RESUMO
Salvia tiliifolia is used in folk medicine as a relaxant agent and for the treatment of diarrhea and neurodegenerative diseases. Tilifodiolide (TFD) is a diterpene obtained from this plant. The purpose of this work was to evaluate the antidiarrheal, vasorelaxant, and neuropharmacological actions of TFD. These effects were selected based on the folk medicinal use of S. tiliifolia. The antidiarrheal activity of 1-50 mg/kg p.o. TFD was assessed with the castor oil related tests. The vasorelaxant effect of TFD (0.9-298 µM) was performed with smooth muscle tissues from rats, and its mechanism of action was evaluated using different inhibitors. The sedative, anxiolytic, and antidepressant effects of 1-100 mg/kg TFD were assessed. The possible mechanisms of action of the anxiolytic and antidepressant effects of TFD were evaluated using inhibitors. TFD exhibited antidiarrheal (ED50 = 10.62 mg/kg) and vasorelaxant (EC50 = 48 ± 3.51 µM) effects. The coadministration of TFD with N(ω)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), reverted the vasorelaxant action showed by TFD alone. TFD exerted anxiolytic actions (ED50 = 20 mg/kg) in the cylinder exploratory test, whereas TFD (50 mg/kg) showed antidepressant actions in the tail suspension test by 44%. The pretreatment with 2 mg/kg flumazenil partially reverted the anxiolytic actions of TFD, whereas the pretreatment with 1 mg/kg yohimbine abolished the antidepressant effects of TFD. In summary, TFD exerted antidiarrheal activity by decreasing the intestinal fluid accumulation and vasorelaxant effects mediated by nitric oxide and cyclic guanosine monophosphate. TFD showed anxiolytic and antidepressant effects by the partial involvement of gamma-Aminobutyric acid (GABA) receptors and the possible participation of α2-adrenoreceptors, respectively.
Assuntos
Antidiarreicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Diterpenos/farmacologia , Músculo Liso/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Diterpenos/antagonistas & inibidores , Relação Dose-Resposta a Droga , Interações Medicamentosas , Flumazenil/farmacologia , Hipnóticos e Sedativos/farmacologia , Masculino , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Oxidiazóis/farmacologia , Quinoxalinas/farmacologia , Vasodilatadores/antagonistas & inibidores , Ioimbina/farmacologiaRESUMO
La adaptación al medio extrauterino incluye un aumento considerable de la PaO2, que induce especialmente cambios estructurales y vasoactivos en la circulación pulmonar, que llevarán a una circulación previamente pobremente irrigada, a recibir ∼100% del gasto cardíaco del recién nacido, permitiendo el normal intercambio gaseoso. La regulación local de la circulación arterial pulmonar neonatal basal, es mantenida por un delicado equilibrio entre agentes vasoconstrictores y vasodilatadores. Este equilibrio, permite mantener la circulación pulmonar como un territorio de gran flujo sanguíneo y baja resistencia. La acción de los vasoconstrictores permite la formación de las interacciones entre actina y la cadena liviana de la miosina, esta es inducida en la célula muscular lisa principalmente por dos vías: a) dependiente de calcio, que consiste en aumentar el calcio intracelular, facilitando finalmente la unión de actina y miosina, y b) independiente de calcio, la cual a través de consecutivas fosforilaciones logra sensibilizar a las proteínas involucradas promoviendo la unión de actina y miosina. Estas acciones son mediadas por agonistas generados principalmente en el endotelio pulmonar, como endotelina-1 y tromboxano, o por agonistas provenientes de otros tipos celulares como la serotonina. Los agentes vasodilatadores regulan la respuesta vasoconstrictora, principalmente inhibiendo la señalización que induce la vasocontricción independiente de calcio, a través de la activación de proteínas quinasas que inhibirán la función de la ROCK quinasa, uno de los últimos efectores de la vasocontricción antes de la formación de la unión de actina y miosina. Esta revisión describe estos mecanismos de primordial importancia en las primeras horas de nuestra vida como individuos independientes.
The extrauterine-milieu adaptation includes a considerable increase in PaO2, that specifically induces structural and vasoactive changes at pulmonary circulation. Such changes transform a poor irrigated circulation into a circulation that receive ∼100% of neonatal cardiac output, supporting the normal alveolar-capillary gas exchange. Local regulation of basal neonatal pulmonary circulation is maintaining by a delicate equilibrium between vasoconstrictor and vasodilator agents. This equilibrium, allows to maintain the pulmonary circulation as an hemodynamic system with a high blood flow and a low vascular resistance. Vasocontrictors action allows actin and light-chain myosin interaction. Two main pathways induced this effect in smooth muscle cell: a) a calcium dependent pathway, that increases intracellular calcium, facilitating actin - myosin binding, and b) the independent calcium pathway, which achieves through consecutive phosphorylation reactions sensitize the proteins involved, promoting the binding of actin and light-chain myosin. These actions are mediated by agonists produced mainly in the pulmonary endothelium, such as endothelin-1 and thromboxane, or by agonists from other cell types such as serotonin. Vasodilator agents regulate the vasoconstrictor response, mainly by inhibiting signals that induce calcium-independent vasoconstriction, through activation of protein kinases, which in turn will inhibit the function of ROCK kinase, one of the last effectors of vasoconstriction before formation of the actin and light-chain myosin binding. This review will focus on describing these mechanisms of primal importance in the first hours of our lives as independent individuals.
Assuntos
Humanos , Recém-Nascido/fisiologia , Circulação Pulmonar/fisiologia , Pulmão/irrigação sanguínea , Resistência Vascular , Vasoconstrição/fisiologia , Vasoconstritores/antagonistas & inibidores , Vasodilatação/fisiologia , Vasodilatadores/antagonistas & inibidores , Adaptação Fisiológica , Serotonina/fisiologia , Tromboxanos/fisiologia , Cálcio , Endotelina-1/fisiologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Aspidosperma subincanum is a medicinal herb that is known to be useful for the treatment of cardiovascular-related illnesses. However, its effects and pharmacological mechanisms of action have not been studied. The aim of the present study was to determine the effect of an ethanol extract of Aspidosperma subincanum (EEAS) on blood pressure (in vivo) and vascular tension (in vitro) in the rat thoracic aorta. MATERIALS AND METHODS: Catheters were inserted into the right femoral vein and artery of anesthetized rats for EEAS infusion and the measurement of blood pressure, heart rate and aortic blood flow (flow probes were placed around the aorta). Moreover, the vasodilator effect of EEAS in isolated pre-contracted rat aortas was examined. RESULTS: Intravenous infusion of EEAS resulted in significant and dose-dependent hypotension, bradycardia and increased aortic blood flow. In isolated arteries, EEAS (0-27 µg/mL) induced a concentration-dependent relaxation of pre-contracted aortic rings; endothelial denudation potentiated this effect. Pre-treatment of the aortic rings with ODQ, an inhibitor of soluble guanylyl cyclase (sGC); MDL-12,330A, an inhibitor of adenylyl cyclase (AC); or CPA, a SERCA inhibitor, reduced EEAS-induced vasorelaxation. Treatment with an EEAS impaired contractions induced by phenylephrine (an adrenergic agonist) and Bay K 8644 (an L-type Ca(2+) channel activator). The blockade of K(+) channels with tetraethylammonium, clotrimazole, glibenclamide or 4-aminopyridine reduced the relaxation stimulated by EEAS. CONCLUSIONS: These findings suggest that EEAS induces hypotension associated with bradycardia. EEAS induces endothelium-independent vascular relaxation. The sGC/cGMP and AC/cAMP pathways, SERCA activation and Ca(2+) and K(+) flux across the sarcolemma, are likely involved in this relaxation.
Assuntos
Inibidores Enzimáticos/farmacologia , Interações Ervas-Drogas/fisiologia , Extratos Vegetais/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/antagonistas & inibidores , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Agonistas Adrenérgicos/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Aspidosperma/química , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Etanol/química , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Técnicas In Vitro , Masculino , Fenilefrina/antagonistas & inibidores , Fenilefrina/farmacologia , Extratos Vegetais/antagonistas & inibidores , Extratos Vegetais/química , Ratos , Ratos Wistar , Vasodilatação/fisiologia , Vasodilatadores/antagonistas & inibidores , Vasodilatadores/químicaRESUMO
This study investigated the endothelium-dependent vasorelaxant effects of the essential oil of Ocimum gratissimum (EOOG) in aortas and mesenteric vascular beds isolated from rats. EOOG (3-300 µg/mL) relaxed the tonic contractions induced by phenylephrine (0.1 µmol/L) in isolated aortas in a concentration-dependent manner in both endothelium-containing and endothelium-denuded preparations. This effect was partially reversed by L-NAME (100 µmol/L) but not by indomethacin (10 µmol/L) or TEA (5 mmol/L). In mesenteric vascular beds, bolus injections of EOOG (30, 50, 100, and 300 ng) decreased the perfusion pressure induced by noradrenaline (6 µmol/L) in endothelium-intact preparations but not in those treated with deoxycholate. L-NAME (300 µmol/L) but not TEA (1 mmol/L) or indomethacin (3 µmol/L) significantly reduced the vasodilatory response to EOOG at all of the doses tested. Our data showed that EOOG exerts a dose-dependent vasodilatory response in the resistance blood vessels of rat mesenteric vascular beds and in the capacitance blood vessel, the rat aorta. This action is completely dependent on endothelial nitric oxide (NO) release in the mesenteric vascular beds but only partially dependent on NO in the aorta. These novel effects of EOOG highlight interesting differences between resistance and capacitance blood vessels.
Assuntos
Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/efeitos dos fármacos , Ocimum/química , Óleos Voláteis/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/enzimologia , Aorta Torácica/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Endotélio Vascular/fisiologia , Técnicas In Vitro , Masculino , Artérias Mesentéricas/enzimologia , Artérias Mesentéricas/metabolismo , Veias Mesentéricas/enzimologia , Veias Mesentéricas/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Norepinefrina/antagonistas & inibidores , Norepinefrina/metabolismo , Óleos Voláteis/química , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Wistar , Capacitância Vascular/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Vasoconstritores/antagonistas & inibidores , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/antagonistas & inibidoresRESUMO
During a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), producing cranial vasodilatation and central nociception; hence, trigeminal inhibition may prevent this vasodilatation and abort migraine headache. This study investigated the role of spinal α2-adrenoceptors and their subtypes (i.e. α(2A), α(2B) and/or α(2C)-adrenoceptors) in the inhibition of the canine external carotid vasodilator responses to capsaicin. Anaesthetized vagosympathectomized dogs were prepared to measure arterial blood pressure, heart rate and external carotid conductance. The thyroid artery was cannulated for one-min intracarotid infusions of capsaicin, α-CGRP and acetylcholine. A cannula was inserted intrathecally for spinal (C1-C3) administration of 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo-[5,4-d]-azepin-dihydrochloride (B-HT 933; a selective α2-adrenoceptor agonist) and/or the α2-adrenoceptor antagonists rauwolscine (α(2A/2B/2C)), 2-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL44408; α(2A)), imiloxan (α(2B)) or acridin-9-yl-[4-(4-methylpiperazin-1-yl)-phenyl]amine (JP-1302; α(2C)). Infusions of capsaicin, α-CGRP and acetylcholine dose-dependently increased the external carotid conductance. Intrathecal B-HT 933 (1000 and 3100 µg) inhibited the vasodilator responses to capsaicin, but not those to α-CGRP or acetylcholine. This inhibition, abolished by rauwolscine (310 µg), was: (i) unaffected by 3,100 µg imiloxan; (ii) partially blocked by 310 µg of BRL44408 or 100 µg of JP-1302; and (iii) abolished by 1,000 µg of BRL44408 or 310 µg of JP-1302. Thus, intrathecal B-HT 933 inhibited the external carotid vasodilator responses to capsaicin. This response, mediated by spinal α2-adrenoceptors unrelated to the α(2B)-adrenoceptor subtype, resembles the pharmacological profile of α(2C)-adrenoceptors and, to a lesser extent, α(2A)-adrenoceptors.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Artéria Carótida Externa/efeitos dos fármacos , Modelos Animais de Doenças , Transtornos de Enxaqueca/tratamento farmacológico , Receptores Adrenérgicos alfa 2/metabolismo , Medula Espinal/efeitos dos fármacos , Vasoconstritores/uso terapêutico , Acetilcolina/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 2/química , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/antagonistas & inibidores , Analgésicos não Narcóticos/uso terapêutico , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/antagonistas & inibidores , Capsaicina/toxicidade , Artéria Carótida Externa/fisiologia , Vértebras Cervicais , Cães , Hemodinâmica/efeitos dos fármacos , Infusão Espinal , Masculino , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Receptores Adrenérgicos alfa 2/química , Fluxo Sanguíneo Regional/efeitos dos fármacos , Medula Espinal/metabolismo , Vasoconstritores/administração & dosagem , Vasoconstritores/antagonistas & inibidores , Vasodilatadores/antagonistas & inibidores , Vasodilatadores/toxicidadeRESUMO
Although the vasorelaxing effects of testosterone (T) and various androgen metabolites have been observed in a variety of blood vessels and species, previous studies have not systematically compared the vasorelaxing effects of androgen metabolites in different vascular beds within the same species. Therefore, we studied the vasorelaxing effects of T and its 5-reduced metabolites (5α- and 5ß-DHT) on KCl-induced contractions of the canine left coronary artery, femoral artery and saphenous vein, using standard isometric recordings. KCl contractions were inhibited by each androgen in a concentration-dependent manner from 1.8 to 310µM. Vascular sensitivity and efficacy were expressed as inhibitory concentration 50 (IC50) and maximal relaxation (R(max)), respectively. The coronary artery was significantly more sensitive to androgen-induced vasorelaxation than the saphenous vein or femoral artery. These vasorelaxing responses were unaffected by an antiandrogen (Flutamide) or the sulfhydryl reagent, N-ethylmaleimide, suggesting a nongenomic mechanism independent of signaling mediated by the androgen receptor or G proteins. Concentration-response curves were unchanged in endothelium-denuded preparations; thus, the endothelium appears to have no role in androgen-induced vasorelaxation. 5ß-DHT was the most potent androgen in both coronary and femoral artery, but all three androgens were equipotent in the saphenous vein. It is concluded that: 1) significant regional differences exist in vasorelaxing effects of androgen metabolites in the canine vasculature; 2) structural differences in these androgens determine their vasorelaxing efficacy; and 3) regional differences in androgen-induced vasorelaxation may account for some of the conflicting findings reported on the vasorelaxing effects of the androgens.
Assuntos
Androgênios/metabolismo , Vasos Sanguíneos/metabolismo , Di-Hidrotestosterona/metabolismo , Testosterona/metabolismo , Vasodilatação , Vasodilatadores/metabolismo , Antagonistas de Androgênios/farmacologia , Androgênios/química , Animais , Vasos Sanguíneos/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Di-Hidrotestosterona/antagonistas & inibidores , Di-Hidrotestosterona/química , Cães , Etilmaleimida/farmacologia , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/metabolismo , Flutamida/farmacologia , Técnicas In Vitro , Masculino , Concentração Osmolar , Reprodutibilidade dos Testes , Veia Safena/efeitos dos fármacos , Veia Safena/metabolismo , Estereoisomerismo , Reagentes de Sulfidrila/farmacologia , Testosterona/antagonistas & inibidores , Vasodilatação/efeitos dos fármacos , Vasodilatadores/antagonistas & inibidores , Vasodilatadores/químicaRESUMO
A aterosclerose é uma doença caracterizada por inflamação vascular, sendo a proteína C-reativa ultrassensível, a interleucina-6 e o óxido nítrico, alguns de seus marcadores, e cujas complicações incluem o infarto agudo do miocárdio e o acidente vascular cerebral. Uma das principais causas de aterosclerose é a dislipidemia. O cilostazol atua como vasodilatador, antiagregante de plaquetas e antitrombótico. Essa droga também promove a diminuição de triglicerídeos e o aumento de lipoproteínas de alta densidade em diabéticos e em doentes com doença arterial obstrutiva periférica, podendo interferir na aterosclerose. Baseados nesses dados, há a possibilidade de efeitos benéficos do cilostazol na lipemia pós-prandial, nos mediadores da inflamação e na função endotelial.
Atherosclerosis is a disorder that is characterized by vascular inflammation, with ultra-sensitive C-reactive protein, interleukin-6 and nitric oxide being some of its biomarkers, and whose complications include acute myocardial infarction and stroke. One of the main causes of atherosclerosis is dyslipidemia. Cilostazol acts as a vasodilator, antiplatelet, and antithrombotic agent. It also promotes triglycerides decrease and high density lipoproteins increase in diabetics and in patients with obstructive peripheral arterial disease, potentially interfering with atherosclerosis. Based on these data, cilostazol may have beneficial effects on postprandial lipemia, inflammatory mediators, and endothelial function.
Assuntos
Aterosclerose/complicações , Aterosclerose/diagnóstico , Aterosclerose/etiologia , Aterosclerose/patologia , Aterosclerose/terapia , Dislipidemias/complicações , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Dislipidemias/patologia , Inibidores de Fosfodiesterase , Proteína C-Reativa , Vasodilatadores/antagonistas & inibidores , VasodilatadoresRESUMO
Himatanthus lancifolius, popularly known as "agoniada" in Brazil, is largely used in folk medicine against asthma, dysmenorrhea and as an emenagogue and abortive. This study reveals the effects of an alkaloid rich fraction (AlkF) obtained from the bark of Himatanthus lancifolius in vascular and non-vascular smooth muscle responsiveness. Incubation of AlkF (3-30 microg/ml) during 15 min generates a concentration-related and fully reversible reduction in maximal contractile responses evoked by acetylcholine and phenylephrine in rat jejune and aorta preparations, respectively. Exposition of endothelium-denuded pre-contracted rat aorta rings to AlkF results in a complete relaxation, with EC(50) of 22.2 (16.2-28.2 microg/ml). AlkF is also able to induce a concentration-related rightward shift of cumulative concentration curves for calcium in uterus and aorta rings maintained in depolarizing nutritive solution. Moreover, addition of AlkF in calcium-free solution also reduces, in a concentration-dependent manner, the ability of caffeine and phenylephrine to contract aorta rings. This study reveals that the bark of Himatanthus lancifolius possesses one or more indole alkaloids able to alter non-vascular and vascular smooth muscle responsiveness, an event that may involve the blocking of calcium entry or changes on intracellular calcium utilization or mobilization.
Assuntos
Alcaloides/farmacologia , Apocynaceae/química , Músculo Liso/efeitos dos fármacos , Acetilcolina/antagonistas & inibidores , Acetilcolina/farmacologia , Alcaloides/química , Animais , Aorta Torácica/efeitos dos fármacos , Cálcio/fisiologia , Cloreto de Cálcio/farmacologia , Cromatografia Líquida de Alta Pressão , Feminino , Íleo/efeitos dos fármacos , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Fenilefrina/farmacologia , Casca de Planta/química , Ratos , Ratos Wistar , Contração Uterina/efeitos dos fármacos , Ducto Deferente/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatadores/antagonistas & inibidores , Vasodilatadores/farmacologiaRESUMO
1. Pregnancy in rats is characterized by a reduction in arterial pressure that is associated with a decreased response to vasoconstrictors. However, the responses to vasodilators in isolated vessels remain controversial and are not well established in hypertensive pregnant rats. 2. In the present study, we investigated the effect of pregnancy on the bradykinin (BK)-induced vasodilator responses of the isolated mesenteric arterial bed (MAB) from Wistar normotensive and spontaneously hypertensive rats (SHR) and determined the role of nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and angiotensin-converting enzyme (ACE) in these responses. 3. Mean arterial pressure (MAP) in pregnant normotensive and pregnant hypertensive rats (93 +/- 1 and 122 +/- 2 mmHg, respectively) was lower than in non-pregnant controls (128 +/- 1 and 163 +/- 2 mmHg, respectively; P < 0.05). In MAB isolated from normotensive rats and precontracted with phenylephrine, the effects of bradykinin, acetylcholine (ACh) and nitroglycerine (NG) were not influenced by pregnancy. In contrast, the vasodilator responses to BK were significantly reduced in pregnant compared with non-pregnant SHR and seemed to be specific to BK. 4. The ACE inhibitor captopril potentiated BK vasodilator responses and abolished the differences between pregnant and non-pregnant SHR. Inhibition of nitric oxide (NO) synthase by N(G)-nitro-L-arginine methyl ester (l-NAME) significantly reduced the vasodilator effect of BK in all groups. In the presence of l-NAME plus high K+ solution (47 mmol/L), BK-induced vasodilation was completely blocked. The NO-dependent component of the responses seems to be more important in hypertensive rats and pregnancy does not modify this profile. 5. Our results suggest that increased ACE activity may be involved in the pregnancy associated reduction in vasodilator responses to BK in the MAB of hypertensive rats. Pregnancy does not modify the relative contribution of the EDHF and NO to the vasodilator effect of BK.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bradicinina/antagonistas & inibidores , Bradicinina/farmacologia , Captopril/farmacologia , Hipertensão/fisiopatologia , Complicações Cardiovasculares na Gravidez/fisiopatologia , Vasodilatação/efeitos dos fármacos , Acetilcolina/antagonistas & inibidores , Acetilcolina/farmacologia , Animais , Fatores Biológicos/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Feminino , Técnicas In Vitro , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III , Peptidil Dipeptidase A/metabolismo , Gravidez , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Circulação Esplâncnica/efeitos dos fármacos , Vasodilatadores/antagonistas & inibidores , Vasodilatadores/farmacologiaRESUMO
The vasorelaxant effects of SR 47063 (4-(2-cyanimino-1, 2-dihydropyrid-1-yl)-2,2-dimethyl-6-nitr ochromene), a new K(+)-channel opener structurally related to levcromakalim, were examined in isolated human saphenous vein (HSV) and rat aorta (RA). HSV or RA rings were precontracted with either KCl or noradrenaline and cumulative relaxant concentration-response curves were obtained for SR 47063 (0.1 nM to 1 microM) in the presence or absence of 3 microM glibenclamide. SR 47063 potently relaxed HSV and RA precontracted with 20 mM (but not 60 mM) KCl or 10 microM noradrenaline in a concentration-dependent manner, showing slightly greater activity in the aorta. The potency of the effect of SR 47063 on HSV and RA was 12- and 58-fold greater, respectively, than that reported for the structurally related K(+)-channel opener levcromakalim. The vasorelaxant action of SR 47063 in both blood vessels was strongly inhibited by 3 microM glibenclamide, consistent with a mechanism of action involving ATP-dependent K(+)-channels.
Assuntos
Aorta/efeitos dos fármacos , Cromanos/farmacologia , Veia Safena/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Aorta/fisiologia , Cromanos/antagonistas & inibidores , Glibureto/farmacologia , Humanos , Masculino , Norepinefrina , Ratos , Ratos Wistar , Veia Safena/fisiologia , Vasodilatação/fisiologia , Vasodilatadores/antagonistas & inibidoresRESUMO
The vasorelaxant effects of SR 47063 (4-(2-cyanimino-1,2-dihydropyrid-1-yl)-2,2-dimethyl-6-nitrochromene), a new K+-channel opener structurally related to levcromakalim, were examined in isolated human saphenous vein (HSV) and rat aorta (RA). HSV or RA rings were precontracted with either KCl or noradrenaline and cumulative relaxant concentration-response curves were obtained for SR 47063 (0.1 nM to 1 µM) in the presence or absence of 3 µM glibenclamide. SR 47063 potently relaxed HSV and RA precontracted with 20 mM (but not 60 mM) KCl or 10 µM noradrenaline in a concentration-dependent manner, showing slightly greater activity in the aorta. The potency of the effect of SR 47063 on HSV and RA was 12- and 58-fold greater, respectively, than that reported for the structurally related K+-channel opener levcromakalim. The vasorelaxant action of SR 47063 in both blood vessels was strongly inhibited by 3 µM glibenclamide, consistent with a mechanism of action involving ATP-dependent K+-channels
Assuntos
Humanos , Animais , Masculino , Ratos , Aorta/efeitos dos fármacos , Cromanos/farmacologia , Veia Safena/efeitos dos fármacos , Vasodilatadores/farmacologia , Cromanos/antagonistas & inibidores , Glibureto/farmacologia , Norepinefrina , Ratos Wistar , Vasodilatadores/antagonistas & inibidoresRESUMO
To investigate the role of nitric oxide in human sepsis, ten patients with severe septic shock requiring vasoactive drug therapy and mechanical ventilation were enrolled in a prospective, open, non-randomized clinical trial to study the acute effects of methylene blue, an inhibitor of guanylate cyclase. Hemodynamic and metabolic variables were measured before and 20, 40, 60, and 120 min after the start of a 1-h intravenous infusion of 4 mg/kg of methylene blue. Methylene blue administration caused a progressive increase in mean arterial pressure (60 [55-70] to 70 [65-100] mmHg, median [25-75th percentiles]; P<0.05), systemic vascular resistance index (649 [479-1084] to 1066 [585-1356] dyne s-1 cm-5 m-2; P<0.05) and the left ventricular stroke work index (35 [27-47] to 38 [32-56] g m-1 m-2; P<0.05) from baseline to 60 min. The pulmonary vascular resistance index increased from 150 [83-207] to 186 [121-367] dyne s-1 cm-5 m-2 after 20 min (P<0.05). Mixed venous saturation decreased from 65 [56-76] to 63 [55-69] per cent (P<0.05) after 60 min. The PaO2/FiO2 ratio decreased from 168 [131-215] to 132 [109-156] mmHg (P<0.05) after 40 min. Arterial lactate concentration decreased from 5.1 + or - 2.9 to 4.5 + or - 2.1 mmol/l, mean + or - SD (<0.05) after 60 min. Heart rate, cardiac filling pressures, cardiac output, oxygen delivery and consumption did not change. Methylene blue administration was safe and no adverse effect was observed. In severe human septic shock, a short infusion of methylene blue increases systemic vascular resistance and may improve myocardial function. Although there was a reduction in blood lactate concentration, this was not explained by an improvement in tissue oxygenation, since overall oxygen availability did not change. However, there was a significant increase in pulmonary vascular tone and a deterioration in gas exchange. Further studies are needed to demonstrate if nitric oxide blockade with methylene blue can be safe for patients with septic shock and, particularly, if it has an effect on pulmonary function.