RESUMEN
4-hydroxybenzaldehyde (4HB), known as ρ-hydroxybenzaldehyde, is commonly present in traditional Chinese medicine herb, most frequently used for hypertension treatment. This research aims to determine the potency of 4HB's vasorelaxant action. In the study, the vasodilation effect of 4HB was evaluated using in vitro isolated rat aortic rings assay. The aortic rings were pre-incubated with respective antagonists before being pre-contracted with phenylephrine (PE) and challenged with various concentrations of 4HB for mechanistic action studies. Rmax (maximal vasodilation) and pEC50 (negative logarithm of half-maximal effective concentration) values of each experiment were determined for comparison purposes. 4HB caused vasodilation on endothelium-intact aortic rings which pre-contracted with PE (pEC50 = 3.53 ± 0.05, Rmax = 100.95 ± 4.25%) or potassium chloride (pEC50 = 2.96 ± 0.13, Rmax = 72.13 ± 4.93%). The vasodilation effect of 4HB was significantly decreased in the absence of an endothelium (pEC50 = 2.21 ± 0.25, Rmax = 47.96 ± 4.16%). The atropine, 4-aminopyridine, Nω-nitro-L-arginine methyl ester, glibenclamide, and propranolol significantly reduced the vasorelaxation effect of 4HB. Besides that, 4HB blocked the voltage-operated calcium channel (VOCC) and regulated the intracellular Ca2+ release from the sarcoplasmic reticulum (SR) in the aortic ring. Thus, the results indicated that 4HB exerted its vasodilatory effect via cGMP and ß2 pathways, M3-dependent PLC/IP3 pathways, and potassium and calcium channels.
Asunto(s)
Factores Relajantes Endotelio-Dependientes , Vasodilatación , Animales , Aorta Torácica , Benzaldehídos , Calcio/metabolismo , Canales de Calcio/metabolismo , Endotelio , Endotelio Vascular , Factores Relajantes Endotelio-Dependientes/metabolismo , Factores Relajantes Endotelio-Dependientes/farmacología , Óxido Nítrico/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta/metabolismo , Vasodilatadores/farmacologíaRESUMEN
Aneurysmal subarachnoid hemorrhage (aSAH) patients develop delayed cerebral ischemia and delayed deficits (DCI) within 2 weeks of aneurysm rupture at a rate of approximately 30%. DCI is a major contributor to morbidity and mortality after SAH. The cause of DCI is multi-factorial with contributions from microthrombi, blood vessel constriction, inflammation, and cortical spreading depolarizations. Platelets play central roles in hemostasis, inflammation, and vascular function. Within this review, we examine the potential roles of platelets in microthrombi formation, large artery vasospasm, microvessel constriction, inflammation, and cortical spreading depolarization. Evidence from experimental and clinical studies is provided to support the role(s) of platelets in each pathophysiology which contributes to DCI. The review concludes with a suggestion for future therapeutic targets to prevent DCI after aSAH.
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Plaquetas/fisiología , Infarto Cerebral/fisiopatología , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Hemorragia Subaracnoidea/fisiopatología , Aneurisma Roto/complicaciones , Aneurisma Roto/epidemiología , Animales , Infarto Cerebral/complicaciones , Infarto Cerebral/prevención & control , Constricción , Depresión de Propagación Cortical/fisiología , Factores Relajantes Endotelio-Dependientes/farmacología , Epoprostenol/farmacología , Humanos , Inflamación/fisiopatología , Trombosis Intracraneal/fisiopatología , Microvasos/fisiopatología , Modelos Animales , Enfermedades del Sistema Nervioso/epidemiología , Óxido Nítrico/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Hemorragia Subaracnoidea/epidemiología , Hemorragia Subaracnoidea/mortalidad , Factores de Tiempo , Vasoespasmo Intracraneal/fisiopatologíaRESUMEN
In this study, we evaluated the effect of eight weeks of administration of 10% fructose solution to adult Wistar Kyoto (WKY) rats on systolic blood pressure (SBP), plasma and biometric parameters, vasoactive properties of the thoracic aorta (TA), NO synthase (NOS) activity, and the expression of enzymes producing NO and H2S. Eight weeks of fructose administration did not affect SBP, glycaemia, or the plasma levels of total cholesterol or low-density and high-density lipoprotein; however, it significantly increased the plasma levels of γ-glutamyl transferase and alanine transaminase. Chronic fructose intake deteriorated endothelium-dependent vasorelaxation (EDVR) and increased the sensitivity of adrenergic receptors to noradrenaline. Acute NOS inhibition evoked a reduction in EDVR that was similar between groups; however, it increased adrenergic contraction more in fructose-fed rats. CSE inhibition decreased EDVR in WKY but not in fructose-fed rats. The application of a H2S scavenger evoked a reduction in the EDVR in WKY rats and normalized the sensitivity of adrenergic receptors in rats treated with fructose. Fructose intake did not change NOS activity but reduced the expression of eNOS and CBS in the TA and CSE and CBS in the left ventricle. Based on our results, we could assume that the impaired vascular function induced by increased fructose intake was probably not directly associated with a decreased production of NO, but rather with impairment of the NO-H2S interaction and its manifestation in vasoactive responses.
Asunto(s)
Aorta Torácica/efectos de los fármacos , Azúcares de la Dieta/metabolismo , Factores Relajantes Endotelio-Dependientes/farmacología , Fructosa/metabolismo , Sulfuro de Hidrógeno/farmacología , Óxido Nítrico/farmacología , Animales , Aorta Torácica/fisiología , Presión Sanguínea/efectos de los fármacos , Azúcares de la Dieta/administración & dosificación , Factores Relajantes Endotelio-Dependientes/metabolismo , Fructosa/administración & dosificación , Gasotransmisores/metabolismo , Gasotransmisores/farmacología , Sulfuro de Hidrógeno/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ratas Endogámicas WKY , Transducción de Señal/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
BACKGROUND: Protective effects of Ruscus extract on macromolecular permeability depend on its capacity to stimulate muscarinic receptors on endothelial cells and induce the release of endothelium derived relaxing factors (EDRFs). OBJECTIVE: To investigate if these effects depend only on activation of muscarinic receptors or if EDRFs release are also necessary. We have also investigated the participation of Ruscus extract on muscarinic-induced release of EDRFs on microvascular diameters. METHODS: Hamsters were treated daily during two weeks with Ruscus extract (50, 150 and 450âmg/kg/day) and then macromolecular permeability induced by histamine and arteriolar and venular diameters after cyclooxygenase (COX) and nitric oxide synthase (NOS) inhibitors: indomethacin and Nω-Nitro-L-arginine (LNA), respectively applied topically at 10-8M, 10-6M and 10-4M were observed on the cheek pouch preparation. RESULTS: Ruscus extract decreased macromolecular permeability in a dose-dependent fashion and did not affect microvascular diameters. NOS and COX inhibitors enhanced its effect on microvascular permeability. NOS inhibition reduced arteriolar diameter and COX blocking decreased arteriolar and venular diameters at the lowest dose and increased them at higher doses of Ruscus extract. CONCLUSION: The protective effect of Ruscus extract on macromolecular permeability seems to be mediated only via muscarinic receptors. Muscarinic activation attenuated vasoconstrictive tone through cyclooxygenase-independent endothelium derived relaxing factors.
Asunto(s)
Células Endoteliales/metabolismo , Factores Relajantes Endotelio-Dependientes/uso terapéutico , Extractos Vegetales/química , Receptores Muscarínicos/química , Ruscus/química , Animales , Factores Relajantes Endotelio-Dependientes/farmacología , Masculino , Mesocricetus , Óxido Nítrico/farmacologíaRESUMEN
Diabetes mellitus (DM)-related morbidity and mortality are steadily rising worldwide, affecting about half a billion people worldwide. A significant proportion of diabetic cases are in the elderly, which is concerning given the increasing aging population. Proper nutrition is an important component in the effective management of diabetes in the elderly. A plethora of active substances of plant origin exhibit potency to target the pathogenesis of diabetes mellitus. The nutraceutical and pharmaceutical effects of anthocyanins have been extensively studied. In this study, the effect of Hungarian sour cherry, which is rich in anthocyanins, on hyperglycemia-induced endothelial dysfunction was tested using human umbilical cord vein endothelial cells (HUVECs). HUVECs were maintained under both normoglycemic (5 mM) and hyperglycemic (30 mM) conditions with or without two concentrations (1.50 ng/µL) of anthocyanin-rich sour cherry extract. Hyperglycemia-induced oxidative stress and inflammatory response and damaged vasorelaxation processes were investigated by evaluating the level of reactive oxygen species (ROS) and gene expression of four proinflammatory cytokines, namely, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1α (IL-1α), as well as the gene expression of nitric oxide synthase (NOS) endothelin-1 (ET-1) and endothelin-converting enzyme-1 (ECE-1). It was found that hyperglycemia-induced oxidative stress was significantly suppressed by anthocyanin-rich sour cherry extract in a concentration-dependent manner. The gene expression of the tested proinflammatory cytokines increased under hyperglycemic conditions but was significantly reduced by both 1 and 50 ng/µL anthocyanin-rich sour cherry extract. Further, although increased ET-1 and ECE-1 expression due to hyperglycemia was reduced by anthocyanin-rich sour cherry extract, NOS expression was increased by the extract. Collectively, these data suggest that anthocyanin-rich sour cherry extract could alleviate hyperglycemia-induced endothelial dysfunction due to its antioxidant, anti-inflammatory, and vasorelaxant effects.
Asunto(s)
Antocianinas/farmacología , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Factores Relajantes Endotelio-Dependientes/farmacología , Hiperglucemia/tratamiento farmacológico , Extractos Vegetales/farmacología , Prunus avium , Línea Celular , Citocinas/metabolismo , Endotelio Vascular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Inflamación , Óxido Nítrico Sintasa de Tipo I/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Vasodilatación/efectos de los fármacosRESUMEN
Purpose: To correlate outflow function and outflow tract vessel diameter changes induced by nitric oxide (NO). Methods: In a porcine anterior segment perfusion model, the effects of a nitric oxide donor (100 µM DETA-NO) on outflow facility were compared with controls (n = 8 per group) with trabecular meshwork (TM) and after circumferential ab interno trabeculectomy (AIT). Outflow structures were assessed with spectral-domain optical coherence tomography (SD-OCT) before and after NO, or an NO synthase inhibitor (100 µM L-NAME) and the vasoconstrictor, endothelin-1 (100 pg/mL ET-1). Scans were processed with a custom macroscript and aligned for automated reslicing and quantification of cross-sectional outflow tract areas (CSA). Results: The facility increased after DETA-NO (Δ of 0.189 ± 0.081 µL/min·mm Hg, P = 0.034) and AIT (Δ of 0.251 ± 0.094 µL/min·mm Hg, P = 0.009), respectively. Even after AIT, DETA-NO increased the facility by 61.5% (Δ of 0.190 ± 0.074 µL/min·mm Hg, P = 0.023) and CSA by 13.9% (P < 0.001). L-NAME + ET-1 decreased CSA by -8.6% (P < 0.001). NO increased the diameter of focal constrictions 5.0 ± 3.8-fold. Conclusions: NO can dilate vessels of the distal outflow tract and increase outflow facility in a TM-independent fashion. There are short, focally constricting vessel sections that display large diameter changes and may have a substantial impact on outflow.
Asunto(s)
Humor Acuoso/fisiología , Factores Relajantes Endotelio-Dependientes/farmacología , Óxido Nítrico/farmacología , Malla Trabecular/efectos de los fármacos , Animales , Endotelina-1/farmacología , Inhibidores Enzimáticos/farmacología , Presión Intraocular/fisiología , NG-Nitroarginina Metil Éster/farmacología , Porcinos , Tomografía de Coherencia Óptica , Malla Trabecular/diagnóstico por imagen , Malla Trabecular/fisiopatología , TrabeculectomíaRESUMEN
BACKGROUND: Nitric oxide is a wound mediator that promotes wound healing. We hypothesized that topical application of nitric oxide would speed reepithelialization, enhance angiogenesis, and reduce scar thickness in a partial thickness porcine burn model. METHODS: While under general anesthesia, 20 partial thickness burns were created on the backs of four female Yorkshire swine using a 2.5cm×2.5cm×7.5cm, 150-g aluminum bar, preheated to 80°C and applied for 20s. The necrotic epidermis was removed and the burns were randomized to low, medium, and high concentrations of a novel nitric-oxide (NO) releasing drug or its ointment vehicle applied 3 times weekly for 28 days. Full thickness punch biopsies were performed at 8, 11, 14 and 28 days after injury to determine percentage wound reepithelialization and scar thickness using H&E staining and blood vessel density using CD31 staining. RESULTS: At day 11, the percentages (SD) wound reepithelialization were: control, 26.3 (34.6); low NO, 23.9 (36.9); medium NO, 43.3 (42.9); and high NO, 59.9 (43.6); ANOVA, P=0.02. The number of CD31 stained blood vessels at days 8 and 11 were greater in wounds treated with high dose NO vs. controls (48.1 vs. 22.9 [P<0.001] and 44.0 vs. 33.5 [P=0.05] per 1mm2 respectively). Scar thicknesses (SD) in mm at day 28 by treatment allocation were: control, 4.8 (1.2); low NO, 4.7 (1.2); medium NO, 4.3 (1.2); and high NO, 4.1 (1.0); P=0.22. CONCLUSIONS: Treatment of partial thickness porcine burns with high concentrations of topical NO resulted in earlier reepithelization and increased angiogenesis but not reduced scar thickness compared with its control vehicle in a partial thickness porcine burn model.
Asunto(s)
Quemaduras/patología , Factores Relajantes Endotelio-Dependientes/farmacología , Neovascularización Fisiológica/efectos de los fármacos , Óxido Nítrico/farmacología , Repitelización/efectos de los fármacos , Piel/efectos de los fármacos , Administración Cutánea , Animales , Cicatriz/etiología , Cicatriz/patología , Modelos Animales de Enfermedad , Femenino , Piel/irrigación sanguínea , Piel/patología , Sus scrofa , Porcinos , Cicatrización de Heridas/efectos de los fármacosRESUMEN
INTRODUCTION: Treatment of co-morbidities, including bronchial asthma (BA) and coronary heart disease (CHD), is a relevant issue of modern therapy. The aim of the research is to study the impact of long-term intake of pioglitazone on the development of inflammation and ED in patients with BA concurrent with CHD. MATERIAL AND METHODS: The clinical study involved 50 people aged 40-75 who suffered from asthma concurrent with CHD. On the first day of the study, blood samples were collected and clinical examinations were performed, after which patients were randomized and divided into the control group who continued to receive only the standard therapy, and the study group, who received pioglitazone (Pioglar, Ranbaxy, India) 15 mg once a day along with comprehensive therapy. Re-examination was carried out in 6 months. RESULTS: It has been found that inclusion of pioglitazone in the course of standard therapy in patients with asthma concurrent with coronary heart within 6 months is a more efficient scheme than the course of standard therapies. According to the data obtained from the patients, there was a significant decrease in respiratory rate (p<0.01), levels of systolic blood pressure (p<0.001) and diastolic blood pressure (p<0.001). Administering pioglitazone contributed to the improvement of respiratory function and airflow obstruction, increased FEV1 performance (p<0.01) and Tiffeneau index (p<0.05). In patients of the study group, intake of pioglitazone helped to reduce angina. Intake of pioglitazone showed a significant decrease in the frequency of angina pectoris FC II (p<0.05) and a significant increase in the frequency of angina FC I (p<0.05), increase in the rate of threshold load power (p<0.05). In assessing endothelium-dependent vasodilation of the brachial artery, it has been noted that intake of pioglitazone by patients with asthma concurrent with coronary heart disease resulted in a statistically significant increase in the diameter of the brachial artery by an average of 4% (p<0.0001), the maximum blood flow velocity (TAMX) by an average of 40 % (p<0.0001), Δ% diameter increase in the brachial artery (p<0.0001), and achieved positive indicators of RI (p<0.0001). In assessing endothelium-dependent vasodilation of brachial artery in patients treated with pioglitazone, there was a significant increase in the diameter of brachial artery on average by 5% (p<0.0001) after taking nitroglycerin, an increase in ?% diameter of brachial artery (p<0.0001) and RI (p<0.0001). Inclusion of pioglitazone in the complex therapy for 6 months resulted in a significant decrease in the index of systemic inflammation hs-CRP (p<0.0001) and adhesion marker sVCAM-1 (p<0.0001), total cholesterol (p<0.001), triglycerides (p<0.001). CONCLUSION: Thus, these data demonstrate the anti-inflammatory and endothelium protective effects of pioglitazone against the background of standard therapy in patients with BA concurrent with CHD within 6 months, which may enhance the clinical efficacy in the treatment of these diseases.
Asunto(s)
Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Factores Relajantes Endotelio-Dependientes/uso terapéutico , Isquemia Miocárdica/tratamiento farmacológico , Tiazolidinedionas/uso terapéutico , Adulto , Anciano , Antiinflamatorios/farmacología , Asma/complicaciones , Velocidad del Flujo Sanguíneo , Quimioterapia Combinada , Endotelio Vascular/fisiopatología , Factores Relajantes Endotelio-Dependientes/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/complicaciones , Pioglitazona , Pruebas de Función Respiratoria , Factores de Riesgo , Tiazolidinedionas/farmacologíaRESUMEN
BACKGROUND: Hypoxia induced relaxation of larger retinal arterioles has been shown to be mediated by nitric oxide (NO) and cyclo-oxygenase (COX) products both in vivo and in vitro. However, the involvement of smaller retinal vessels in the response is unknown. Therefore, the purpose of the present study was to investigate the effect of blocking the synthesis of NO and COX on hypoxia induced changes in the diameter of smaller porcine retinal vessels at different branching level. METHODS: Porcine hemiretinas were mounted in a tissue chamber and were constricted with the prostaglandin agonist U46619. Changes in the diameter of arterioles, pre-capillary arterioles and capillaries were studied during hypoxia, in the presence of the COX inhibitor ibuprofen and the NO synthase inhibitor L-NAME. RESULTS: In the presence of L-NAME hypoxia induced dilatation was significantly smaller in arterioles and capillaries than in precapillary arterioles (p < 0.04), whereas in the presence of ibuprofen the dilatation was significantly smaller in capillaries and pre-capillary arterioles than in arterioles (p < 0.04). CONCLUSIONS: The mechanisms underlying hypoxia induced dilatation differ among smaller porcine retinal vessels with different caliber ex vivo. This may reflect differences in the responses of retinal vessels to changes in metabolism, and may point to possible targets for pharmacological intervention on the diameter of retinal vessels with different caliber in vivo.
Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Hipoxia/fisiopatología , Óxido Nítrico/farmacología , Enfermedades de la Retina/fisiopatología , Vasos Retinianos/fisiopatología , Vasodilatación/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Factores Relajantes Endotelio-Dependientes/farmacología , Hipoxia/tratamiento farmacológico , Hipoxia/patología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiopatología , Oxígeno/metabolismo , Enfermedades de la Retina/tratamiento farmacológico , Enfermedades de la Retina/patología , Vasos Retinianos/efectos de los fármacos , Vasos Retinianos/metabolismo , PorcinosRESUMEN
Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction that results from an inflammatory process affecting the airways and lung parenchyma. Despite major abnormalities taking place in bronchial and alveolar structures, changes in pulmonary vessels also represent an important component of the disease. Alterations in vessel structure are highly prevalent and abnormalities in their function impair gas exchange and may result in pulmonary hypertension (PH), an important complication of the disease associated with reduced survival and worse clinical course. The prevalence of PH is high in COPD, particularly in advanced stages, although it remains of mild to moderate severity in the majority of cases. Endothelial dysfunction, with imbalance between vasodilator/vasoconstrictive mediators, is a key determinant of changes taking place in pulmonary vasculature in COPD. Cigarette smoke products may perturb endothelial cells and play a critical role in initiating vascular changes. The concurrence of inflammation, hypoxia and emphysema further contributes to vascular damage and to the development of PH. The use of drugs that target endothelium-dependent signalling pathways, currently employed in pulmonary arterial hypertension, is discouraged in COPD due to the lack of efficacy observed in randomized clinical trials and because there is compelling evidence indicating that these drugs may worsen pulmonary gas exchange. The subgroup of patients with severe PH should be ideally managed in centres with expertise in both PH and chronic lung diseases because alterations of pulmonary vasculature might resemble those observed in pulmonary arterial hypertension. Because this condition entails poor prognosis, it warrants specialist treatment.
Asunto(s)
Factores Relajantes Endotelio-Dependientes/farmacología , Hipertensión Pulmonar , Pulmón , Arteria Pulmonar , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Pulmón/irrigación sanguínea , Pulmón/fisiopatología , Pronóstico , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Circulación Pulmonar , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatologíaRESUMEN
KEY POINTS: Increase in endothelial cell (EC) calcium activates calcium-sensitive intermediate and small conductance potassium (IK and SK) channels, thereby causing hyperpolarization and endothelium-dependent vasodilatation. Endothelial cells express inward rectifier potassium (Kir) channels, but their role in endothelium-dependent vasodilatation is not clear. In the mesenteric arteries, only ECs, but not smooth muscle cells, displayed Kir currents that were predominantly mediated by the Kir2.1 isoform. Endothelium-dependent vasodilatations in response to muscarinic receptor, TRPV4 (transient receptor potential vanilloid 4) channel and IK/SK channel agonists were highly attenuated by Kir channel inhibitors and by Kir2.1 channel knockdown. These results point to EC Kir channels as amplifiers of vasodilatation in response to increases in EC calcium and IK/SK channel activation and suggest that EC Kir channels could be targeted to treat endothelial dysfunction, which is a hallmark of vascular disorders. ABSTRACT: Endothelium-dependent vasodilators, such as acetylcholine, increase intracellular Ca(2+) through activation of transient receptor potential vanilloid 4 (TRPV4) channels in the plasma membrane and inositol trisphosphate receptors in the endoplasmic reticulum, leading to stimulation of Ca(2+) -sensitive intermediate and small conductance K(+) (IK and SK, respectively) channels. Although strong inward rectifier K(+) (Kir) channels have been reported in the native endothelial cells (ECs) their role in EC-dependent vasodilatation is not clear. Here, we test the idea that Kir channels boost the EC-dependent vasodilatation of resistance-sized arteries. We show that ECs, but not smooth muscle cells, of small mesenteric arteries have Kir currents, which are substantially reduced in EC-specific Kir2.1 knockdown (EC-Kir2.1(-/-) ) mice. Elevation of extracellular K(+) to 14 mm caused vasodilatation of pressurized arteries, which was prevented by endothelial denudation and Kir channel inhibitors (Ba(2+) , ML-133) or in the arteries from EC-Kir2.1(-/-) mice. Potassium-induced dilatations were unaffected by inhibitors of TRPV4, IK and SK channels. The Kir channel blocker, Ba(2+) , did not affect currents through TRPV4, IK or SK channels. Endothelial cell-dependent vasodilatations in response to activation of muscarinic receptors, TRPV4 channels or IK/SK channels were reduced, but not eliminated, by Kir channel inhibitors or EC-Kir2.1(-/-) . In angiotensin II-induced hypertension, the Kir channel function was not altered, although the endothelium-dependent vasodilatation was severely impaired. Our results support the concept that EC Kir2 channels boost vasodilatory signals that are generated by Ca(2+) -dependent activation of IK and SK channels.
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Células Endoteliales/fisiología , Arterias Mesentéricas/fisiología , Canales de Potasio de Rectificación Interna/fisiología , Acetilcolina/farmacología , Animales , Calcio/fisiología , Células Endoteliales/efectos de los fármacos , Factores Relajantes Endotelio-Dependientes/farmacología , Masculino , Arterias Mesentéricas/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/fisiología , Canales de Potasio de Rectificación Interna/genética , VasodilataciónRESUMEN
OBJECTIVE: To describe and to characterize the relaxing effect of an extract of the bark of Combretum leprosum on isolated arterial rings from different animals. METHODS: Rings (3 to 4mm) from rabbit, rat, or porcine arteries rings were suspended in an organ bath (Krebs, 37°C, 95%O2/5%CO2) to record isometric contractions. After the stabilization period (2 to 3 hours) contractions were induced by the addition of phenylephrine (0.1 to 0.3µM) or U46619 (10 to 100nM), and Combretum leprosum extract was added on the plateau of the contractions. Experiments were performed to determine the potency, duration, reversibility, and to get insights on the potential mechanism involved in extract-induced relaxations. RESULTS: In all rings tested, Combretumleprosum extract (1.5µg/mL) was able to cause relaxations, which were strictly endothelium-dependent. In rabbit or rat thoracic aorta rings, the relaxations were reversed by vitamin B12a or L-NG-nitroarginine. In porcine right coronary arteries and rabbit abdominal aorta, extract caused both L-NG-nitroarginine-sensitive and L-NG-nitroarginine-resistant relaxations. In rabbit thoracic aorta, the extract was relatively potent (EC50=0.20µg/mL) and caused relaxations; intriguingly the endothelium continued to produce relaxing factors for a long period after removing the extract. The magnitude of extract-induced relaxations was significantly reduced in the absence of extracellular Ca2+; in addition, the TRPs channels blocker ruthenium red (10µM) was able to revert extract-induced relaxations. Phytochemical analyses indicated that the extract was rich in polyphenol-like reacting substances. CONCLUSIONS: Combretum leprosum extract contains bioactive compounds capable of promoting Ca2+-dependent stimulation of endothelial cells which results in a prolonged production of relaxing factors.
Asunto(s)
Combretum/química , Factores Relajantes Endotelio-Dependientes/farmacología , Relajación Muscular/efectos de los fármacos , Óxido Nítrico/farmacología , Acetilcolina/farmacología , Animales , Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/fisiología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Arteria Carótida Común/efectos de los fármacos , Arteria Carótida Común/fisiología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Femenino , Cobayas , Masculino , Arteria Mesentérica Superior/efectos de los fármacos , Arteria Mesentérica Superior/fisiología , Ratones , Relajación Muscular/fisiología , Corteza de la Planta/química , Conejos , Ratas Wistar , Porcinos , Factores de TiempoRESUMEN
Objective To describe and to characterize the relaxing effect of an extract of the bark of Combretum leprosum on isolated arterial rings from different animals.Methods Rings (3 to 4mm) from rabbit, rat, or porcine arteries rings were suspended in an organ bath (Krebs, 37°C, 95%O2/5%CO2) to record isometric contractions. After the stabilization period (2 to 3 hours) contractions were induced by the addition of phenylephrine (0.1 to 0.3µM) or U46619 (10 to 100nM), and Combretum leprosum extract was added on the plateau of the contractions. Experiments were performed to determine the potency, duration, reversibility, and to get insights on the potential mechanism involved in extract-induced relaxations.Results In all rings tested, Combretumleprosum extract (1.5μg/mL) was able to cause relaxations, which were strictly endothelium-dependent. In rabbit or rat thoracic aorta rings, the relaxations were reversed by vitamin B12a or L-NG-nitroarginine. In porcine right coronary arteries and rabbit abdominal aorta, extract caused both L-NG-nitroarginine-sensitive and L-NG-nitroarginine-resistant relaxations. In rabbit thoracic aorta, the extract was relatively potent (EC50=0.20µg/mL) and caused relaxations; intriguingly the endothelium continued to produce relaxing factors for a long period after removing the extract. The magnitude of extract-induced relaxations was significantly reduced in the absence of extracellular Ca2+; in addition, the TRPs channels blocker ruthenium red (10µM) was able to revert extract-induced relaxations. Phytochemical analyses indicated that the extract was rich in polyphenol-like reacting substances.ConclusionsCombretum leprosum extract contains bioactive compounds capable of promoting Ca2+-dependent stimulation of endothelial cells which results in a prolonged production of relaxing factors.
Objetivo Descrever e caracterizar os relaxamentos induzidos por um extrato das cascas de Combretum leprosum em anéis de artérias de diferentes espécies de animais.Métodos Anéis (3 a 4mm) de artérias de coelho, rato e porco foram montados em cubas para órgão isolado (Krebs, 37°C, 95%O2/5%CO2) para registro das contrações isométricas. Após um período de estabilização (2 a 3 horas), as contrações foram induzidas com fenilefrina (0,1 a 0,3µM) ou U46619 (10 a 100nM); no platô dessas contrações, adicionamos o extrato Combretum leprosum. Diferentes protocolos foram realizados para determinar potência, duração, reversibilidade e mecanismo dos relaxamentos induzidos pelo extrato.Resultados Em todas as preparações testadas, o extrato de Combretum leprosum (1,5µg/mL) provocou relaxamentos dependentes de endotélio. Em aorta torácica de coelho ou rato, os relaxamentos foram revertidos pela vitamina B12a ou L-NG-nitro-arginina. Em anéis de aorta abdominal de coelho e de artérias coronárias de porco, o extrato causou relaxamentos sensíveis e resistentes à L-NG-nitro-arginina. Em aorta torácica de coelho, o extrato foi relativamente muito potente (EC50=0,20μg/mL) e quando causou relaxamentos; intrigantemente o endotélio continuou a produzir fatores relaxantes por um longo período após remoção do extrato. A magnitude dos relaxamentos induzidos pelo extrato foi significativamente reduzida em ausência Ca2+ extracelular; ademais, o vermelho de rutênio (10μM), um bloqueador de canais TRPs, foi capaz de reverter os relaxamentos induzidos pelo extrato. Análises preliminares indicaram que o extrato continha compostos com reatividade química semelhante à polifenóis.Conclusão O extrato de Combretum leprosum contem compostos bioativos capazes de promover estimulação dependente de Ca2+ das células endoteliais a qual resulta numa produção prolongada de fatores relaxantes.
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Animales , Femenino , Cobayas , Masculino , Ratones , Conejos , Combretum/química , Factores Relajantes Endotelio-Dependientes/farmacología , Relajación Muscular/efectos de los fármacos , Óxido Nítrico/farmacología , Acetilcolina/farmacología , Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/fisiología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Arteria Carótida Común/efectos de los fármacos , Arteria Carótida Común/fisiología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Arteria Mesentérica Superior/efectos de los fármacos , Arteria Mesentérica Superior/fisiología , Relajación Muscular/fisiología , Corteza de la Planta/química , Ratas Wistar , Porcinos , Factores de TiempoRESUMEN
Mitochondrial respiration has never been directly examined in intact cerebral arteries. We tested the hypothesis that mitochondrial energetics of large cerebral arteries ex vivo are sex dependent. The Seahorse XFe24 analyzer was used to examine mitochondrial respiration in isolated cerebral arteries from adult male and female Sprague-Dawley rats. We examined the role of nitric oxide (NO) on mitochondrial respiration under basal conditions, using N(ω)-nitro-l-arginine methyl ester, and following pharmacological challenge using diazoxide (DZ), and also determined levels of mitochondrial and nonmitochondrial proteins using Western blot, and vascular diameter responses to DZ. The components of mitochondrial respiration including basal respiration, ATP production, proton leak, maximal respiration, and spare respiratory capacity were elevated in females compared with males, but increased in both male and female arteries in the presence of the NOS inhibitor. Although acute DZ treatment had little effect on mitochondrial respiration of male arteries, it decreased the respiration in female arteries. Levels of mitochondrial proteins in Complexes I-V and the voltage-dependent anion channel protein were elevated in female compared with male cerebral arteries. The DZ-induced vasodilation was greater in females than in males. Our findings show that substantial sex differences in mitochondrial respiratory dynamics exist in large cerebral arteries and may provide the mechanistic basis for observations that the female cerebral vasculature is more adaptable after injury.
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Arterias Cerebrales/efectos de los fármacos , Diazóxido/farmacología , Factores Relajantes Endotelio-Dependientes/farmacología , Inhibidores Enzimáticos/farmacología , Mitocondrias/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/farmacología , Vasodilatadores/farmacología , Adenosina Trifosfato/metabolismo , Animales , Respiración de la Célula/efectos de los fármacos , Arterias Cerebrales/metabolismo , Femenino , Masculino , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Factores SexualesRESUMEN
Aging is a major risk factor for carotid artery disease that may lead to stroke and dementia. Vascular effects associated with aging include increased vasomotor tone, as well as enhanced contractility to endothelial vasoconstrictor prostanoids and reduced nitric oxide (NO) bioactivity partly due to increased oxidative stress. We hypothesized that vascular NADPH oxidase (Nox)-derived superoxide may be involved in prostanoid- and NO-related functional aging. NO-mediated relaxations and prostanoid-mediated contractions to acetylcholine as well as phenylephrine-dependent contractions were investigated in the carotid artery from young (4 months) and aged mice (24 months). Gene expression of Nox subunits and endothelial NO synthase (eNOS) was determined in the carotid artery and aorta. In young mice, the thromboxane-prostanoid receptor antagonist SQ 29,548 fully blocked acetylcholine-induced contractions while reducing responses to phenylephrine by 75 %. The Nox2-targeted inhibitor Nox2ds-tat and the superoxide scavenger tempol reduced acetylcholine-stimulated, prostanoid-mediated contractions by 85 and 75 %, respectively, and phenylephrine-dependent contractions by 45 %. Unexpectedly, in aged mice, the substantial Nox2-dependent component of acetylcholine- and phenylephrine-induced, prostanoid-mediated contractions was abolished. In addition, endothelium-dependent, NO-mediated relaxations were impaired with aging. The expression of Nox subunits was greater in the aorta compared with the carotid artery, in which Nox1 was undetectable. eNOS gene expression was reduced in the aorta of aged compared to young mice. In conclusion, aging decreases prostanoid-mediated contractility in the carotid artery involving a loss of Nox2 activity and is associated with impaired endothelium-dependent, NO-mediated relaxation. These findings may contribute to a better understanding of the pathophysiology of carotid artery disease and the aging process.
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Acetilcolina/farmacología , Envejecimiento/fisiología , Arterias Carótidas/efectos de los fármacos , Glicoproteínas de Membrana/fisiología , NADPH Oxidasas/fisiología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Vasodilatadores/farmacología , Animales , Antioxidantes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes , Arterias Carótidas/fisiología , Óxidos N-Cíclicos/farmacología , Factores Relajantes Endotelio-Dependientes/farmacología , Ácidos Grasos Insaturados , Hidrazinas/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasa 2 , Óxido Nítrico/farmacología , Óxido Nítrico Sintasa de Tipo III/genética , Fenilefrina/farmacología , ARN Mensajero/metabolismo , Receptores de Tromboxanos/antagonistas & inhibidores , Marcadores de Spin , Técnicas de Cultivo de Tejidos , Vasoconstrictores/farmacologíaRESUMEN
BACKGROUND: Endotoxin (i.e. LPS) administration induces a robust inflammatory response with accompanying cardiovascular dysfunction and insulin resistance. Overabundance of nitric oxide (NO) contributes to the vascular dysfunction. However, inflammation itself also induces insulin resistance in skeletal muscle. We sought to investigate whether the cardiovascular dysfunction induced by increased NO availability without inflammatory stress can promote insulin resistance. Additionally, we examined the role of inducible nitric oxide synthase (iNOS or NOS2), the source of the increase in NO availability, in modulating LPS-induced decrease in insulin-stimulated muscle glucose uptake (MGU). METHODS: The impact of NO donor infusion on insulin-stimulated whole-body and muscle glucose uptake (hyperinsulinemic-euglycemic clamps), and the cardiovascular system was assessed in chronically catheterized, conscious mice wild-type (WT) mice. The impact of LPS on insulin action and the cardiovascular system were assessed in WT and global iNOS knockout (KO) mice. Tissue blood flow and cardiac function were assessed using microspheres and echocardiography, respectively. Insulin signaling activity, and gene expression of pro-inflammatory markers were also measured. RESULTS: NO donor infusion decreased mean arterial blood pressure, whole-body glucose requirements, and MGU in the absence of changes in skeletal muscle blood flow. LPS lowered mean arterial blood pressure and glucose requirements in WT mice, but not in iNOS KO mice. Lastly, despite an intact inflammatory response, iNOS KO mice were protected from LPS-mediated deficits in cardiac output. LPS impaired MGU in vivo, regardless of the presence of iNOS. However, ex vivo, insulin action in muscle obtained from LPS treated iNOS KO animals was protected. CONCLUSION: Nitric oxide excess and LPS impairs glycemic control by diminishing MGU. LPS impairs MGU by both the direct effect of inflammation on the myocyte, as well as by the indirect NO-driven cardiovascular dysfunction.
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Factores Relajantes Endotelio-Dependientes/farmacología , Glucosa/metabolismo , Corazón/efectos de los fármacos , Resistencia a la Insulina , Lipopolisacáridos/farmacología , Músculo Esquelético/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico/farmacología , Animales , Presión Arterial/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Quimiocina CCL2/genética , Ecocardiografía , Expresión Génica , Técnica de Clampeo de la Glucosa , Inflamación , Interleucina-6/genética , Ratones , Ratones Noqueados , Microesferas , Células Musculares/efectos de los fármacos , Células Musculares/inmunología , Células Musculares/metabolismo , Músculo Esquelético/inmunología , Músculo Esquelético/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Flujo Sanguíneo Regional/efectos de los fármacos , Serpina E2/genética , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
The present review provides an update of the biological actions of Pycnogenol® in the treatment of metabolic syndrome and related disorders such as obesity, dyslipidaemia, diabetes and hypertension. Pycnogenol® is a French maritime pine bark extract produced from the outer bark of Pinus pinaster Ait. Subsp. atlantica. Its strong antioxidant, antiinflammatory, endothelium-dependent vasodilator activity, and also its anti-thrombotic effects make it appropriate for targeting the multifaceted pathophysiology of metabolic syndrome. Clinical studies have shown that it can reduce blood glucose levels in people with diabetes, blood pressure in mild to moderate hypertensive patients, and waist circumference, and improve lipid profile, renal and endothelial functions in metabolic syndrome. This review highlights the pathophysiology of metabolic syndrome and related clinical research findings on the safety and efficacy of Pycnogenol®. The results of clinical research studies performed with Pycnogenol® are discussed using an evidence-based, target-oriented approach following the pathophysiology of individual components as well as in metabolic syndrome overall.
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Flavonoides/uso terapéutico , Síndrome Metabólico/tratamiento farmacológico , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Glucemia , Presión Sanguínea/efectos de los fármacos , Ensayos Clínicos como Asunto , Diabetes Mellitus/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Factores Relajantes Endotelio-Dependientes/farmacología , Humanos , Hipertensión/tratamiento farmacológico , Síndrome Metabólico/fisiopatología , Pinus/química , Corteza de la Planta/química , Extractos Vegetales/farmacología , Vasodilatadores/farmacología , Circunferencia de la CinturaRESUMEN
BACKGROUND: A "classic" response to acute vasodilator testing (drop of >10 mm Hg in mean pulmonary artery pressure [mPAP] to <40 mm Hg) confers an excellent prognosis in patients with idiopathic pulmonary arterial hypertension (IPAH) and identifies candidates for treatment with calcium channel blockers (CCB). Little is known about vasodilator responsiveness (VR) in other types of PAH, or about outcomes in patients with a significant but "non-classic" decrease in mPAP. We hypothesized that VR occurs in non-idiopathic PAH and non-classic VR portends a better prognosis than no VR in PAH. METHODS: Acute VR testing with nitric oxide was performed on 155 consecutive patients referred for PH evaluation. Non-classic response was defined as decrease in mPAP >10 mm Hg to >40 mm Hg with preserved cardiac output. Demographics and functional status were assessed at baseline and the first clinic visit after VR testing, and survival was followed over time. RESULTS: Twenty patients (13%) displayed classic VR. Among classic responders, 12 (60%) had IPAH and 8 (40%) had connective tissue disease-associated PAH (CTD-PAH); however, only responders with IPAH had improved survival compared with non-responders (p = 0.02). Thirteen patients (8%) had a non-classic VR. Non-classic response was not associated with improved survival compared with non-responders (p = 0.86). Acute change in mPAP or pulmonary vascular resistance in the entire cohort did not predict survival. CONCLUSIONS: Classic acute VR occurs in CTD-PAH as well as IPAH; however, only IPAH patients have improved outcomes. A significant but non-classic VR is not associated with improved survival.
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Bloqueadores de los Canales de Calcio/administración & dosificación , Hipertensión Pulmonar/fisiopatología , Presión Esfenoidal Pulmonar/efectos de los fármacos , Resistencia Vascular/efectos de los fármacos , Vasodilatación/fisiología , Enfermedad Aguda , Relación Dosis-Respuesta a Droga , Factores Relajantes Endotelio-Dependientes/farmacología , Femenino , Estudios de Seguimiento , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Óxido Nítrico/farmacología , Pronóstico , Estudios Retrospectivos , Factores de Tiempo , Vasodilatación/efectos de los fármacosRESUMEN
In addition to nitric oxide and carbon monoxide, hydrogen sulfide (H2S), synthesized enzymatically from l-cysteine or l-homocysteine, is the third gasotransmitter in mammals. Endogenous H2S is involved in the regulation of many physiological processes, including vascular tone. Although initially it was suggested that in the vascular wall H2S is synthesized only by smooth muscle cells and relaxes them by activating ATP-sensitive potassium channels, more recent studies indicate that H2S is synthesized in endothelial cells as well. Endothelial H2S production is stimulated by many factors, including acetylcholine, shear stress, adipose tissue hormone leptin, estrogens and plant flavonoids. In some vascular preparations H2S plays a role of endothelium-derived hyperpolarizing factor by activating small and intermediate-conductance calcium-activated potassium channels. Endothelial H2S signaling is up-regulated in some pathologies, such as obesity and cerebral ischemia-reperfusion. In addition, H2S activates endothelial NO synthase and inhibits cGMP degradation by phosphodiesterase 5 thus potentiating the effect of NO-cGMP pathway. Moreover, H2S-derived polysulfides directly activate protein kinase G. Finally, H2S interacts with NO to form nitroxyl (HNO)-a potent vasorelaxant. H2S appears to play an important and multidimensional role in endothelium-dependent vasorelaxation.
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Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Factores Relajantes Endotelio-Dependientes/farmacología , Sulfuro de Hidrógeno/farmacología , Vasodilatación/efectos de los fármacos , Animales , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/metabolismo , GMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Humanos , Sulfuro de Hidrógeno/metabolismo , Leptina , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismoRESUMEN
UNLABELLED: Studies about the effects of inhaled nitric oxide (iNO) on bleeding time and platelet aggregation in newborns are limited in number and have inconclusive results. Thromboelastogram (TEG) shows the combined effects of coagulation factors and platelet functions. In this preliminary study, we aimed to evaluate the effects of iNO on coagulation using TEG in newborns with persistent pulmonary hypertension (PPH). TEG assays were performed in 10 term infants receiving iNO treatment for PPH and 32 healthy term infants. Samples of the iNO group were collected before and during iNO. Clot reaction time (R), clot kinetics (K), maximum amplitude (MA), and alpha angle were obtained from the TEG tracing. TEG-R values were statistically higher during iNO treatment (7.75 ± 3.34) when compared to the values before iNO (4.83 ± 1.38) and the healthy controls (3.75 ± 0.98). The alpha angle was lower in iNO treated infants at both periods (before iNO, 55.33 ± 8.58; during iNO, 42.90 ± 18.34) compared to the control group (64.95 ± 6.88). MA values before iNO treatment were the lowest (44.43 ± 14.09) and improved with the iNO treatment (48.40 ± 9.49) despite still being lower compared to the controls (53.67 ± 5.56). CONCLUSION: Both PPH and iNO may negatively effect in vitro coagulation tests. Therefore, newborns with PPH requiring iNO treatment should be closely monitored for coagulation problems.