RESUMO
Levamisole is an anthelmintic drug restricted to veterinary use but is currently detected as the most widely used cocaine cutting agent in European countries. Levamisole-adulterated cocaine has been linked to acute kidney injury, marked by a decrease in glomerular filtration rate, which involves reduced renal blood flow, but data on the alteration of renovascular response produced by levamisole are scarce. Renal arteries were isolated from healthy rabbits and used for isometric tension recording in organ baths and protein analysis. We provide evidence that depending on its concentration, levamisole modulates renovascular tone by acting as a non-selective α-adrenergic receptor blocker and down-regulates α1-adrenoceptor expression. Furthermore, levamisole impairs the endothelium-dependent relaxation induced by acetylcholine without modifying endothelial nitric oxide synthase (eNOS) expression. However, exposure to superoxide dismutase (SOD) partially prevents the impairment of ACh-induced relaxation by levamisole. This response is consistent with a down-regulation of SOD1 and an up-regulation of NADPH oxidase 4 (Nox4), suggesting that endothelial NO loss is due to increased local oxidative stress. Our findings demonstrate that levamisole can interfere with renal blood flow and the coordinated response to a vasodilator stimulus, which could worsen the deleterious consequences of cocaine use.
Assuntos
Levamisol , Óxido Nítrico , Artéria Renal , Vasodilatação , Animais , Levamisol/farmacologia , Levamisol/toxicidade , Coelhos , Artéria Renal/efeitos dos fármacos , Artéria Renal/metabolismo , Artéria Renal/fisiopatologia , Óxido Nítrico/metabolismo , Vasodilatação/efeitos dos fármacos , Masculino , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/toxicidade , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Superóxido Dismutase/metabolismo , NADPH Oxidase 4/metabolismo , Relação Dose-Resposta a Droga , Superóxido Dismutase-1/metabolismo , Vasodilatadores/farmacologiaRESUMO
Sodium valproate (VPA), a histone deacetylase (HDAC) inhibitor, could be a promising candidate to treat acute myocardial infarction (AMI). In this study, AMI was induced in New Zealand White rabbits by occluding the left circumflex coronary artery for 1 h, followed by reperfusion. The animals were distributed into three experimental groups: the sham-operated group (SHAM), the AMI group and the AMI + VPA group (AMI treated with VPA 500 mg/kg/day). After 5 weeks, abdominal aorta was removed and used for isometric recording of tension in organ baths or protein expression by Western blot, and plasma for the determination of nitrate/nitrite (NOx) levels by colorimetric assay. Our results indicated that AMI induced a reduction of the endothelium-dependent response to acetylcholine without modifying the endothelium-independent response to sodium nitroprusside, leading to endothelial dysfunction. VPA treatment reversed AMI-induced endothelial dysfunction and even increased NO sensitivity in vascular smooth muscle. This response was consistent with an antioxidant effect of VPA, as it was able to reverse the superoxide dismutase 1 (SOD 1) down-regulation induced by AMI. Our experiments also ruled out that the VPA mechanism was related to eNOS, iNOS, sGC and arginase expression or changes in NOx plasma levels. Therefore, we conclude that VPA improves vasodilation by increasing NO bioavailability, likely due to its antioxidant effect. Since endothelial dysfunction was closely related to AMI, VPA treatment could increase aortic blood flow, making it a potential agent in reperfusion therapy that can prevent the vascular damage.
Assuntos
Infarto do Miocárdio , Ácido Valproico , Coelhos , Animais , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico , Antioxidantes , Infarto do Miocárdio/metabolismo , Aorta/metabolismo , Endotélio/metabolismo , Endotélio Vascular/metabolismoRESUMO
Activation of the aryl hydrocarbon receptor (AhR) has been shown to be important in physiological processes other than detoxification, including vascular homeostasis. Although AhR is highly expressed in the endothelium, its function has been poorly studied. This systematic review aims to summarise current knowledge on the AhR role in the endothelium and its cardiovascular implications. We focus on endogenous AhR agonists, such as some uremic toxins and other agonists unrelated to environmental pollutants, as well as studies using AhR knockout models. We conclude that AhR activation leads to vascular oxidative stress and endothelial dysfunction and that blocking AhR signalling could provide a new target for the treatment of vascular disorders such as cardiovascular complications in patients with chronic kidney disease or pulmonary arterial hypertension.
Assuntos
Poluentes Ambientais , Doenças Vasculares , Humanos , Receptores de Hidrocarboneto Arílico/genética , Hipertensão Pulmonar Primária Familiar , EndotélioRESUMO
The increase of vascular arginase activity during aging causes endothelial dysfunction. This enzyme competes with the endothelial nitric oxide synthase (eNOS) for L-arginine substrate. Our hypothesis is that glucose 6-P dehydrogenase (G6PD) overexpression could improve the endothelial function modulating the arginase pathway in aorta from mice. For this study, three groups of male mice were used: young wild type (WT) (6-9 months), old WT (21-22 months) and old G6PD-Tg (21-22 months) mice. Vascular reactivity results showed a reduced acetylcholine-dependent relaxation in the old WT but not old G6PD-Tg group. Endothelial dysfunction was reverted by nor-NOHA, an arginase inhibitor. Mice overexpressing G6PD underexpressed arginase II and also displayed a lower activity of this enzyme. Moreover, histological analyses demonstrated that age causes a thickness of aortic walls, but this did not occur in G6PD-Tg mice. We conclude that the overexpressing G6PD mouse is a model to improve vascular health via the arginase pathway.
Assuntos
Arginase , Glucosefosfato Desidrogenase , Doenças Vasculares , Animais , Masculino , Camundongos , Envelhecimento/genética , Envelhecimento/metabolismo , Aorta/metabolismo , Arginase/metabolismo , Arginina/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Glucose/metabolismo , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Doenças Vasculares/metabolismoRESUMO
Nanoparticles have a promising future in biomedical applications and knowing whether they affect ex vivo vascular reactivity is a necessary step before their use in patients. In this study, we have evaluated the vascular effect of cerium dioxide nanoparticles (CeO2NPs) on the human saphenous vein in response to relaxing and contractile agonists. In addition, we have measured the protein expression of key enzymes related to vascular homeostasis and oxidative stress. We found that CeO2NPs increased expression of both SOD isoforms, and the consequent reduction of superoxide anion would enhance the bioavailability of NO explaining the increased vascular sensitivity to sodium nitroprusside in the presence of CeO2NPs. The NOX4 reduction induced by CeO2NPs may lead to lower H2O2 synthesis associated with vasodilation through potassium channels explaining the lower vasodilation to bradykinin. In addition, we showed for the first time, that CeO2NPs increase the expression of ACE2 in human saphenous vein, and it may be the cause of the reduced contraction to angiotensin II. Moreover, we ruled out that CeO2NPs have effect on the protein expression of eNOS, sGC, BKca channels and angiotensin II receptors or modify the vascular response to noradrenaline, endothelin-1 and TXA2 analogue. In conclusion, CeO2NPs show antioxidant properties, and together with their vascular effect, they could be postulated as adjuvants for the treatment of cardiovascular diseases.
Assuntos
Nanopartículas , Veia Safena , Humanos , Antioxidantes/farmacologia , Angiotensina II , Peróxido de HidrogênioRESUMO
Levamisole, a veterinary anthelmintic drug, is one of the most widely used and dangerous cocaine adulterants. Like cocaine, levamisole acutely blocks noradrenaline reuptake but with much less potency, although its vascular effects are not well known. In this study, we evaluated the vascular effects of levamisole and cocaine in rabbit aortic rings used for isometric recording of tension in organ baths and protein expression by western blot. Our results indicated that levamisole (10-5-10-3 M) induced a concentration-dependent relaxation in rings precontracted with noradrenaline (10-7-3 × 10-7 M). Furthermore, it reduced the contractile response to phenylephrine (10-9-3 × 10-5 M) that was not modified by cocaine (10-5-10-4 M), and reduced α1-adrenergic receptor expression. Levamisole (10-6-10-4 M) produced a potentiation of the electrical field stimulation that was not further enhanced by the combination of both drugs. However, high concentrations of levamisole (10-3 M) abolished adrenergic neurotransmission whether administered alone or with cocaine (10-4 M). In addition, levamisole (10-5-10-3 M) also decreased endothelium-dependent relaxation to acetylcholine that was not further impaired by cocaine (10-4 M), and that was partially reversed by superoxide dismutase (SOD, 200 U/ml). These results demonstrate that levamisole has a dual effect on the adrenergic system, and its effects are independent of the presence of cocaine. At lower concentrations, it enhances the contractile sympathetic response by blocking presynaptic α2-adrenergic receptors, while at high concentrations, the effect of the antagonism of α1-adrenergic receptor prevails. In addition, levamisole induces endothelial dysfunction by reducing NO bioavailability, and this effect could be in part mediated by oxidative stress.
Assuntos
Cocaína , Levamisol , Adrenérgicos , Animais , Aorta/metabolismo , Cocaína/toxicidade , Levamisol/metabolismo , Levamisol/toxicidade , Norepinefrina/metabolismo , Coelhos , Receptores Adrenérgicos alfa 2RESUMO
BACKGROUND AND AIMS: Underlying mechanisms associated with vascular dysfunction in metabolic syndrome (MetS) remain unclear and can even vary from one vascular bed to another. METHODS: In this study, MetS was induced by a high-fat, high-sucrose diet, and after 28 weeks, aorta and renal arteries were removed and used for isometric recording of tension in organ baths, protein expression by Western blot, and histological analysis to assess the presence of atherosclerosis. RESULTS: MetS induced a mild hypertension, pre-diabetes, central obesity and dyslipidaemia. Our results indicated that MetS did not change the contractile response in either the aorta or renal artery. Conversely, vasodilation was affected in both arteries in a different way. The aorta from MetS showed vascular dysfunction, including lower response to acetylcholine and sodium nitroprusside, while the renal artery from MetS presented a preserved relaxation to acetylcholine and an increased sensitivity to sodium nitroprusside. We did not find vascular oxidative stress in the aorta from MetS, but we found a significant decrease in PPARγ, phospho-Akt (p-Akt) and phospho-eNOS (p-eNOS) protein expression. On the other hand, we found oxidative stress in the renal artery from MetS, and PPARγ, Akt and p-Akt were overexpressed. No evidence of atherosclerosis was found in arteries from MetS. CONCLUSIONS: MetS affects vascular function differently depending on the vessel. In the aorta, it decreases both the vasodilation and the expression of the PPARγ/Akt/eNOS pathway, while in the renal artery, it increases the expression of PPARγ/Akt signalling pathway without decreasing the vasodilation.
Assuntos
Síndrome Metabólica , Animais , Endotélio Vascular , Modelos Teóricos , Óxido Nítrico Sintase Tipo III , PPAR gama , Proteínas Proto-Oncogênicas c-akt , Coelhos , VasodilataçãoRESUMO
Atherosclerosis is a chronic vascular inflammatory disease associated to oxidative stress and endothelial dysfunction. Oxidation of low-density lipoprotein (LDL) cholesterol is one of the key factors for the development of atherosclerosis. Nonoxidized LDL have a low affinity for macrophages, so they are not themselves a risk factor. However, lowering LDL levels is a common clinical practice to reduce oxidation and the risk of major events in patients with cardiovascular diseases (CVD). Atherosclerosis starts with dysfunctional changes in the endothelium induced by disturbed shear stress which can lead to endothelial and platelet activation, adhesion of monocytes on the activated endothelium, and differentiation into proinflammatory macrophages, which increase the uptake of oxidized LDL (oxLDL) and turn into foam cells, exacerbating the inflammatory signalling. The atherosclerotic process is accelerated by a myriad of factors, such as the release of inflammatory chemokines and cytokines, the generation of reactive oxygen species (ROS), growth factors, and the proliferation of vascular smooth muscle cells. Inflammation and immunity are key factors for the development and complications of atherosclerosis, and therefore, the whole atherosclerotic process is a target for diagnosis and treatment. In this review, we focus on early stages of the disease and we address both biomarkers and therapeutic approaches currently available and under research.
Assuntos
Aterosclerose/genética , Humanos , Inflamação , Estresse OxidativoRESUMO
KEY POINTS: Some of the beneficial effects of exercise in preventing vascular related diseases are mediated by the enhancement of endothelial function where the role of nitric oxide (NO) is well documented, although the relevance of calcium activated potassium channels is not fully understood. The impact of oxidative stress induced by training on endothelial function remains to be clarified. By evaluating different endothelial vasodilator pathways on two vascular beds in a rabbit model of chronic exercise, we found a decreased NO bioavailability and endothelial nitric oxide synthase expression in both carotid and femoral arteries. Physical training induced carotid endothelial dysfunction as a result of an increase in oxidative stress and a reduction in superoxide dismutase expression. In the femoral artery, the lower production of NO was counteracted by an increased participation of large conductance calcium activated potassium channels, preventing endothelial dysfunction. ABSTRACT: The present study aimed to evaluate the effects of chronic exercise on vasodilator response in two different arteries. Rings of carotid and femoral arteries from control and trained rabbits were suspended in organ baths for isometric recording of tension. Endothelial nitric oxide synthase (eNOS), Cu/Zn and Mn-superoxide dismutase (SOD), and large conductance calcium activated potassium (BKCa) channel protein expression were measured by western blotting. In the carotid artery, training reduced the relaxation to ACh (10-9 to 3 × 10-6 m) that was reversed by N-acetylcysteine (10-3 m). l-NAME (10-4 m) reduced the relaxation to ACh in both groups, although the effect was lower in the trained group (in mean ± SEM, 39 ± 2% vs. 28 ± 3%). Physical training did not modify the relaxation to ACh in femoral arteries, although the response to l-NAME was lower in the trained group (in mean ± SEM, 41 ± 5% vs. 17 ± 2%). Charybdotoxin (10-7 m) plus apamin (10-6 m) further reduced the maximal relaxation to ACh only in the trained group. The remaining relaxation in both carotid and femoral arteries was abolished by KCl (2 × 10-2 m) and BaCl2 (3 × 10-6 m) plus ouabain (10-4 m) in both groups. Physical training decreased eNOS expression in both carotid and femoral arteries and Cu/Zn and Mn-SOD expression only in the carotid artery. BKCa channels were overexpressed in the trained group in the femoral artery. In conclusion, chronic exercise induces endothelial dysfunction in the carotid artery as a result of oxidative stress. In the femoral artery, it modifies the vasodilator pathways, enhancing the participation of BKCa channels, thus compensating for the impairment of NO-mediated vasodilatation.
Assuntos
Artérias Carótidas/metabolismo , Artéria Femoral/metabolismo , Óxido Nítrico/metabolismo , Condicionamento Físico Animal , Animais , Artérias Carótidas/fisiologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Artéria Femoral/fisiologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Masculino , Estresse Oxidativo , CoelhosRESUMO
Aims.Bifidobacterium pseudocatenulatum CECT 7765 improves metabolic and immunological altered functions in high fat fed mice, however little is known about the effects of potential probiotics on vascular reactivity. The aim of the present study was to investigate the effects of a potential probiotic strain, Bifidobacterium pseudocatenulatum CECT 7765, on vascular response in obese mice. Methods. Aorta samples were obtained from mice, which were divided into three groups: a control group, receiving a standard diet; an obese group, receiving a high-fat diet; and an obese group receiving high-fat diet and a daily dose of B. pseudocatenulatum CECT 7765 by oral gavage. Aortic rings were suspended in organ baths for isometric recording of tension. mRNA expression of eNOS was evaluated by real-time polymerase chain reaction. Results. Contractions induced by KCl, noradrenaline and thromboxane analogue were 33%, 30% and 45% lower respectively in aortic rings from obese mice. Bifidobacteria administration reversed this effect. eNOS inhibition increased the response to noradrenaline in the three groups with a significant lower magnitude in aortic rings from obese mice receiving bifidobacteria supplement. Acetylcholine caused a greater vasodilation in aorta from obese group (46±3% for control and 69±4% for obese group; p<0.05) and bifidobacteria reversed it (57±5%). Response to sodium nitroprusside was displaced 2.9 times to the left in a parallel manner in obese group. Relaxation to sodium nitroprusside remained unchanged in the bifidobacteria fed group. There was about five-fold decreased mRNA expression of eNOS in aortic segments from the group receiving bifidobacteria. Conclusion.Bifidobacterium pseudocatenulatum CECT 7765 restores the obesity-induced altered vascular function mainly by reducing nitric oxide release.
Assuntos
Bifidobacterium pseudocatenulatum/química , Óxido Nítrico Sintase Tipo III/genética , Obesidade/dietoterapia , Probióticos/administração & dosagem , Animais , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Obesos , Óxido Nítrico/metabolismo , Nitroprussiato/administração & dosagem , Obesidade/genética , Obesidade/patologia , Probióticos/química , Remodelação Vascular/efeitos dos fármacosRESUMO
Alzheimer's disease (AD), a neurodegenerative illness involving synaptic dysfunction with extracellular accumulation of Aß1-42 toxic peptide, glial activation, inflammatory response and oxidative stress, can lead to neuronal death. Endogenous cannabinoid system is implicated in physiological and physiopathological events in central nervous system (CNS), and changes in this system are related to many human diseases, including AD. However, studies on the effects of cannabinoids on astrocytes functions are scarce. In primary cultured astrocytes we studied cellular viability using MTT assay. Inflammatory and oxidative stress mediators were determined by ELISA and Western-blot techniques both in the presence and absence of Aß1-42 peptide. Effects of WIN 55,212-2 (a synthetic cannabinoid) on cell viability, inflammatory mediators and oxidative stress were also determined. Aß1-42 diminished astrocytes viability, increased TNF-α and IL-1ß levels and p-65, COX-2 and iNOS protein expression while decreased PPAR-γ and antioxidant enzyme Cu/Zn SOD. WIN 55,212-2 pretreatment prevents all effects elicited by Aß1-42. Furthermore, cannabinoid WIN 55,212-2 also increased cell viability and PPAR-γ expression in control astrocytes. In conclusion cannabinoid WIN 55,212-2 increases cell viability and anti-inflammatory response in cultured astrocytes. Moreover, WIN 55,212-2 increases expression of anti-oxidant Cu/Zn SOD and is able to prevent inflammation induced by Aß1-42 in cultured astrocytes. Further studies would be needed to assess the possible beneficial effects of cannabinoids in Alzheimer's disease patients.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Astrócitos/efeitos dos fármacos , Benzoxazinas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Morfolinas/farmacologia , Naftalenos/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Receptores de Canabinoides/genética , Peptídeos beta-Amiloides/farmacologia , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Feto , Regulação da Expressão Gênica , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/genética , PPAR gama/metabolismo , Fragmentos de Peptídeos/farmacologia , Cultura Primária de Células , Ratos , Receptores de Canabinoides/metabolismo , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: Previous studies have shown that asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and nitric oxide (NO) play a prominent role in liver dysfunction. The objective of this study was to determine whether plasma levels of ADMA, SDMA and NO are altered in patients with chronic hepatitis C. MATERIAL AND METHODS: Plasma levels of ADMA, SDMA and NO (nitrite plus nitrate) were measured in 22 patients with chronic hepatitis C and 24 patients with sustained virologic response after treatment with peginterferon plus ribavirin. Seven healthy volunteers served as controls. RESULTS: Plasma levels of ADMA, SDMA and NO were not significantly different between groups: chronic hepatitis C, ADMA 0.55+/-0.06, SDMA 0.22+/-0.03, NO 36.3+/-5.9 micromol/l; treated patients, ADMA 0.60+/-0.15, SDMA 0.31+/-0.05, NO 36.1+/-5.5 micromol/l; controls, ADMA 0.65+/-0.08, SDMA 0.28+/-0.05, NO 40.7+/-8.9 micromol/l). CONCLUSIONS: Our results show that plasma NO, ADMA and SDMA concentrations are not changed in patients with chronic hepatitis C without superimposed signs of acute inflammatory activity. Furthermore, no significant differences in plasma values of NO and dimethylarginines were observed between the group of untreated patients and the group of patients treated with interferon plus ribavirin.
Assuntos
Arginina/análogos & derivados , Hepatite C Crônica/sangue , Óxido Nítrico/sangue , Adulto , Antivirais/uso terapêutico , Arginina/sangue , Estudos de Casos e Controles , Feminino , Hepatite C Crônica/tratamento farmacológico , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis , Proteínas Recombinantes , Ribavirina/uso terapêuticoRESUMO
OBJECTIVE: The present experiments were designed to evaluate differences in the effects of cyclooxygenase (COX)-1 and COX-2 inhibition on contractile responses of human gastroepiploic artery and saphenous vein elicited by vasopressin. DESIGN: Laboratory investigation. SETTING: University laboratory. SUBJECTS: Rings of human gastroepiploic artery were obtained from 32 patients undergoing gastrectomy, and rings of saphenous vein were obtained from 30 patients undergoing coronary artery bypass surgery. INTERVENTIONS: The rings were suspended in organ baths for isometric recording of tension. We studied the responses to vasopressin in the absence and in the presence of either the vasopressin V1-receptor antagonist d(CH2)5Tyr(Me)AVP or the COX inhibitors aspirin, nimesulide, or SC-560. MEASUREMENTS AND MAIN RESULTS: Vasopressin (10(-11)-10(-6) mol/L) produced concentration-dependent contractions with an EC50 value of 4.3 x 10(-10) mol/L for gastroepiploic artery and 3.4 x 10(-8) mol/L for saphenous vein. The vasopressin V1-receptor antagonist d(CH2)5Tyr(Me)AVP (10(-7) mol/L) induced significant shifts (p < .001) of the control curves to the right. The COX-1 and COX-2 inhibitor aspirin (10(-6)-10(-5) mol/L) and the COX-2 inhibitor nimesulide (10(-6) mol/L) induced leftward shifts of the concentration-response curve for vasopressin in gastroepiploic artery. Lower concentrations of aspirin or the COX-1 inhibitor SC-560 (10(-8) mol/L) did not affect the responses of gastroepiploic artery. COX-1 or COX-2 inhibition did not modify the contraction of saphenous vein to vasopressin. CONCLUSION: The results provide functional evidence that aspirin at high concentrations and the COX-2 selective inhibitor nimesulide potentiate the contractile response of gastroepiploic artery to vasopressin, thus suggesting the release of relaxant prostaglandins by the peptide. However, contractions of human saphenous vein were unaffected by COX inhibition, indicating that vasopressin does not stimulate the release of prostanoids. The amplifying effect of aspirin on vasopressin-induced contraction may contribute to early graft failure when the gastroepiploic artery is used as a coronary artery bypass graft.
Assuntos
Aspirina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Artéria Gastroepiploica , Humanos , Masculino , Pessoa de Meia-Idade , Veia Safena , VasopressinasRESUMO
BACKGROUND: The aim of the present study was to evaluate the intervention of COX-1- and COX-2-derived prostaglandins in the responses of human gastroepiploic artery to sympathetic stimulation and norepinephrine. METHODS: Rings of human gastroepiploic artery were obtained from 45 patients (26 men and 19 women) undergoing gastrectomy. The rings were suspended in organ baths for isometric recording of tension. We studied the responses to electrical field stimulation, norepinephrine, and acetylcholine, in the absence and presence of COX-1 or COX-2 inhibition. RESULTS: The COX-1 and COX-2 inhibitor aspirin at high concentrations (10(-6) to 10(-5) mol/L) and the COX-2 inhibitor nimesulide (10(-6) mol/L) potentiated the contractile responses of the arterial rings to sympathetic neurogenic stimulation and norepinephrine. In contrast, lower concentrations of aspirin (10(-8) to 10(-7) mol/L) or the COX-1 inhibitor SC-560 (3 x10(-8) mol/L) did not affect these responses. The vascular relaxation induced by acetylcholine was not affected by COX-1 and COX-2 inhibition. CONCLUSIONS: The results provide functional evidence that vasodilator prostaglandins are active components of the response of human gastroepiploic artery to neurogenic stimulation and norepinephrine. Aspirin at high concentrations and the COX-2 selective inhibitor nimesulide potentiated the contractile response of gastroepiploic artery to adrenergic stimulation by inhibiting COX-2-derived PGI(2). Aspirin at low concentrations and the COX-1 selective inhibitor SC-560 did not modify the contractile responses, possibly due to minor importance of vasoconstrictor prostaglandins (TXA(2)) as active components of the response of gastroepiploic artery to adrenergic stimulation.
Assuntos
Aspirina/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Artéria Gastroepiploica/efeitos dos fármacos , Prostaglandinas/metabolismo , Sulfonamidas/farmacologia , Acetilcolina/análise , Ciclo-Oxigenase 1/efeitos dos fármacos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Estimulação Elétrica , Feminino , Artéria Gastroepiploica/fisiologia , Humanos , Técnicas In Vitro , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Pirazóis/farmacologiaRESUMO
BACKGROUND: We studied the participation of K(+) channels on the adrenergic responses in human saphenous veins as well as the intervention of dihydropyridine-sensitive Ca(2+) channels on modulation of adrenergic responses by K(+) channels blockade. METHODS: Saphenous vein rings were obtained from 40 patients undergoing coronary artery bypass surgery. The vein rings were suspended in organ bath chambers for isometric recording of tension. RESULTS: Iberiotoxin (10(-7) mol/L), an inhibitor of large conductance Ca(2+)-activated K(+) channels, and charybdotoxin (10(-7) mol/L), an inhibitor of both large and intermediate conductance Ca(2+)-activated K(+) channels, enhanced the contractions elicited by electrical field stimulation and produced a leftward shift of the concentration-response curve to norepinephrine. In contrast, the inhibitor of small conductance Ca(2+)-activated K(+) channels apamin (10(-6) mol/L) did not modify the contractile response to electrical field stimulation or norepinephrine. In the presence of the dihydropyridine Ca(2+)-channel blocker nifedipine (10(-6) mol/L), iberiotoxin and charybdotoxin failed to enhance the contractile responses to electrical field stimulation and norepinephrine. CONCLUSIONS: The results suggest that large conductance Ca(2+)-activated K(+) channels are activated by stimulation with norepinephrine to counteract the adrenergic-induced contractions of human saphenous vein. Thus, inhibition of these channels increases significantly the contraction, an effect that appears to be mediated by an increase in Ca(2+) entry through L-type voltage-dependent Ca(2+) channels.
Assuntos
Músculo Liso Vascular/fisiologia , Norepinefrina/fisiologia , Canais de Potássio Cálcio-Ativados/fisiologia , Veia Safena/fisiologia , Vasoconstrição/fisiologia , Bloqueadores dos Canais de Cálcio , Estimulação Elétrica , Feminino , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Tono Muscular/fisiologia , NifedipinoRESUMO
BACKGROUND: We recently reported that endothelium-dependent relaxation is impaired in forearm veins from patients with chronic renal failure. However, assessment of responses to norepinephrine remains controversial. We examined the contractile response to norepinephrine in forearm veins from patients on chronic hemodialysis and the role of nitric oxide (NO), prostanoids, and Ca(2+)-activated K(+) channels in this response. METHODS: Isometric contraction curves were obtained in rings of forearm vein from 21 dialyzed patients and 12 multiorgan donors in response to norepinephrine (1 nmol/L to 10 micromol/L) or KCl (5 to 100 mmol/L). RESULTS: Veins from uremic patients were markedly less responsive to norepinephrine (7.6 +/- 0.6 g) and KCl (6.0 +/- 0.3 g) than those from organ donors (12.0 +/- 0.7 g and 10.4 +/- 0.5 g, respectively, P < .05). Treatment with N(G)-monomethyl-l-arginine (100 micromol/L), an inhibitor of NO synthase, or indomethacin (10 micromol/L), an inhibitor of prostacyclin synthesis, increased the response to norepinephrine in veins from control subjects but not in veins from dialyzed patients. Additional blockade of Ca(2+)-activated K(+) channels did not correct the hyporesponsiveness. In veins incubated in Ca(2+)-free solution containing either 100 mmol/L KCl or 1 micromol/L norepinephrine, addition of calcium chloride (0.1 to 30 mmol/L) elicited contractile responses that were significantly lower in veins from dialyzed patients. CONCLUSIONS: The results demonstrate that norepinephrine-mediated contractions of forearm veins are markedly decreased in dialyzed patients. Endothelium-derived relaxing factors are not involved in this effect. The reduced contractile response is most likely caused by a decreased calcium entry through voltage- and receptor-dependent calcium channels.
Assuntos
Antebraço/irrigação sanguínea , Falência Renal Crônica , Norepinefrina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Veias/efeitos dos fármacosRESUMO
In patients with cirrhosis, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and possibly symmetric dimethylarginine (SDMA) have been linked to the severity of the disease. We investigated whether plasma levels of dimethylarginines and NO are elevated in patients with hepatorenal syndrome (HRS), compared with patients with cirrhosis without renal failure (no-HRS). Plasma levels of NO, ADMA, SDMA, and l-arginine were measured in 11 patients with HRS, seven patients with no-HRS, and six healthy volunteers. SDMA concentration in HRS was higher than in no-HRS and healthy subjects (1.47 +/- 0.25 vs. 0.38 +/- 0.06 and 0.29 +/- 0.04 microM, respectively; P < 0.05). ADMA and NOx concentrations were higher in HRS and no-HRS patients than in healthy subjects (ADMA, 1.20 +/- 0.26, 1.11 +/- 0.1, and 0.53 +/- 0.06 microM, respectively; P < 0.05; NOx, 94 +/- 9.1, 95.5 +/- 9.54, and 37.67 +/- 4.62 microM, respectively; P < 0.05). In patients with HRS there was a positive correlation between serum creatinine and plasma SDMA (r2 =0.765, P < 0.001) but not between serum creatinine and ADMA or NOx. The results suggest that renal dysfunction is a main determinant of elevated SDMA concentration in HRS. Accumulation of ADMA as a result of impaired hepatic removal may be the causative factor initiating renal vasoconstriction and SDMA retention in the kidney.
Assuntos
Arginina/análogos & derivados , Fibrose/sangue , Síndrome Hepatorrenal/sangue , Insuficiência Renal/sangue , Arginina/sangue , Estudos de Casos e Controles , Creatinina/sangue , Fibrose/patologia , Síndrome Hepatorrenal/patologia , Humanos , Rim/metabolismo , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/sangue , Insuficiência Renal/patologiaRESUMO
We measured cyclic GMP formation and relaxation response to sildenafil given either alone or in combination with sodium nitroprusside (SNP) in pulmonary arteries obtained from 13 multi-organ donors. Sildenafil (10(-9)-10(-4) M) caused concentration-dependent relaxations and amplified the relaxation induced by SNP. Relaxation was unaffected by endothelium removal or by pre-treatment with the inhibitor of nitric oxide synthase L-NMMA (10(-4) M). SNP (10(-7) M) caused elevation of cyclic GMP levels that was potentiated by sildenafil (10(-6) M). Thus, the enhancement of SNP-induced relaxation by sildenafil is mainly due to an increase in cyclic GMP accumulation.