF-1alpha) was analyzed by Western blotting at day 1 postischemia. Infarct volume and ischemic damage to endothelial and neuronal cells were significantly reduced by DP treatment. This cytoprotection was associated with a reduction in ROS production, perfusion deficits, and astrocytic activation. DP treatment also resulted in significant changes in HO-1 (+100%) and HIF-1alpha (-50%) protein expression at the level of the ischemic core. These results report the efficacy of the liposoluble iron chelator DP in reducing histological damage induced by permanent focal ischemia.