RESUMO
The innate and adaptive immune systems play an important role in the development of cardiac diseases. Therefore, it has become critical to identify molecules that can modulate inflammation in the injured heart. In this regard, activation of the cholinergic system in animal models of heart disease has been shown to exert protective actions that include immunomodulation of cardiac inflammation. In this mini-review, we briefly present our current understanding on the cardiac cellular sources of acetylcholine (ACh) (neuronal vs. nonneuronal), followed by a discussion on its contribution to the regulation of inflammatory cells. Although the mechanism behind ACh-mediated protection still remains to be fully elucidated, the beneficial immunomodulatory role of the cholinergic signaling emerges as a potential key regulator of cardiac inflammation.
Assuntos
Acetilcolina/metabolismo , Anti-Inflamatórios/uso terapêutico , Cardiotônicos/uso terapêutico , Cardiopatias/metabolismo , Cardiopatias/prevenção & controle , Coração/efeitos dos fármacos , Acetilcolina/administração & dosagem , Animais , Anti-Inflamatórios/farmacologia , Cardiotônicos/farmacologia , Humanos , Inflamação/metabolismo , Inflamação/prevenção & controle , Neurônios/efeitos dos fármacos , Neurônios/metabolismoRESUMO
Neuronal nitric oxide synthase (nNOS) is expressed in the cardiovascular system and besides NO, generates H2O2. nNOS has been proposed to contribute to the control of blood pressure in healthy humans. The aim of this study was to verify the hypothesis that nNOS can contribute to the control of vascular relaxation and blood pressure in hypertensive patients undergoing drug treatment. The study was conducted in resistance mesenteric arteries from 63 individuals, as follows: 1) normotensive patients; 2) controlled hypertensive patients (patients on antihypertensive treatment with blood pressure normalized); 3) uncontrolled hypertensive patients (patients on antihypertensive treatment that remained hypertensive). Only mesenteric arteries from uncontrolled hypertensive patients showed impaired endothelium-dependent vasorelaxation in response to acetylcholine (ACh). Selective nNOS blockade with inhibitor 1 and catalase, which decomposes H2O2, decreased vasorelaxation in the three groups. However, the inhibitory effect was greater in controlled hypertensive patients. Decreased eNOS expression was detected in both uncontrolled and controlled hypertensive groups. Interestingly nNOS expression and ACh-stimulated H2O2 production were greater in controlled hypertensive patients, than in the other groups. ACh-stimulated NO production was lower in controlled hypertensive when compared to normotensive patients, while uncontrolled hypertensive patients showed the lowest levels. Catalase and nNOS blockade inhibited ACh-induced H2O2 production. In conclusion, nNOS-derived H2O2 contributes to the endothelium-dependent vascular relaxation in human resistance mesenteric arteries. The endothelial dysfunction observed in uncontrolled hypertensive patients involves decreased eNOS expression and NO production. The normalization of vascular relaxation and blood pressure in controlled hypertensive patients involves increased nNOS-derived H2O2 and NO production.
Assuntos
Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Artérias Mesentéricas/fisiologia , Óxido Nítrico Sintase Tipo I/metabolismo , Acetilcolina/administração & dosagem , Acetilcolina/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Estudos de Casos e Controles , Feminino , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Técnicas de Cultura de Órgãos , Vasodilatação/efeitos dos fármacosRESUMO
Abstract Objective: To test the efficacy of Acetylcholine chloride use in obtaining intraoperative miosis on phacoemulsification cataract surgery. Methods: Patients with cataract diagnosis and elected for surgical phacoemulsification procedure were selected. All patients underwent conventional phacoemulsification procedure performed by a single surgeon and all patients had 0.2 ml of Acetylcholine chloride 1% irrigated in the anterior chamber at the end of the surgery. The pupillary diameter was measured immediately before the beginning of surgery, immediately before and two minutes after the use of acetylcholine chloride 1%. Results: A total of 30 eyes from 30 patients were included in the study. 18 were female, and mean age was of 69.5 years with a 7.2y standard deviation on the population study. The mean pupillary diameter immediately before the beginning of surgery was 7.5 mm with a standard deviation of 0.56 mm; the mean pupillary diameter immediately before the acetylcholine chloride 1% use (after the intraocular lens im-plantation) was 7.1 mm with a standard deviation of 0.57 mm. The mean pupillary diameter two minutes after the use of acetylcholine chloride 1% in the anterior chamber was 3.4 mm with standard deviation of 0.66 mm. The mean maximum action time of ACH chloride 1% was 64 seconds, with a standard deviation of 8 seconds. The mean intraocular pressure on the first postoperative day was 19.1 mmHg with a standard deviation of 2.45 mmHg. Conclusion: We conclude that acetylcholine chloride 1% is an important drug to obtaining intraoperative miosis in cataract surgery.
Resumo Objetivo: Demonstrar a eficácia do cloridrato de acetilcolina 1% na obtenção da miose intraoperatória na cirurgia de catarata pela técnica de facoemulsificação. Métodos: Pacientes com diagnóstico de catarata e indicação de cirurgia foram selecionados para participar do presente estudo. Todos os pacientes foram operados pela técnica de facoemulsificação convencional pelo mesmo cirurgião, todos foram submetidos à aplicação de 0,2 ml do cloridrato de acetilcolina 1% na câmara anterior ao final do procedimento cirúrgico. A medida do diâmetro pupilar foi realizada imediatamente antes do início da cirurgia, imediatamente antes do uso do cloridrato de acetilcolina 1% e após 2 minutos. Resultados: Foram estudados 30 olhos de 30 pacientes, destes, 18 eram do sexo feminino, a média de idade do estudo foi de 69,5 anos com desvio padrão de 7,2 anos. A média do diâmetro pupilar imediatamente antes do início da cirurgia foi 7,55 mm com desvio padrão de 0,56mm, a média do diâmetro pupilar imediatamente antes do uso do cloridrato de acetilcolina 1% (após implante da lente intraocular no saco capsular) foi 7,1mm com desvio padrão de 0,57mm. A média do diâmetro pupilar após 2 minutos da aplicação da acetilcolina na câmara anterior foi de 3,4 mm com desvio padrão de 0,66mm. O tempo médio de ação máxima do medicamento foi de 64 segundos, com desvio padrão de 8 segundos. A média da pressão intraocular no primeiro dia do pós-operatório foi de 19,1 mmHg com desvio padrão de 2,45mmHg. Conclusão: O estudo acima mostrou que a acetilcolina apresenta boa eficácia na obtenção de miose intraoperatória na cirurgia de facoemulsificação, permitindo uma maior facilidade na confecções das suturas corneanas ou corneo-escleral, reduzindo a incidência de sinéquias anteriores periféricas. Concluimos que o cloridrato de acetilcolina 1% é um importante medicamento na obtenção da miose intraoperatória na cirurgia de catarata.
Assuntos
Humanos , Masculino , Feminino , Idoso , Acetilcolina/administração & dosagem , Miose/induzido quimicamente , Pupila/efeitos dos fármacos , Facoemulsificação/métodos , Mióticos/administração & dosagem , Acetilcolina/farmacologia , Implante de Lente Intraocular/métodos , Cuidados Intraoperatórios , Irrigação Terapêutica/métodos , Lentes Intraoculares , Câmara Anterior/efeitos dos fármacos , Mióticos/farmacologiaRESUMO
Leprosy is a chronic granulomatous infection of skin and peripheral nerves caused by Mycobacterium leprae and is considered the main infectious cause of disability worldwide. Despite the several studies regarding leprosy, little is known about its effects on microvascular structure and function in vivo. Thus, we have aimed to compare skin capillary structure and functional density, cutaneous vasomotion (spontaneous oscillations of arteriolar diameter), which ensures optimal blood flow distribution to skin capillaries) and cutaneous microvascular blood flow and reactivity between ten men with lepromatous leprosy (without any other comorbidity) and ten age- and gender-matched healthy controls. Orthogonal polarization spectral imaging was used to evaluate skin capillary morphology and functional density and laser Doppler flowmetry to evaluate blood flow, vasomotion and spectral analysis of flowmotion (oscillations of blood flow generated by vasomotion) and microvascular reactivity, in response to iontophoresis of acetylcholine and sodium nitroprusside. The contribution of different frequency components of flowmotion (endothelial, neurogenic, myogenic, respiratory and cardiac) was not statistically different between groups. However, endothelial-dependent and -independent vasodilatations elicited by acetylcholine and sodium nitroprusside iontophoresis, respectively, were significantly reduced in lepromatous leprosy patients compared to controls, characterizing the existence of microvascular dysfunction. These patients also presented a significant increase in the number of capillaries with morphological abnormalities and in the diameters of the dermal papilla and capillary bulk when compared to controls. Our results suggest that lepromatous leprosy causes severe microvascular dysfunction and significant alterations in capillary structure. These structural and functional changes are probably induced by exposure of the microvascular bed to chronic inflammation evoked by the Mycobacterium leprae.
Assuntos
Capilares/fisiopatologia , Hanseníase Virchowiana/fisiopatologia , Microcirculação , Dermatopatias Bacterianas/fisiopatologia , Pele/irrigação sanguínea , Acetilcolina/administração & dosagem , Adulto , Estudos Transversais , Feminino , Humanos , Iontoforese , Fluxometria por Laser-Doppler , Hanseníase Virchowiana/diagnóstico , Masculino , Mycobacterium leprae/isolamento & purificação , Nitroprussiato/administração & dosagem , Fluxo Sanguíneo Regional , Pele/fisiopatologia , Dermatopatias Bacterianas/diagnóstico , VasodilataçãoRESUMO
Metabolic acidosis has profound effects on vascular tone. This study investigated the in vivo effects of acute metabolic acidosis (AMA) and chronic metabolic acidosis (CMA) on hemodynamic parameters and endothelial function. CMA was induced by ad libitum intake of 1% NH4Cl for 7 days, and AMA was induced by a 3-h infusion of 6 M NH4Cl (1 mL/kg, diluted 1:10). Phenylephrine (Phe) and acetylcholine (Ach) dose-response curves were performed by venous infusion with simultaneous venous and arterial blood pressure monitoring. Plasma nitrite/nitrate (NOx) was measured by chemiluminescence. The CMA group had a blood pH of 7.15±0.03, which was associated with reduced bicarbonate (13.8±0.98 mmol/L) and no change in the partial pressure of arterial carbon dioxide (PaCO2). The AMA group had a pH of 7.20±0.01, which was associated with decreases in bicarbonate (10.8±0.54 mmol/L) and PaCO2 (47.8±2.54 to 23.2±0.74 mmHg) and accompanied by hyperventilation. Phe or ACh infusion did not affect arterial or venous blood pressure in the CMA group. However, the ACh infusion decreased the arterial blood pressure (ΔBP: -28.0±2.35 mm Hg [AMA] to -4.5±2.89 mmHg [control]) in the AMA group. Plasma NOx was normal after CMA but increased after AMA (25.3±0.88 to 31.3±0.54 µM). These results indicate that AMA, but not CMA, potentiated the Ach-induced decrease in blood pressure and led to an increase in plasma NOx, reinforcing the effect of pH imbalance on vascular tone and blood pressure control.
Assuntos
Acetilcolina/administração & dosagem , Acidose/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Hipotensão/induzido quimicamente , Desequilíbrio Ácido-Base/metabolismo , Acidose/induzido quimicamente , Acidose/metabolismo , Doença Aguda , Animais , Bicarbonatos/sangue , Pressão Sanguínea/fisiologia , Determinação da Pressão Arterial , Dióxido de Carbono/análise , Doença Crônica , Endotélio Vascular/metabolismo , Hemodinâmica/fisiologia , Hiperventilação/metabolismo , Luminescência , Masculino , Nitratos/sangue , Óxido Nítrico/metabolismo , Nitritos/sangue , CoelhosRESUMO
Metabolic acidosis has profound effects on vascular tone. This study investigated the in vivo effects of acute metabolic acidosis (AMA) and chronic metabolic acidosis (CMA) on hemodynamic parameters and endothelial function. CMA was induced by ad libitum intake of 1% NH4Cl for 7 days, and AMA was induced by a 3-h infusion of 6 M NH4Cl (1 mL/kg, diluted 1:10). Phenylephrine (Phe) and acetylcholine (Ach) dose-response curves were performed by venous infusion with simultaneous venous and arterial blood pressure monitoring. Plasma nitrite/nitrate (NOx) was measured by chemiluminescence. The CMA group had a blood pH of 7.15±0.03, which was associated with reduced bicarbonate (13.8±0.98 mmol/L) and no change in the partial pressure of arterial carbon dioxide (PaCO2). The AMA group had a pH of 7.20±0.01, which was associated with decreases in bicarbonate (10.8±0.54 mmol/L) and PaCO2 (47.8±2.54 to 23.2±0.74 mmHg) and accompanied by hyperventilation. Phe or ACh infusion did not affect arterial or venous blood pressure in the CMA group. However, the ACh infusion decreased the arterial blood pressure (ΔBP: -28.0±2.35 mm Hg [AMA] to -4.5±2.89 mmHg [control]) in the AMA group. Plasma NOx was normal after CMA but increased after AMA (25.3±0.88 to 31.3±0.54 μM). These results indicate that AMA, but not CMA, potentiated the Ach-induced decrease in blood pressure and led to an increase in plasma NOx, reinforcing the effect of pH imbalance on vascular tone and blood pressure control.
Assuntos
Animais , Masculino , Coelhos , Acetilcolina/administração & dosagem , Acidose/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Hipotensão/induzido quimicamente , Doença Aguda , Desequilíbrio Ácido-Base/metabolismo , Acidose/induzido quimicamente , Acidose/metabolismo , Determinação da Pressão Arterial , Bicarbonatos/sangue , Pressão Sanguínea/fisiologia , Doença Crônica , Dióxido de Carbono/análise , Endotélio Vascular/metabolismo , Hemodinâmica/fisiologia , Hiperventilação/metabolismo , Luminescência , Nitratos/sangue , Óxido Nítrico/metabolismo , Nitritos/sangueRESUMO
AIM: The endothelium, mainly via nitric oxide (NO) release, adjusts the coronary flow. Cardiac function is closely linked to blood flow; thus, we tested the hypothesis that NO modulation in coronary arteries could be differentially adjusted after myocardial infarction (MI) in the presence or absence of heart failure (HF). METHODS AND RESULTS: Four weeks after coronary occlusion, the infarcted rats were subdivided into rats without (MI) or with HF signs according to haemodynamic parameters. The septal coronary arteries were subsequently used to perform functional and molecular experiments. Acetylcholine (ACh)-induced relaxation was decreased in the coronary arteries following HF, whereas it was enhanced in the arteries of the MI compared with those of SHAM-operated (SO) rats. The relaxation induced by the NO donor was similar among the groups. NO production, which was evaluated by 4,5-diaminofluorescein diacetate, was reduced in the coronary arteries of the HF group and increased in the arteries with MI after ACh-induced stimulation. HF coronary arteries exhibited oxidative stress, which was evaluated via ethidium bromide-positive nuclei, whereas it was decreased in MI. To evaluate the mechanisms involved in the enhanced ACh-induced relaxation in the arteries following MI, certain septal coronary arteries were pre-incubated with L-NAME (a nonselective NO synthase (NOS) inhibitor), 7-NI (a selective neuronal NOS (nNOS) inhibitor) or LY294002 (a PI3-kinase inhibitor). L-NAME and LY294002 reduced ACh-induced relaxation in the MI and SO rats; however, these effects were greater in the MI arteries. 7-NI reduced only the ACh-relaxation in MI. In addition, the eNOS, nNOS, Akt, and superoxide dismutase isoform protein expressions were greater in the coronary arteries of the MI than in those of the SO groups. CONCLUSION: Our data suggested that endothelial function was closely related to cardiac function after coronary occlusion. The coronary arteries from the HF rats exhibited reduced NO bioavailability, whereas the MI rats exhibited increased NO bioavailability because of increased eNOS/nNOS/PI3-kinase/Akt pathway and a reduction in ROS generation. These results suggest that enhanced NO modulation can prevent the onset of HF.
Assuntos
Insuficiência Cardíaca/metabolismo , Infarto do Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Vasodilatação/efeitos dos fármacos , Acetilcolina/administração & dosagem , Animais , Disponibilidade Biológica , Oclusão Coronária , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Humanos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , NG-Nitroarginina Metil Éster/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Ratos , Vasodilatadores/administração & dosagemRESUMO
PURPOSE: To assess the probable actions of ropivacaine, 50% enantiomeric excess bupivacaine mixture (S75-R25) and levobupivacaine on neuromuscular transmission in vitro. METHODS: Thirty rats were distributed into groups (n=5) according to the drug used: ropivacaine, bupivacaine (S75-R25) and levobupivacaine. The concentration used for the three local anesthetics (LA) was 5 µg.mL. (-1)The following parameters were evaluated: 1) LA effects on membrane potential (MP) and miniature end plate potential (MEPP). A chick biventer cervicis preparation was also used to evaluate LA effects on the contracture response to acetylcholine. RESULTS: LA did not alter MP values and decreased the frequency and amplitude of MEPP. In a chick biventer cervicis preparation, bupivacaine (S75-R25) and levobupivacaine decreased the contracture response to acetylcholine with statistical significance, in comparison to ropivacaine. CONCLUSIONS: In the concentrations used, levobupivacaine and bupivacaine (S75-R25) exhibited presynaptic and postsynaptic actions evidenced by alterations in miniature end plate potentials and contracture response to acetylcholine. Ropivacaine only had a presynaptic action.
Assuntos
Amidas/farmacologia , Anestésicos Locais/farmacologia , Bupivacaína/análogos & derivados , Bupivacaína/farmacologia , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Acetilcolina/administração & dosagem , Acetilcolina/farmacologia , Amidas/administração & dosagem , Anestésicos Locais/administração & dosagem , Animais , Bupivacaína/administração & dosagem , Levobupivacaína , Masculino , Potenciais da Membrana/efeitos dos fármacos , Ratos , Ratos Wistar , Ropivacaina , Sinapses/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
PURPOSE: To assess the probable actions of ropivacaine, 50% enantiomeric excess bupivacaine mixture (S75-R25) and levobupivacaine on neuromuscular transmission in vitro. METHODS: Thirty rats were distributed into groups (n=5) according to the drug used: ropivacaine, bupivacaine (S75-R25) and levobupivacaine. The concentration used for the three local anesthetics (LA) was 5 µg.mL.-1The following parameters were evaluated: 1) LA effects on membrane potential (MP) and miniature end plate potential (MEPP). A chick biventer cervicis preparation was also used to evaluate LA effects on the contracture response to acetylcholine. RESULTS: LA did not alter MP values and decreased the frequency and amplitude of MEPP. In a chick biventer cervicis preparation, bupivacaine (S75-R25) and levobupivacaine decreased the contracture response to acetylcholine with statistical significance, in comparison to ropivacaine. CONCLUSIONS: In the concentrations used, levobupivacaine and bupivacaine (S75-R25) exhibited presynaptic and postsynaptic actions evidenced by alterations in miniature end plate potentials and contracture response to acetylcholine. Ropivacaine only had a presynaptic action.
Assuntos
Animais , Masculino , Ratos , Amidas/farmacologia , Anestésicos Locais/farmacologia , Bupivacaína/análogos & derivados , Bupivacaína/farmacologia , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Acetilcolina/administração & dosagem , Acetilcolina/farmacologia , Amidas/administração & dosagem , Anestésicos Locais/administração & dosagem , Bupivacaína/administração & dosagem , Potenciais da Membrana/efeitos dos fármacos , Ratos Wistar , Sinapses/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
OBJECTIVE: Malaria causes more deaths worldwide than any other parasitic disease. Many aspects of the biology that governs the pathogenesis of this parasite are still unclear. Therefore insight into the complexity of the pathogenesis of malaria is vital to understand the disease, particularly as it relates to blood pressure. METHODS: In vivo and in vitro experimental models were used for this study. In the in vivo study, mean arterial pressure, pulse rates and heart rates were recorded by cannulation of the carotid artery of rats. In the in vitro study, ring preparations of blood vessels from the rat aorta were studied using standard organ bath techniques. Dose-response curves for phenylepherine (PE) - and acetylcholine (Ach) -induced relaxation were constructed for rings pre-contracted with PE. RESULTS: Our results showed a significant (p < 0.05) reduction in the mean arterial pressure and pulse rates, while the heart rates remained unaltered in rats with malaria parasites, compared with the controls. Incubation of rat aortic rings with parasitised blood resulted in a significant (p < 0.05) increase in maximum contractile response to phenylephrine in the rat aortic rings but there was no effect on the baseline. The dose-response curve showed a significant (p < 0.05) leftward shift following the addition of parasitised blood and the EC(70) (M) values increased from 7 × 10(- 7) to 5 × 10(-6) M. Following exposure to parasitised blood, the magnitude of Ach-induced relaxation responses reduced significantly (p < 0.05) from 73 ± 3.6 to 24.75 ± 7.25% in the rat aortic rings. CONCLUSIONS: The results suggest that malaria parasitaemia caused in vivo reduction in blood pressure, and enhanced the responses to contractile agents and reduced relaxation responses to acetylcholine in vitro. This appears to be a paradox but is explainable by the complex cardiovascular control mechanisms in vivo. This may be independent of direct action on vascular smooth muscle.
Assuntos
Aorta Torácica/microbiologia , Pressão Sanguínea/fisiologia , Malária/fisiopatologia , Plasmodium berghei , Acetilcolina/administração & dosagem , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Pressão Sanguínea/efeitos dos fármacos , Células Cultivadas , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Modelos Animais , Contração Muscular/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Fenilefrina/administração & dosagem , Ratos , Ratos WistarRESUMO
The production of nitric oxide (NO) from l-arginine is catalyzed by NO synthase (NOS), which exists as the following three isoforms: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). The participation of this pathway in peripheral antinociception has been extensively established by our group with the use of several types of drugs, including opioids, cannabinoids, cholinergic, and α(2C) adrenoceptor agonists and nonsteroidal anti-inflammatory drugs (NSAIDS), and even non-pharmacological procedures such as electroacupuncture. In this study, we aimed to refine the previous data to investigate which type of NOS isoform is involved in the peripheral antinociception mechanism induced by anandamide, morphine, SNC80, bremazocine, acetylcholine, xylazine, baclofen, dipyrone, and diclofenac. After hyperalgesia was induced by intraplantar injection of prostaglandin E(2) in male Wistar rats, we measured peripheral nociception with the paw pressure test. All drugs that were used induced a peripheral antinociception effect that was completely blocked by injection of the selective neuronal NO synthase inhibitor, L-NPA (24µg/paw). The exception was the GABA(B) agonist baclofen, which induced an effect that was not antagonized. We used the inhibitors L-NIO and -NIL (24µg/paw) to exclude the involvement of endothelial and inducible NO synthase, respectively. These drugs were ineffective against the antinociception effect induced by all analgesic drugs that we utilized. Based on the experimental evidence, we conclude that the local injection of analgesic drugs activates nNOS to release NO and induce peripheral antinociception.
Assuntos
Analgésicos/farmacologia , Hiperalgesia/enzimologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/metabolismo , Acetilcolina/administração & dosagem , Acetilcolina/farmacologia , Analgésicos/administração & dosagem , Animais , Ácidos Araquidônicos/administração & dosagem , Ácidos Araquidônicos/farmacologia , Arginina/administração & dosagem , Arginina/análogos & derivados , Arginina/farmacologia , Dinoprostona/administração & dosagem , Dinoprostona/farmacologia , Endocanabinoides , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Isoenzimas/metabolismo , Masculino , Óxido Nítrico/metabolismo , Medição da Dor , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/enzimologia , Alcamidas Poli-Insaturadas/administração & dosagem , Alcamidas Poli-Insaturadas/farmacologia , Ratos , Ratos WistarRESUMO
BACKGROUND: Considering that recent studies have demonstrated endothelial dysfunction in subjects with periodontitis and that there is no information about vascular function in coexistence of periodontitis and atherosclerosis, we assessed the impact of oral inoculation with the periodontal pathogen Porphyromonas gingivalis on vascular reactivity in healthy and hypercholesterolemic apolipoprotein E-deficient (ApoE) mice. In vitro preparations of mesenteric arteriolar bed were used to determine the vascular responses to acetylcholine, sodium nitroprusside and phenylephrine (PE). RESULTS: Alveolar bone resorption, an evidence of periodontitis, was assessed and confirmed in all infected mice. Acetylcholine- and sodium nitroprusside-induced vasorelaxations were similar among all groups. Non-infected ApoE mice were hyperreactive to PE when compared to non-infected healthy mice. P gingivalis infection significantly enhanced the vasoconstriction to PE in both healthy and spontaneous atherosclerotic mice, when compared to their respective controls. CONCLUSIONS: This study demonstrates that oral P gingivalis affects the alpha-adrenoceptor-mediated vascular responsiveness in both healthy and spontaneous atherosclerotic mice, reinforcing the association between periodontitis and cardiovascular diseases.
Assuntos
Aterosclerose/complicações , Infecções por Bacteroidaceae/complicações , Infecções por Bacteroidaceae/microbiologia , Vasos Sanguíneos/patologia , Saúde , Boca/microbiologia , Porphyromonas gingivalis/fisiologia , Acetilcolina/administração & dosagem , Acetilcolina/farmacologia , Perda do Osso Alveolar/sangue , Perda do Osso Alveolar/complicações , Perda do Osso Alveolar/microbiologia , Animais , Apolipoproteínas E/metabolismo , Arteríolas/efeitos dos fármacos , Arteríolas/patologia , Aterosclerose/sangue , Aterosclerose/microbiologia , Infecções por Bacteroidaceae/sangue , Vasos Sanguíneos/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Relação Dose-Resposta a Droga , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Boca/efeitos dos fármacos , Boca/patologia , Nitroprussiato/administração & dosagem , Nitroprussiato/farmacologia , Fenilefrina/administração & dosagem , Fenilefrina/farmacologia , Porphyromonas gingivalis/efeitos dos fármacosRESUMO
OBJECTIVE: Adherence of erythrocytes infected with Plasmodium falciparum (P falciparum) to microvascular endothelial cells (sequestration) is considered to play an important role in parasite virulence and pathogenesis. In this study, we have examined the possibility that there is altered vascular reactivity due to the direct interaction between the parasitized erythrocytes and vascular endothelial cells and that it could be tissue specific. METHOD: Ring preparations of blood vessels from the rabbit carotid and rat aorta were studied using standard organ bath techniques. Dose response curves for phenylephrine (PE) and acetylcholine (Ach)-induced relaxation were constructed in rings pre-contracted with PE. RESULTS: Incubation of rat aortic rings with parasitized blood resulted in a significant (p < 0.05) increase in maximum contractile response to phenylephrine in the rat aortic rings but there was no effect on the rabbit carotid artery. The dose-response curve showed a significant (p < 0.05) left-ward shift following the addition of parasitized blood. Parasitised blood had no effect on baseline in both tissues. Following exposure to parasitized blood, the magnitude of Ach-induced relaxation responses reduced significantly (p < 0.05) in rat aortic rings and (p < 0.05) in rabbit carotid rings; relaxations to acetylcholine was more pronounced in the aortic compared to the carotid rings. CONCLUSIONS: Malaria altered vascular reactivity through an endothelium-dependent mechanism. The regulation of vascular tone by various vasoactive agents following exposure to malaria parasites might be altered in a vessel-specific manner. This may contribute to or exacerbate the abnormal haemodynamics observed in the microcirculation of numerous vascular beds in malaria.
Assuntos
Endotélio Vascular/fisiopatologia , Malária Falciparum/fisiopatologia , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Acetilcolina/administração & dosagem , Animais , Aorta Torácica/fisiopatologia , Artérias Carótidas/fisiopatologia , Relação Dose-Resposta a Droga , Eritrócitos/parasitologia , Técnicas In Vitro , Microcirculação/fisiologia , Fenilefrina/administração & dosagem , Coelhos , Ratos , Vasoconstritores/administração & dosagem , Vasodilatadores/administração & dosagemRESUMO
We have previously demonstrated that low dose of inhaled dopamine (0.5-2 microg kg(-1) min(-1)) induces broncodilatacion in patients with acute asthma attack, suggesting that this dopamine effect is mediated by dopaminergic rather than by adrenergic receptors. To understand better these dopamine effect, rat tracheal smooth muscle was used as a model to evaluate the responses of beta2-, alpha1-, alpha2-adrenergic and DA1 and DA2 dopaminergic antagonists. Tracheal rings from male Sprague-Dawley rats (n = 90) were excised and placed in an organ bath containing modified Krebs-Ringer bicarbonate buffer at 37 degrees C, and gassed with O2 (95%) and CO2 (5%). Contractile responses were recorded with an isometric transducer in a polygraph (Letica, Spain). Contraction was induced by accumulative doses of acetylcholine (0.1, 0.3, 1, 3, 10 mM) or by electric field stimulation (10 Hz at 2 milliseconds), and accumulative doses of dopamine were added to the bath. Low concentration (0.1-0.3 mM) elicited a small initial contraction, followed by a marked relaxation. Cholinergic contraction was completely reversed at 6 mM of dopamine. This biphasic dopaminergic response was not blocked by incubation with beta2-adrenergic antagonist propranolol (0.1 microM), alpha1-antagonist, terazosin (0.1 mM), alpha2-antagonist, yohimbine (0.1 mM), or by DA2 antagonist metoclopramide (1-8 mM); DA1 antagonist SCH23390 (0.1 microM) produced a sustained increase of basal tone but did not block initial dopaminergic contraction and partially inhibited bronchodilator effect of dopamine. Dopaminergic relaxation in rat trachea is mediated by DA1 rather than by DA2 receptors; and adrenergic receptors are not involved in such dopamine-induced response. Finally, DA1 antagonist SCH23390 exerts intrinsic contractile activity on airway smooth muscle that deserves further research.
Assuntos
Dopamina/farmacologia , Contração Muscular/efeitos dos fármacos , Receptores de Dopamina D1/efeitos dos fármacos , Traqueia/efeitos dos fármacos , Acetilcolina/administração & dosagem , Acetilcolina/farmacologia , Animais , Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Estimulação Elétrica , Técnicas In Vitro , Masculino , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Traqueia/metabolismo , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacologiaRESUMO
A cirurgia de revascularização do miocárdio, realizada com o auxílio da circulação extracorpórea, está associada a alterações importantes na microcirculação e na produção e circulação de citocinas e marcadores inflamatórios. No presente estudo, foram avaliados 23 pacientes com indicação de revascularização do miocárdio, no dia do procedimento e 7 e 28 dias após a cirurgia. A microcirculação cutânea, enquanto reflexo da microcirculação coronariana, foi estudada através da hiperemia térmica e/ou reativa pós oclusiva e da iontoforese de substâncias vasoativas por mecanismos dependentes e independentes do endotélio. A rigidez arterial foi aferida através da análise da onda de pulso digital. Foi avaliado ainda o impacto da doença e do procedimento cirúrgico sobre a produção e circulação sérica de citocinas e marcadores inflamatórios, tais como: PCR-HS, nitrito/nitrato, IL-6, II-7, IL-10, IFN-y, TNT-alfa e G-CSF. Foi observada uma tendência à redução da vasodilatação da microcirculação cutânea após a administração de doses acumulativas de acetilcolina (endotélio dependente) através da iontoforese de 7 e 28 dias após o procedimento cirúrgico. A hiperemia térmica foi mais pronunciada na avaliação basal do que aos 7 e 28 dias. A hiperemia reativa pós oclusiva não demonstrou alterações 7 dias após o procedimento. Aos 28 dias, houve um aumento da condutância microvascular cutânea. Quando avaliada a vasodilatação endotélio-independente (nitroprussiato de sódio), observamos aumento do fluxo microvascular cutâneo diretamente proporcional à carga/dose aplicada, sem diferenças nos valores obtidos no basal e 7 e 28 dias após o procedimento. A rigidez arterial não apresentou alterações. A análise dos fatores inflamatórios e das citocinas demonstrou aumento marcante da IL-6 e da IL-8 após 7 dias do procedimento cirúrgico, com retorno parcial aos níveis basais da IL-6 e total da IL-8 após 28 dias. O IFN-y, TNF-alfa e G-CSF apenas apresentaram níveis detectáveis...
Myocardial revascularization with cardiopulmonary bypass is associated with important modifications in the microcirculation and in the production and circulation of cytokines and inflammatory markers. In the present study 23 patients were evaluated on the day of the myocardial revascularization (baseline) and 7 and 28 days after the surgical procedure. The skin microcirculation that is in close relationship with coronary microcirculation was evaluated by iontophoresis of vasoactive substances, thermal hyperemia and post occlusive reactive hyperemia. The arterial stiffness was studied by digital pulse wave analysis. Cytokines and inflammatory markers such as C-reactive protein, nitrite/nitrate, IL-6, II-7, IL-8, IL-10, IFN-y, TNF-alfa e G-CSF were also analyzed. A reduction in the skin microvascular vasodilatation was observed after iontophoresis of cumulative doses of acetylcholine (endothelium dependent) 7 and 28 days after the surgical procedure. Skin vasodilation after thermal hyperemia was more important before the surgery than 7 and 28 days after the procedure. The post occlusive reactive hyperemia did not cause vasodilation after 7 days of the surgery. After 28 days, the cutaneous microvascular conductance was higher than before. The iontophoresis of sodium nitroprusside (endothelium independent) showed increasing vasodilation according to the doses/charge applied but there was no difference among the days of the study. The level of IL-6 and IL-8 increased after 7 days and the level of IL-8 returned to baseline after 28 days. IL-6 showed a reduction after 28 days but did not reach the baseline. INF-y, TNF-alfa e G-CSF were detected only on the day of the surgical procedure and the level of IL-7 and IL-10 was similar before, 7 days and 28 days after the surgery. Nitrite/nitrate was reduced after 7 days of the surgical procedure. In conclusion we observed that the small difference between endothelium dependent vasodilation 7 days after the surgical...
Assuntos
Humanos , Masculino , Feminino , Acetilcolina/administração & dosagem , Artérias/fisiopatologia , Circulação Extracorpórea/métodos , Endotélio Vascular/fisiologia , Iontoforese , Revascularização Miocárdica , Microcirculação/fisiologia , Procedimentos Cirúrgicos Cardiovasculares , Síndrome de Resposta Inflamatória SistêmicaRESUMO
Microinjection of acetylcholine chloride (ACh) in the nucleus of the solitary tract (NTS) of awake rats caused a transient and dose-dependent hypotension and bradycardia. Because it is known that cardiovascular reflexes are affected by nitric oxide (NO) produced in the NTS, we investigated whether these ACh-induced responses depend on NO in the NTS. Responses to ACh (500 pmol in 100 nl) were strongly reduced by ipsilateral microinjection of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 nmol in 100 nl) in the NTS: mean arterial pressure (MAP) fell by 50 +/- 5 mmHg before L-NAME to 9 +/- 4 mmHg, 10 min after L-NAME, and HR fell by 100 +/- 26 bpm before L-NAME to 20 +/- 10 bpm, 10 min after L-NAME (both P < 0.05). Microinjection of the selective inhibitor of neuronal nitric oxide synthase (nNOS), 1-(2-trifluoromethylphenyl) imidazole (TRIM; 13.3 nmol in 100 nl), in the NTS also reduced responses to ACh: MAP fell from 42 +/- 3 mmHg before TRIM to 27 +/- 6 mmHg, 10 min after TRIM (P < 0.05). TRIM also tended to reduce ACh-induced bradycardia, but this effect was not statistically significant. ACh-induced hypotension and bradycardia returned to control levels 30-45 min after NOS inhibition. Control injections with D-NAME and saline did not affect resting values or the response to ACh. In conclusion, injection of ACh into the NTS of conscious rats induces hypotension and bradycardia, and these effects may be mediated at least partly by NO produced in NTS neurons.
Assuntos
Acetilcolina/metabolismo , Pressão Sanguínea , Sistema Cardiovascular/inervação , Fibras Colinérgicas/metabolismo , Frequência Cardíaca , Neurônios Nitrérgicos/metabolismo , Óxido Nítrico/metabolismo , Núcleo Solitário/metabolismo , Acetilcolina/administração & dosagem , Animais , Pressão Sanguínea/efeitos dos fármacos , Bradicardia/metabolismo , Bradicardia/fisiopatologia , Fibras Colinérgicas/efeitos dos fármacos , Fibras Colinérgicas/enzimologia , Inibidores Enzimáticos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hipotensão/metabolismo , Hipotensão/fisiopatologia , Imidazóis/farmacologia , Masculino , Microinjeções , NG-Nitroarginina Metil Éster/farmacologia , Neurônios Nitrérgicos/efeitos dos fármacos , Neurônios Nitrérgicos/enzimologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I , Ratos , Ratos Wistar , Núcleo Solitário/citologia , Núcleo Solitário/efeitos dos fármacos , Fatores de Tempo , VigíliaRESUMO
It is known that the endothelial function is compromised in atherosclerosis and arterial hypertension and that angiotensin is an important factor contributing to both pathophysiologies. The aim of this study was to evaluate the vascular function in a hypercholesterolemia/atherosclerosis model, in the angiotensin II-dependent 2-kidney 1-clip (2K1C) hypertension model and when both conditions coexist. Eight-week-old apolipoprotein E knockout (apoE; n=20) and C57BL/6 (C57; n=20) mice underwent a 2K1C or sham operation and were studied 28 days later. Mean arterial pressure was higher in apoE-2K1C and C57-2K1C (126+/-3 and 128+/-3 mm Hg) when compared with the apoE-Sham and C57-Sham (103+/-2 and 104+/-2 mm Hg, respectively; P<0.05). The vascular reactivity to norepinephrine (NE; 10(-9) to 2 x 10(-3) mol/L), acetylcholine (ACh), and sodium nitroprusside (SNP; 10(-10) to 10(-3) mol/L) was evaluated in the mesenteric arteriolar bed through concentration-effect curves. NE caused vascular hyper-reactivity in apoE-Sham, apoE-2K1C, and C57-2K1C (maximal response 146+/-5, 144+/-5, and 159+/-4 mm Hg, respectively) compared with C57-Sham (122+/-7 mm Hg; P<0.05). The ACh-induced relaxation was smaller (P<0.05) in apoE-2K1C and C57-2K1C (maximal response 53+/-3% and 46+/-3%) than in apoE-Sham and C57-Sham mice (78+/-5% and 73+/-4%). SNP-induced vascular relaxation showed similar concentration-effect curves in all groups. We conclude that in C57-2K1C mice, the increased reactivity to NE and the decreased endothelium-dependent relaxation contribute to the maintenance of hypertension. The apoE mouse, at early stages of atherosclerosis, shows hyper-reactivity to NE but does not have endothelium dysfunction yet. However, the concurrence of both pathophysiologies does not result in additive effects on the vascular function.
Assuntos
Angiotensinas/metabolismo , Apolipoproteínas E/deficiência , Vasos Sanguíneos/fisiopatologia , Hipertensão Renovascular/fisiopatologia , Acetilcolina/administração & dosagem , Acetilcolina/farmacologia , Animais , Aterosclerose/fisiopatologia , Pressão Sanguínea , Relação Dose-Resposta a Droga , Hipercolesterolemia/fisiopatologia , Hipertensão Renovascular/metabolismo , Masculino , Camundongos , Camundongos Knockout , Nitroprussiato/administração & dosagem , Nitroprussiato/farmacologia , Norepinefrina/administração & dosagem , Norepinefrina/farmacologia , Vasoconstrição , Vasoconstritores/administração & dosagem , Vasoconstritores/farmacologia , Vasodilatação , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacologiaRESUMO
Although cholinergic agonists such as pilocarpine injected peripherally can act directly on salivary glands to induce salivation, it is possible that their action in the brain may contribute to salivation. To investigate if the action in the brain is important to salivation, we injected pilocarpine intraperitoneally after blockade of central cholinergic receptors with atropine methyl bromide (atropine-mb). In male Holtzman rats with stainless steel cannulas implanted into the lateral ventricle and anesthetized with ketamine, atropine-mb (8 and 16 nmol) intracerebroventricularly reduced the salivation induced by pilocarpine (4 micro mol/kg) intraperitoneally (133 + 42 and 108 + 22 mg/7 min, respectively, vs. saline, 463 + 26 mg/7 min), but did not modify peripheral cardiovascular responses to intravenous acetylcholine. Similar doses of atropine-mb intraperitoneally also reduced pilocarpine-induced salivation. Therefore, systemically injected pilocarpine also enters the brain and acts on central muscarinic receptors, activating autonomic efferent fibers to induce salivation.
Assuntos
Pilocarpina/farmacologia , Receptores Muscarínicos/fisiologia , Salivação/efeitos dos fármacos , Acetilcolina/administração & dosagem , Acetilcolina/farmacologia , Animais , Derivados da Atropina/farmacologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Antagonistas Muscarínicos/farmacologia , Fibras Nervosas/efeitos dos fármacos , Neurônios Eferentes/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Pilocarpina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores Colinérgicos/efeitos dos fármacos , Receptores Muscarínicos/efeitos dos fármacosRESUMO
Two quinoline alkaloids, (-)-R-geilbalansine (1) and hyemaline (2), as well as aromatic amide, N-[2-(3,4-dimethoxyphenyl)-2-methoxyethyl)-2-methoxyethyl]benzamide (O-methylbalsamide) (3), were isolated as new natural products from the stem barks of Zanthoxylum hyemale, together with seven known compounds. Their structures were determined on the basis of spectroscopic data (IR, (1)H- and (13)C-NMR, MS). In addition, the antispasmodic activity of the crude extract of Z. hyemale and three other more abundant isolated compounds (4, 5 and 10) were studied in two different antispasmodic test models on isolated rat ileum and only the crude ethanolic extract presented antispasmodic activity.
Assuntos
Alcaloides/farmacologia , Amidas/farmacologia , Benzamidas/farmacologia , Extratos Vegetais/farmacologia , Quinolinas/farmacologia , Rutaceae , Acetilcolina/administração & dosagem , Alcaloides/química , Alcaloides/isolamento & purificação , Amidas/química , Amidas/isolamento & purificação , Animais , Compostos de Bário/administração & dosagem , Benzamidas/química , Benzamidas/isolamento & purificação , Benzofenantridinas , Cloretos/administração & dosagem , Relação Dose-Resposta a Droga , Íleo/efeitos dos fármacos , Íleo/fisiologia , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Masculino , Estrutura Molecular , Contração Muscular/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Fenantridinas/isolamento & purificação , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Quinolinas/química , Quinolinas/isolamento & purificação , Ratos , Ratos Wistar , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
OBJECTIVE: This study was performed to investigate the endothelium-dependent relaxation and contractile responses to endothelin-1 in subcutaneous resistive arteries from Caribbean patients with advanced atherosclerotic femoro-crural arterial disease. DESIGN AND METHODS: Small subcutaneous arteries (inner diameter 200 um) from control subjects (n=8) and atherosclerotic patients (n=8) were dissected from fat biopsies obtained at routine vascular surgery and mounted in vitro on a wire-myograph measuring parietal tension under isometric conditions. RESULTS: Acetylcholine-induced relaxation (10-6 M) was significantly reduced in pre-contracted arteries from atherosclerotic patients (24 + or - 16 percent vs 17 percent in control, p<0.001). Smooth muscle relaxation to sodium nitroprusside was comparable in both groups. Contractions elicited by endothelin-1 (10-9 M) were significantly lower and almost suppressed in both the atherosclerotic group (1.2 + or - 0.8 Kpa) and in the hypertensive subgroup of control subjects (n=4, 1.2= 0r - 1.2 Kpa) comparatively to normotensive control subjects (12.3 + or - 6.9 Kpa, p<0.001). Contractile responses induced by endothelin-1 at higher concentrations (10-8 - 10-7 M), noradrenaline and hyperosmolar potassium were comparable in both groups. CONCLUSIONS: These data suggest a specific impairment of both endothelium-dependent relaxation and contractility in lower limb subcutaneous resistive arteries from Caribbean patients with atherosclerotic femoro-crural arterial disease. These changes in vessels which largely determine proximal vascular resistance may contribute to ischaemic complications in this vascular bed including skin ulcerations and gangrene.(Au)