RESUMO
OBJECTIVES: Elevation of serum total homocysteine (tHcy) is considered to contribute to endothelial cell dysfunction, which is considered to be the initial event in posttransplant vascular disease. We sought to investigate whether an association existed between serum tHcy levels and vascular endothelial function during cyclosporine (CsA) treatment. MATERIALS AND METHODS: Endothelium-dependent and -independent relaxation responses (to acetylcholine [ACh] and sodium nitroprusside [SNP]) were determined on thoracic aortae from CsA-treated rats (5 mg kg/d, subcutaneously, for 14 days). A correlation analysis was performed between ACh responses and tHcy levels. RESULTS: CsA decreased the responses to ACh and the pD(2) values of the concentration-response curves compared with controls (P < .05). Responses to SNP and serum tHcy levels were unchanged among the groups. tHcy negatively correlated with the ACh pD(2) values among control (r = -0.69; P < .05) and vehicle (r = -0.73; P < .05) groups, indicating that the increase in tHcy was associated with decreased sensitivity to ACh. In CsA-treated rats, no association was observed between these parameters. Also, no correlation was noted between CsA concentrations and tHcy levels. CONCLUSION: These data suggested a possible link between serum tHcy and decreased vascular sensitivity to endothelium-dependent vasorelaxation in control aortae, but CsA-induced vascular endothelial dysfunction was not associated with an effect of the drug on homocysteine metabolism.
Assuntos
Aorta Torácica/fisiologia , Ciclosporina/farmacologia , Endotélio Vascular/fisiopatologia , Homocisteína/sangue , Animais , Aorta Torácica/efeitos dos fármacos , Ciclosporina/sangue , Emulsões/farmacologia , Endotélio Vascular/efeitos dos fármacos , Imunossupressores/farmacologia , Técnicas In Vitro , Masculino , Nitroprussiato/farmacologia , Polietilenoglicóis/farmacologia , Ratos , Ratos Wistar , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
OBJECTIVE: Aprotinin, a non-specific serine protease inhibitor, reduces postoperative bleeding after coronary artery surgery. The mechanism of action for this 'blood-sparing' effect of aprotinin is only partially clarified. We therefore aimed to investigate the effect of aprotinin on the release of nitric oxide (NO), a vasodilator and antiaggregant factor, from rat coronary microvascular endothelial cells and on the NO-mediated endothelium-dependent relaxation of rat thoracic aorta. METHODS: Endothelium-intact and endothelium-denuded thoracic aortic rings from Wistar rats (250-300 g) were suspended in organ chambers. Contractile and relaxant responses in the absence and presence of aprotinin (125, 250 and 500 KIU/ml) were recorded via a mechanotransducer. Coronary microvascular endothelial cells (CMEC) were isolated on a Langendorff system by collagenase perfusion of the hearts from the same rats. Calcium ionophore- (1 microM) induced release of NO from confluent cells was determined spectrophotometrically by measuring its stable metabolites, nitrite and nitrate, via Griess reaction. RESULTS: Aprotinin selectively enhanced phenylephrine-induced contractions in endothelium-intact rat thoracic aortic rings, but not in the endothelium-denuded rings. The use of a nitric oxide synthesis inhibitor Nomega-nitro-L-arginine methyl ester (100 microM) on endothelium-intact rings produced a similar increase in phenylephrine-induced contractions. KCl-induced contractions remained unaltered. Aprotinin inhibited acetylcholine-, calcium ionophore- and L-arginine-induced endothelium-dependent relaxations, but not sodium nitroprusside-induced endothelium-independent relaxation. Aprotinin had no significant effect on basal nitrite-nitrate release from CMEC, while it inhibited calcium ionophore-induced total nitrite accumulation in the supernatants. CONCLUSION: Aprotinin selectively impairs endothelium-dependent relaxation as well as basal NO availability in rat thoracic aortic rings and inhibits NO release from rat CMEC. This effect of the drug may contribute to its 'blood-sparing' action and may also account for the increase in perioperative restenosis risk observed in clinical practice during aprotinin therapy.
Assuntos
Aprotinina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Hemostáticos/farmacologia , Inibidores de Serina Proteinase/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Técnicas de Cultura de Células , Técnicas de Cultura , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Masculino , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Fenilefrina/farmacologia , Ratos , Ratos Wistar , Vasoconstrição/efeitos dos fármacosRESUMO
Leukotrienes are one of the biological mediators that play a role in endotoxic shock. In this study, we investigated the effects of a leukotriene biosynthesis inhibitor, MK-886, in a rabbit model of endotoxic shock. Lipopolysaccharide (Escherichia coli serotype 055:B5) infusion (1 mg kg(-1) h(-1)) to rabbits caused a biphasic decline in arterial blood pressure and decreased the vasoresponsiveness to phenylephrine, potassium chloride, sodium nitroprusside and acetylcholine in abdominal aortic rings. Oral administration of MK-886 (3-(1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl(-2,2-+ ++dimethylpropanoic acid) (5 mg/kg) 3 h prior to lipopolysaccharide infusion significantly inhibited the decline in arterial blood pressure and enhanced the responsiveness to phenylephrine and acetylcholine, whereas the changes in sodium nitroprusside and potassium chloride responses were not significant. However, the pD2 (-log EC50) values for sodium nitroprusside in this group were higher than those of the group that received lipopolysaccharide alone. Neither the administration of the vehicle alone to endotoxemic rabbits, nor MK-886 administration to control animals, caused significant changes. These data suggest that MK-886 attenuates the hypotension and partially reverses the impaired vascular responsiveness observed in endotoxic shock.
Assuntos
Indóis/farmacologia , Leucotrienos/biossíntese , Inibidores de Lipoxigenase/farmacologia , Choque Séptico/metabolismo , Algoritmos , Animais , Pressão Sanguínea/efeitos dos fármacos , Endotoxinas/toxicidade , Hemodinâmica/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Masculino , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Nitroprussiato/farmacologia , Fenilefrina/antagonistas & inibidores , Fenilefrina/farmacologia , Coelhos , Vasoconstritores/antagonistas & inibidores , Vasoconstritores/farmacologiaRESUMO
The effect of a leukotriene D(4) receptor antagonist, (3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl(3-dimethyl amino-3-oxo propyl)thio)methyl)thio) propanoic acid (L-660,711; MK-571), was investigated on nociceptive responses in mice using three different assays: acetic-acid-induced abdominal constrictions, formalin response and tail-flick test. MK-571 (8-32 mg/kg, i.v.) produced dose-dependent protection against acetic-acid-induced abdominal constriction (ED(50)=30 mg/kg). The compound (10-80 mg/kg, i.p.) was also effective, in a dose-dependent manner, on the second phase of the formalin response (ED(50)=26 mg/kg). However, it had no effect on the first phase of the formalin response and in the tail-flick test. Naloxone (1 mg/kg, i.v.), an opioid antagonist, almost completely blocked the antinociceptive effect of MK-571 in both acetic-acid-induced abdominal constriction and the second phase of the formalin test. These results provide evidence for an antinociceptive action of MK-571 at peripheral sites and suggest that opioid mechanisms are involved.
Assuntos
Analgésicos/farmacologia , Antagonistas de Leucotrienos , Antagonistas de Leucotrienos/farmacologia , Proteínas de Membrana , Propionatos/farmacologia , Quinolinas/farmacologia , Receptores de Leucotrienos , Receptores Opioides/metabolismo , Dor Abdominal/induzido quimicamente , Dor Abdominal/prevenção & controle , Acetatos , Analgésicos/uso terapêutico , Animais , Temperatura Corporal/efeitos dos fármacos , Antagonistas de Leucotrienos/uso terapêutico , Masculino , Camundongos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Medição da Dor/efeitos dos fármacos , Propionatos/uso terapêutico , Quinolinas/uso terapêuticoRESUMO
The effects of tianeptine, a novel and unusual tricyclic antidepressant drug, on tail-flick and hot-plate tests, which are two thermal analgesia evaluating methods, have been investigated in mice. Tianeptine (5 and 10 mg/kg), para-chlorophenylalanine (pCPA) (100 mg/kg) and a combination of pCPA and tianeptine (10 mg/kg) or saline were injected to mice intraperitoneally. pCPA (100 mg/kg) was injected 24 h before tianeptine or saline treatment when it was combined with tinaeptine (10 mg/kg) or tested alone. The tail-flick latencies and hot-plate reaction times of the mice were measured between 15th and 180th minutes following injections. Tianeptine (10 mg/kg) exhibited a significant antinociceptive activity that could be measured by both tests as compared to groups which were treated with saline or pCPA alone between 15th and 180th min of the observation period. The lower dose of tianeptine (5 mg/kg) or pCPA (100 mg/kg) did not produce any significant changes on tail-flick latency or hot-plate reaction time of the mice. However, pretreatment with pCPA completely blocked the antinociceptive effect induced by tianeptine (10 mg/kg) in both tests used in the present study. Furthermore, tianeptine (10 mg/kg) did not cause any significant impairment effects on rotarod performance of the mice. Our results suggested that tianeptine has a prominent thermal antinociceptive activity in mice and that increased serotonergic activity may be responsible for the analgesic effect of tianeptine.
Assuntos
Analgésicos/farmacologia , Antidepressivos Tricíclicos/farmacologia , Fenclonina/farmacologia , Dor/fisiopatologia , Tiazepinas/farmacologia , Análise de Variância , Animais , Interações Medicamentosas , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Tempo de ReaçãoRESUMO
The present study evaluated the effect of dietary vitamin E supplementation (1,000 mg/kg chow) on the alterations in vascular reactivity of streptozotocin-diabetic aorta of Wistar rats. After 12 weeks of treatment, thoracic aortic rings of rats were mounted in organ baths and contractile responses to phenylephrine and 5-hydroxytryptamine and relaxant responses to acetylcholine, calcium ionophore and sodium nitroprusside were assessed. Plasma vitamin E concentration as measured by HPLC was markedly decreased in diabetic rats and increased with dietary vitamin E supplementation. Induction of diabetes significantly impaired endothelium-dependent relaxations to acetylcholine and calcium ionophore in aortic rings, but did not change endothelium-independent relaxation to sodium nitroprusside. Vitamin E significantly improved the impaired endothelium-dependent relaxations, further it decreased the enhanced contractile response to phenylephrine and 5-hydroxytryptamine in diabetic rings. The mechanical denudation of endothelium or the chemical inhibition of endothelium-dependent relaxation with N(omega)-nitro-L-arginine methyl ester (100 micromol/l) significantly increased phenylephrine contractility in control rings and the rings of diabetic rats treated with vitamin E; such a difference was not observed in diabetic rats fed with normal diet. Liver and lung malondialdehyde concentrations, as an index of lipid peroxidation, were increased in diabetic rats and significantly decreased with vitamin E supplementation. It is concluded that dietary supplementation of vitamin E improved endothelial dysfunction in insulin-dependent model of uncontrolled diabetes, probably decreasing membranal lipid peroxidation.
Assuntos
Aorta Torácica/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Vasoconstrição/efeitos dos fármacos , Vitamina E/administração & dosagem , Acetilcolina/farmacologia , Animais , Aorta Torácica/fisiopatologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Calcimicina/farmacologia , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Técnicas In Vitro , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Malondialdeído/metabolismo , Nitroprussiato/farmacologia , Fenilefrina/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Serotonina/farmacologia , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Vitamina E/sangueRESUMO
In this study, coronary perfusion pressure and force of contraction were investigated in isolated hearts removed from arthritic rats by using the Langendorff method. A strong coronary vasoconstriction was determined in arthritic hearts which was associated with elevated levels of arachidonate 5-lipoxygenase (5-LOX) products, leukotriene B(4) (LTB(4)) and LTC(4) in coronary effluents. In vivo treatment with the dual inhibitor of cyclooxygenase (COX) and LOX, CI-986 (2 and 10 mg/kg/day) on days 14- 26 following adjuvant injection, prevented the coronary vasoconstriction and the increased production of LTB(4) and LTC(4). These results suggest that the coronary vasoconstriction in the isolated arthritic hearts is associated with an increased activity of the LOX system and CI-986 could have a preventive effect on constriction of coronary arteries.
Assuntos
Artrite Experimental/fisiopatologia , Inibidores de Ciclo-Oxigenase/farmacologia , Leucotrienos/fisiologia , Inibidores de Lipoxigenase/farmacologia , Tiadiazóis/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Testes de Função Cardíaca , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Leucotrienos/metabolismo , Masculino , Contração Miocárdica/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
The current study was designed to evaluate the endotoxin-induced alterations of the mechanisms involved in Ca(2+)handling within the rat thoracic aorta and further to examine whether in vitro inhibition of inducible nitric oxide synthase (iNOS) by aminoguanidine would account for this effect or not. Endothelium denuded aortic rings from rats injected with lipopolysaccharide (LPS) (5 mg kg(-1), i.p. 18 h prior to functional studies) or saline were mounted in isolated organ baths. Various experimental conditions were studied on paired rings of the same animal which were incubated in the presence or absence of aminoguanidine (100 microM). Phenylephrine contractility in Ca(2+)-containing buffer or in Ca(2+)-free buffer, contractions induced by K(+)depolarization and CaCl(2)in depolarized muscle and by caffeine exposure were significantly decreased in LPS-treated rings and were reversed by aminoguanidine exposure. Aminoguanidine also improved the contractions recorded while switching the Ca(2+)-free buffer to Ca(2+)-containing buffer. We conclude that endotoxin induces a generalized contractile defect in vascular smooth muscle including impairment in the influx of extracellular Ca(2+)and release of Ca(2+)from intracellular stores. An increase in iNOS activation leading to excessive nitric oxide synthesis, possibly non-endothelial in origin, may account for this defect.
Assuntos
Aorta Torácica/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Animais , Aorta Torácica/enzimologia , Aorta Torácica/fisiologia , Cálcio/metabolismo , GMP Cíclico/metabolismo , Interações Medicamentosas , Endotoxinas , Técnicas In Vitro , Lipopolissacarídeos/farmacologia , Masculino , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Ratos , Ratos Wistar , Resistência Vascular/efeitos dos fármacosRESUMO
1. Vascular contractile and relaxant responses were evaluated in isolated aortic rings of adjuvant-induced arthritic rats in comparison with control rats, and the effect of an antioxidant treatment on the development of the arthritis was investigated by vitamin E administration (100 mg/kg/day, i.m., for 26 days). 2. Arthritis was induced by an intradermal injection of Freund's complete adjuvant into rat paw. Vascular responses, arthritic lesions and serum copper levels were evaluated after 26 days from adjuvant inoculation. 3. Serum copper levels were significantly lower in arthritic rats than in the control. 4. The contractile response of aortic rings to phenylephrine (PE), but not to KCl, was increased in preparations from arthritic rats, which could be explained by an enhancement of intracellular calcium contents. 5. Acetylcholine (Ach)-mediated endothelium-dependent and sodium nitroprusside (SNP)-mediated endothelium-independent relaxations were not changed significantly in vascular preparations from arthritic rats. 6. In arthritic rats, vitamin E treatment improved arthritic lesions with an increase in copper levels. Despite this ameliorating effect, vitamin E treatment caused an increase in contractile response to PE and a decrease in the relaxant response to Ach and SNP in arthritic rats. 7. These data show that vitamin E provides ameliorating effects in improving systemic signs of experimental arthritis, but it fails to restore abnormalities in vascular function, indicating that adjuvant-induced alterations in vascular function may include mechanisms other than oxygen-free radical formation.