RESUMEN
30 min of moderate-intensity aerobic exercise per day is recommended, but the response and adaptation of endothelial function (EF) to this exercise remains controversial. The purpose of this study was to determine the changes in EF in endurance trained and untrained individuals before and after this exercise and to compare the differences between trained and untrained individuals. Twelve endurance-trained male college athletes (trained group) and 12 untrained male college students (untrained group) performed a 30-min run at an intensity of 60% VO2max. Brachial artery flow-mediated dilation (FMD) was measured before exercise, 30 min and 60 min after exercise, and the following morning. Resting diameter and maximum diameter showed large time effects (p < 0.001, η2 = 0.533; p < 0.001, η2 = 0.502). Resting diameters at 30 and 60 min after exercise were higher than before exercise in both the untrained and trained groups (p < 0.05), and maximum diameters at 30 min after exercise were higher than before exercise in both the untrained and trained groups (p < 0.01). Resting diameter and maximum diameter also exhibited some group effects (p = 0.055, η2 = 0.157; p = 0.041, η2 = 0.176). Resting diameters and maximum diameters were higher in the trained group than in the untrained group before exercise (p < 0.05). FMD (%) showed no time, group, or time-group interaction effects. 30 min of moderate-intensity aerobic exercise can increase resting and maximal arterial diameters in both trained and untrained young men, but has no effect on FMD. Long-term endurance training has the potential to increase resting and maximal arterial diameters in young men, but not necessarily FMD.
Asunto(s)
Arteria Braquial , Endotelio Vascular , Ejercicio Físico , Vasodilatación , Humanos , Masculino , Ejercicio Físico/fisiología , Endotelio Vascular/fisiología , Adulto Joven , Arteria Braquial/fisiología , Vasodilatación/fisiología , Adulto , Atletas , Resistencia Física/fisiologíaRESUMEN
In the brain, a microvascular sensory web coordinates oxygen delivery to regions of neuronal activity. This involves a dense network of capillaries that send conductive signals upstream to feeding arterioles to promote vasodilation and blood flow. Although this process is critical to the metabolic supply of healthy brain tissue, it may also be a point of vulnerability in disease. Deterioration of capillary networks is a feature of many neurological disorders and injuries and how this web is engaged during vascular damage remains unknown. We performed in vivo two-photon microscopy on young adult mural cell reporter mice and induced focal capillary injuries using precise two-photon laser irradiation of single capillaries. We found that ~59% of the injuries resulted in regression of the capillary segment 7 to 14 d following injury, and the remaining repaired to reestablish blood flow within 7 d. Injuries that resulted in capillary regression induced sustained vasoconstriction in the upstream arteriole-capillary transition (ACT) zone at least 21 days postinjury in both awake and anesthetized mice. The degree of vasomotor dynamics was chronically attenuated in the ACT zone consequently reducing blood flow in the ACT zone and in secondary, uninjured downstream capillaries. These findings demonstrate how focal capillary injury and regression can impair the microvascular sensory web and contribute to cerebral hypoperfusion.
Asunto(s)
Capilares , Circulación Cerebrovascular , Animales , Ratones , Capilares/fisiología , Circulación Cerebrovascular/fisiología , Vasoconstricción/fisiología , Encéfalo/irrigación sanguínea , Arteriolas/fisiopatología , Masculino , Vasodilatación/fisiología , Ratones Endogámicos C57BLRESUMEN
Cocoa flavan-3-ols affect endothelium-dependent responses in resistance vessels and microcirculation has received little attention. We tested the effects of dark chocolate consumption (396 mg total flavanols/day for 3 days) in two Groups of 10 men (18-25 years; non-smokers) each comprising equal numbers of White European (WE) and South Asian (SA) ethnicity. In Group 1, dark chocolate did not affect reactive hyperaemia in forearm muscle, but augmented muscle dilatation evoked by acute mental stress, and reactive hyperaemia and acetylcholine (ACh)-evoked dilatation in cutaneous microcirculation. Conversely, in Group 2, chocolate did not affect cutaneous reactive hyperaemia or ACh-evoked dilatation, but these responses were blunted in Group 1 relative to Group 2. Further, when Groups 1 and 2 were combined, responses were blunted in SAs relative to WEs, augmented by chocolate in SAs only. In Group 2 individuals whose ACh-evoked dilatation was attenuated by nitric oxide synthase (NOS) inhibition, ACh-evoked dilatation was not altered after chocolate, but the attenuating effect of NOS inhibition was lost. Conversely, in Group 2 individuals whose ACh-evoked dilatation was enhanced by NOS inhibition, ACh-evoked dilatation was also augmented by chocolate. We propose that in resistance and microvessels of young men, cocoa flavan-3-ols preferentially augment endothelium-dependent dilator responses whose responses are depressed by familial and lifestyle factors more prevalent in SAs than Wes. Flavan-3-ols may facilitate the NOS pathway but also influence other endothelium-dependent dilators.
Asunto(s)
Cacao , Chocolate , Estilo de Vida , Microcirculación , Humanos , Masculino , Adulto Joven , Adulto , Cacao/química , Microcirculación/efectos de los fármacos , Adolescente , Flavonoides/farmacología , Vasodilatación/efectos de los fármacos , Población Blanca , Hiperemia , Endotelio Vascular/efectos de los fármacos , Piel/irrigación sanguínea , Piel/efectos de los fármacos , Piel/metabolismo , Microvasos/efectos de los fármacos , Pueblo Asiatico , Antebrazo/irrigación sanguínea , Acetilcolina/farmacología , Estrés Psicológico , Óxido Nítrico Sintasa/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismoRESUMEN
Studies have demonstrated the therapeutic effects of Lindera plants. This study was undertaken to reveal the antihypertensive properties of Lindera erythrocarpa leaf ethanolic extract (LEL). Aorta segments of Sprague-Dawley rats were used to study the vasodilatory effect of LEL, and the mechanisms involved were evaluated by treating specific inhibitors or activators that affect the contractility of blood vessels. Our results revealed that LEL promotes a vasorelaxant effect through the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway, blocking the Ca2+ channels, opening the K+ channels, and inhibiting the vasoconstrictive action of angiotensin II. In addition, the effects of LEL on blood pressure were investigated in spontaneously hypertensive rats by the tail-cuff method. LEL (300 or 1000 mg/kg) was orally administered to the rats, and 1000 mg/kg of LEL significantly lowered the blood pressure. Systolic blood pressure decreased by -20.06 ± 4.87%, and diastolic blood pressure also lowered by -30.58 ± 5.92% at 4 h in the 1000 mg/kg LEL group. Overall, our results suggest that LEL may be useful to treat hypertensive diseases, considering its vasorelaxing and hypotensive effects.
Asunto(s)
Antihipertensivos , Presión Sanguínea , GMP Cíclico , Hipertensión , Lindera , Óxido Nítrico , Extractos Vegetales , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Animales , Antihipertensivos/farmacología , Extractos Vegetales/farmacología , Óxido Nítrico/metabolismo , Presión Sanguínea/efectos de los fármacos , GMP Cíclico/metabolismo , Masculino , Hipertensión/tratamiento farmacológico , Ratas , Lindera/química , Canales de Potasio/metabolismo , Canales de Potasio/efectos de los fármacos , Canales de Calcio/metabolismo , Canales de Calcio/efectos de los fármacos , Hojas de la Planta/química , Vasodilatación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
Hypercholesterolemia forms the background of several cardiovascular pathologies. LDL receptor-knockout (LDLR-KO) mice kept on a high-fat diet (HFD) develop high cholesterol levels and atherosclerosis (AS). Cannabinoid type 1 receptors (CB1Rs) induce vasodilation, although their role in cardiovascular pathologies is still controversial. We aimed to reveal the effects of CB1Rs on vascular function and remodeling in hypercholesterolemic AS-prone LDLR-KO mice. Experiments were performed on a newly established LDLR and CB1R double-knockout (KO) mouse model, in which KO and wild-type (WT) mice were kept on an HFD or a control diet (CD) for 5 months. The vascular functions of abdominal aorta rings were tested with wire myography. The vasorelaxation effects of acetylcholine (Ach, 1 nM-1 µM) were obtained after phenylephrine precontraction, which was repeated with inhibitors of nitric oxide synthase (NOS) and cyclooxygenase (COX), Nω-nitro-L-arginine (LNA), and indomethacin (INDO), respectively. Blood pressure was measured with the tail-cuff method. Immunostaining of endothelial NOS (eNOS) was carried out. An HFD significantly elevated the cholesterol levels in the LDLR-KO mice more than in the corresponding WT mice (mean values: 1039 ± 162 mg/dL vs. 91 ± 18 mg/dL), and they were not influenced by the presence of the CB1R gene. However, with the defect of the CB1R gene, damage to the Ach relaxation ability was moderated. The blood pressure was higher in the LDLR-KO mice compared to their WT counterparts (systolic/diastolic values: 110/84 ± 5.8/6.8 vs. 102/80 ± 3.3/2.5 mmHg), which was significantly elevated with an HFD (118/96 ± 1.9/2 vs. 100/77 ± 3.4/3.1 mmHg, p < 0.05) but attenuated in the CB1R-KO HFD mice. The expression of eNOS was depressed in the HFD WT mice compared to those on the CD, but it was augmented if CB1R was knocked out. This newly established double-knockout mouse model provides a tool for studying the involvement of CB1Rs in the development of hypercholesterolemia and atherosclerosis. Our results indicate that knocking out the CB1R gene significantly attenuates vascular damage in hypercholesterolemic mice.
Asunto(s)
Modelos Animales de Enfermedad , Hipercolesterolemia , Ratones Noqueados , Receptor Cannabinoide CB1 , Receptores de LDL , Vasodilatación , Animales , Hipercolesterolemia/metabolismo , Hipercolesterolemia/genética , Hipercolesterolemia/patología , Ratones , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB1/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Receptores de LDL/deficiencia , Vasodilatación/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Masculino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/etiología , Remodelación Vascular/efectos de los fármacos , Ratones Endogámicos C57BL , Acetilcolina/farmacologíaRESUMEN
BACKGROUND: In populations with chronic disease, skin autofluorescence (SAF), a measure of long-term fluorescent advanced glycation end-products (AGEs) accumulation in body tissues, has been associated with vascular endothelial function, measured using flow-mediated dilation (FMD). The primary aim of this study was to quantify the relationship between endothelial function and tissue accumulation of AGEs in adults from the general population to determine whether SAF could be used as a marker to predict early impairment of the endothelium. METHODS: A cross-sectional study was conducted with 125 participants (median age: 28.5 y, IQR: 24.4-36.0; 54% women). Endothelial function was measured by fasting FMD. Skin AGEs were measured as SAF using an AGE Reader. Participant anthropometry, blood pressure, and blood biomarkers were also measured. Associations were evaluated using multivariable regression analysis and were adjusted for significant covariates. RESULTS: FMD was inversely correlated with SAF (ρ = -0.50, P < 0.001) and chronological age (ρ = -0.51, P < 0.001). In the multivariable analysis, SAF, chronological age, and male sex were independently associated with reduced FMD (B [95% CI]; -2.60 [-4.40, -0.80]; -0.10 [-0.16, -0.03]; 1.40 [0.14, 2.67], respectively), with the multivariable model adjusted R2 = 0.31, P < 0.001. CONCLUSIONS: Higher skin AGE levels, as measured by SAF, were associated with lower FMD values, in a predominantly young, healthy population. Additionally, older age and male participants exhibited significantly lower FMD values, corresponding with compromised endothelial function. These results suggest that SAF, a simple and inexpensive marker, could be used to predict endothelial impairment before the emergence of any structural artery pathophysiology or classic cardiovascular disease risk markers. TRIAL REGISTRATION: The study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000821897) and concurrently entered into the WHO International Clinical Trials Registry Platform under the same ID number.
Asunto(s)
Biomarcadores , Endotelio Vascular , Productos Finales de Glicación Avanzada , Piel , Vasodilatación , Humanos , Masculino , Femenino , Productos Finales de Glicación Avanzada/metabolismo , Productos Finales de Glicación Avanzada/sangre , Estudios Transversales , Adulto , Piel/irrigación sanguínea , Piel/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Biomarcadores/sangre , Adulto Joven , Factores de Edad , Voluntarios Sanos , Imagen Óptica , Valor Predictivo de las Pruebas , Factores SexualesRESUMEN
Substituted catechols include both natural and synthetic compounds found in the environment and foods. Some of them are flavonoid metabolites formed by the gut microbiota which are absorbed afterwards. Our previous findings showed that one of these metabolites, 4-methylcatechol, exerts potent vasorelaxant effects in rats. In the current study, we aimed at testing of its 22 structural congeners in order to find the most potent structure and to investigate the mechanism of action. 3-methoxycatechol (3-MOC), 4-ethylcatechol, 3,5-dichlorocatechol, 4-tert-butylcatechol, 4,5-dichlorocatechol, 3-fluorocatechol, 3-isopropylcatechol, 3-methylcatechol and the parent 4-methylcatechol exhibited high vasodilatory activities on isolated rat aortic rings with EC50s ranging from â¼10 to 24 µM. Some significant sex-differences were found. The most potent compound, 3-MOC, relaxed also resistant mesenteric artery but not porcine coronary artery, and decreased arterial blood pressure in both male and female spontaneously hypertensive rats in vivo without affecting heart rate. It potentiated the vasodilation mediated by cAMP and cGMP, but did not impact L-type Ca2+-channels. By using two inhibitors, activation of voltage-gated potassium channels (KV) was found to be involved in the mechanism of action. This was corroborated by docking analysis of 3-MOC with the KV7.4 channel. None of the most active catechols decreased the viability of the A-10 rat embryonic thoracic aorta smooth muscle cell line. Our findings showed that various catechols can relax vascular smooth muscles and hence could provide templates for developing new antihypertensive vasodilator agents without affecting coronary circulation.
Asunto(s)
Catecoles , Arterias Mesentéricas , Simulación del Acoplamiento Molecular , Ratas Endogámicas SHR , Vasodilatación , Vasodilatadores , Animales , Vasodilatación/efectos de los fármacos , Masculino , Catecoles/farmacología , Catecoles/química , Vasodilatadores/farmacología , Vasodilatadores/química , Femenino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/metabolismo , Canales de Potasio con Entrada de Voltaje/metabolismo , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Canales de Potasio con Entrada de Voltaje/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Porcinos , Relación Dosis-Respuesta a Droga , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Hipertensión/metabolismo , Presión Arterial/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/metabolismo , Ratas , Factores Sexuales , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Modelos Animales de Enfermedad , Relación Estructura-Actividad , GMP Cíclico/metabolismoRESUMEN
Marinobufagenin (MBG) is implicated in chronic kidney disease, where it removes Fli1-induced inhibition of the collagen-1. We hypothesized that (i) in nephrectomized rats, aortic fibrosis develops due to elevated plasma MBG and inhibited Fli1, and (ii) that the antibody to MBG reduces collagen-1 and improves vasodilatation. A partial nephrectomy was performed in male Sprague-Dawley rats. Sham-operated animals comprised the control group. At 5 weeks following nephrectomy, rats were administered the vehicle (n = 8), or the anti-MBG antibody (n = 8). Isolated aortic rings were tested for their responsiveness to sodium nitroprusside following endothelin-1-induced constriction. In nephrectomized rats, there was an increase in the intensity of collagen staining in the aortic wall vs. the controls. In antibody-treated rats, the structure of bundles of collagen fibers had ordered organization. Western blots of the aorta had lower levels of Fli1 (arbitrary units, 1 ± 0.05 vs. 0.2 ± 0.01; p < 0.001) and greater collagen-1 (arbitrary units, 1 ± 0.01 vs. 9 ± 0.4; p < 0.001) vs. the control group. Administration of the MBG antibody to rats reversed the effect of the nephrectomy on Fli1 and collagen-1 proteins. Aortic rings pretreated with endothelin-1 exhibited 50% relaxation following the addition of sodium nitroprusside (EC50 = 0.28 µmol/L). The responsiveness of the aortic rings obtained from nephrectomized rats was markedly reduced (EC50 = 3.5 mol/L) compared to the control rings. Treatment of rats with the antibody restored vasorelaxation. Thus, the anti-MBG antibody counteracts the Fli1-collagen-1 system and reduces aortic fibrosis.
Asunto(s)
Bufanólidos , Fibrosis , Ratas Sprague-Dawley , Insuficiencia Renal Crónica , Vasodilatación , Animales , Masculino , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Vasodilatación/efectos de los fármacos , Ratas , Bufanólidos/farmacología , Aorta/efectos de los fármacos , Aorta/metabolismo , Anticuerpos/farmacología , Nefrectomía , Nitroprusiato/farmacología , Proteína Proto-Oncogénica c-fli-1/metabolismo , Colágeno Tipo I/metabolismo , Endotelina-1/metabolismoRESUMEN
BACKGROUND: Vasoreactivity testing, such as intracoronary acetylcholine (ACh) or ergometrine (EM), is defined as Class I for the diagnosis of patients with vasospastic angina (VSA) according to recommendations from the Coronary Vasomotion Disorders International Study (COVADIS) group and guidelines from the Japanese Circulation Society (JCS). HYPOTHESIS: Although vasoreactivity testing is a clinically useful tool, it carries some risks and limitations in diagnosing coronary artery spasm. METHODS: Previous reports on vasoreactivity testing for diagnosing the presence of coronary spasm are summarized from the perspective of Class I. RESULTS: There are several problems such as reproducibility, underestimation, overestimation, and inconclusive/nonspecific results associated with daily spasm. Because provoked spasm caused by intracoronary ACh is not always similar to that caused by intracoronary EM, possibly due to different mediators, supplementary use of these vasoreactivity tests is necessary for cardiologists to diagnose VSA when a provoked spasm is not revealed by each vasoactive agent. CONCLUSIONS: Cardiologists should understand the imperfection of these vasoreactivity tests when diagnosing patients with VSA.
Asunto(s)
Acetilcolina , Vasoespasmo Coronario , Ergonovina , Vasodilatadores , Humanos , Vasoespasmo Coronario/fisiopatología , Vasoespasmo Coronario/diagnóstico , Acetilcolina/farmacología , Acetilcolina/administración & dosificación , Vasodilatadores/farmacología , Reproducibilidad de los Resultados , Vasos Coronarios/fisiopatología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/diagnóstico por imagen , Valor Predictivo de las Pruebas , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
Energy drinks are nonalcoholic beverages whose main ingredients are sugar, taurine, and caffeine. The consumption of energy drinks is increasing worldwide, but only a few conflicting studies have investigated the vascular effects of energy drinks in young adults. The aim of this study was to evaluate microvascular reactivity before and after energy drinks consumption in young healthy male volunteers. This was a cross-sectional prospective study. Microvascular reactivity signals were evaluated in the skin of the forearm using laser speckle contrast imaging with acetylcholine (ACh) iontophoresis before and 90 and 180 min after the randomized consumption of one ED or the same volume of water (control), followed by a postocclusive reactive hyperemia (PORH) test. Thirty-two volunteers were evaluated (age: 25.4±4.3 years). Energy drink consumption prevented the rest-induced reduction in cutaneous vascular conductance over time that was observed in the control group. In the control group, there were significant reductions in microvascular vasodilation at 90 and 180 min compared to baseline (P=0.004), but this was not the case in the energy drink group (P=0.76). Our results demonstrated that the reduction in microvascular conductance associated with prolonged immobility can be prevented by the consumption of one energy drink, highlighting the vasodilator effects of this beverage in young individuals at rest. The between-study variability in terms of the brand of energy drinks and the ingested volume, as well as the method of vascular evaluation and the inclusion criteria, may explain the discrepancies among previous studies on the vascular effects of energy drinks.
Asunto(s)
Bebidas Energéticas , Humanos , Masculino , Adulto , Estudios Prospectivos , Estudios Transversales , Adulto Joven , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Descanso/fisiología , Antebrazo/irrigación sanguínea , Microcirculación/efectos de los fármacos , Microcirculación/fisiología , Piel/irrigación sanguínea , Piel/efectos de los fármacos , Hiperemia , Microvasos/efectos de los fármacos , Acetilcolina/administración & dosificación , Acetilcolina/farmacologíaRESUMEN
Torilis japonica (TJ) fruit, is a herb that is traditionally used for erectile dysfunction (ED). Given the shared mechanisms of ED and hypertension through vascular smooth muscle, we hypothesized that TJ would be effective in vasodilation and blood pressure reduction. This study confirmed the authenticity of TJ samples via DNA barcoding and quantified the main active compound, torilin, using HPLC. TJ was extracted with distilled water (TJW) and 50% ethanol (TJE), yielding torilin contents of 0.35 ± 0.01% and 2.84 ± 0.02%, respectively. Ex vivo tests on thoracic aortic rings from Sprague-Dawley rats showed that TJE (3-300 µg/mL) induced endothelium-independent, concentration-dependent vasodilation, unlike TJW. Torilin caused concentration-dependent relaxation with an EC50 of 210 ± 1.07 µM. TJE's effects were blocked by a voltage-dependent K+ channel blocker and alleviated contractions induced by CaCl2 and angiotensin II. TJE inhibited vascular contraction induced by phenylephrine or KCl via extracellular CaCl2 and enhanced inhibition with nifedipine, indicating involvement of voltage-dependent and receptor-operated Ca2+ channels. Oral administration of TJE (1000 mg/kg) significantly reduced blood pressure in spontaneously hypertensive rats. These findings suggest TJ extract's potential for hypertension treatment through vasorelaxant mechanisms, though further research is needed to confirm its efficacy and safety.
Asunto(s)
Presión Sanguínea , Endotelio Vascular , Frutas , Extractos Vegetales , Ratas Sprague-Dawley , Vasodilatación , Animales , Ratas , Vasodilatación/efectos de los fármacos , Extractos Vegetales/farmacología , Presión Sanguínea/efectos de los fármacos , Masculino , Frutas/química , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Antihipertensivos/farmacología , Vasodilatadores/farmacología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Ratas Endogámicas SHR , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/fisiopatologíaRESUMEN
Mammalian and reptilian vascular tissues present basal release of 6-nitrodopamine, which is reduced when the tissues are pre-incubated with the NO synthase inhibitor L-NG-Nitro arginine methyl ester (L-NAME), or when the endothelium is mechanically removed. 6-Nitrodopamine induces vasorelaxation in pre-contracted vascular rings by antagonizing the dopaminergic D2-like receptor. Here it was investigated whether male swine vessels (including carotid, left descendent coronary, renal, and femoral arteries) release 6-nitrodopamine, dopamine, noradrenaline, and adrenaline, as measured by liquid chromatography coupled to tandem mass spectrometry. The in vitro vasorelaxant action of 6-nitrodopamine was evaluated in carotid, coronary, renal, and femoral arteries precontracted by U-46619 (3 nM), and compared to that induced by the dopamine D2-receptor antagonist L-741,626. Expression of tyrosine hydroxylase and the neuromaker calretinin was investigated by immunohistochemistry. All vascular tissues presented basal release of endothelium-derived catecholamines. The relaxation induced by 6-nitrodopamine was not affected by preincubation of the tissues with either L-NAME (100 µM, 30-min preincubation) or the heme-site inhibitor of soluble guanylyl cyclase ODQ (100 µM, 30-min preincubation). Electrical field stimulation (EFS)-induced contractions were significantly potentiated by previous incubation with L-NAME, but unaffected by ODQ preincubation. The contractions induced by EFS were reduced by preincubation with either 6-nitrodopamine or L-741,626. Immunohistochemistry in all arteries revealed the presence of tyrosine hydroxylase in the endothelium, whereas immunoreactivity for calretinin was negative. Swine vessels present basal release of endothelium-derived catecholamines and expression of tyrosine hydroxylase in the endothelium. The vasodilation induced by 6-nitrodopamine is due to blockade of dopaminergic D2-like receptors.
Asunto(s)
Vasodilatación , Animales , Masculino , Vasodilatación/efectos de los fármacos , Porcinos , Arteria Femoral/efectos de los fármacos , Arteria Femoral/metabolismo , Arteria Femoral/fisiología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiología , Vasos Coronarios/metabolismo , Arteria Renal/efectos de los fármacos , Arteria Renal/metabolismo , Arteria Renal/fisiología , Dopamina/metabolismo , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/metabolismo , Arterias Carótidas/fisiología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiología , Vasodilatadores/farmacologíaRESUMEN
BACKGROUND: Obesity is associated with resistance to the metabolic (glucose uptake) and vascular (nitric-oxide mediated dilation and microvascular recruitment) actions of insulin. These vascular effects contribute to insulin sensitivity by increasing tissue delivery of glucose. Studies by us and others suggest that sympathetic activation contributes to insulin resistance to glucose uptake. Here we tested the hypothesis that sympathetic activation contributes to impaired insulin-mediated vasodilation in adult subjects with obesity. METHODS AND RESULTS: In a randomized crossover study, we used a euglycemic hyperinsulinemic clamp in 12 subjects with obesity to induce forearm arterial vasodilation (forearm blood flow) and microvascular recruitment (contrast-enhanced ultrasonography) during an intrabrachial infusion of saline (control) or phentolamine (sympathetic blockade). Insulin increased forearm blood flow on both study days (from 2.21±1.22 to 4.89±4.21 mL/100 mL per min, P=0.003 and from 2.42±0.89 to 7.19±3.35 mL/100 mL per min, P=0.002 for the intact and blocked day, respectively). Sympathetic blockade with phentolamine resulted in a significantly greater increase in microvascular flow velocity (∆microvascular flow velocity: 0.23±0.65 versus 2.51±3.01 arbitrary intensity units (AIU/s) for saline and phentolamine respectively, P=0.005), microvascular blood volume (∆microvascular blood volume: 1.69±2.45 versus 3.76±2.93 AIU, respectively, P=0.05), and microvascular blood flow (∆microvascular blood flow: 0.28±0.653 versus 2.51±3.01 AIU2/s, respectively, P=0.0161). To evaluate if this effect was not due to nonspecific vasodilation, we replicated the study in 6 subjects with obesity comparing intrabrachial infusion of phentolamine to sodium nitroprusside. At doses that produced similar increases in forearm blood flow, insulin-induced changes in microvascular flow velocity were greater during phentolamine than sodium nitroprusside (%microvascular flow velocity=58% versus 29%, respectively, P=0.031). CONCLUSIONS: We conclude that sympathetic activation impairs insulin-mediated microvascular recruitment in adult subjects with obesity.
Asunto(s)
Estudios Cruzados , Antebrazo , Insulina , Microcirculación , Obesidad , Fentolamina , Flujo Sanguíneo Regional , Sistema Nervioso Simpático , Vasodilatación , Humanos , Antebrazo/irrigación sanguínea , Masculino , Fentolamina/farmacología , Femenino , Obesidad/fisiopatología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Adulto , Sistema Nervioso Simpático/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Flujo Sanguíneo Regional/efectos de los fármacos , Microcirculación/efectos de los fármacos , Velocidad del Flujo Sanguíneo , Persona de Mediana Edad , Técnica de Clampeo de la Glucosa , Resistencia a la Insulina , Bloqueo Nervioso Autónomo/métodosRESUMEN
The cold-induced vasodilation (CIVD) response of the human body to Arctic-like environments helps delay or prevent cold injuries to peripheral regions, such as the hands and feet. To more comprehensively predict the thermal responses of these body regions to cold stress, here we extended our previously developed and validated anatomically accurate three-dimensional whole-body thermoregulatory human model by incorporating a new phenomenological formulation of the CIVD mechanism. In this formulation, we modulated the cyclic vasodilation and vasoconstriction flow of warm blood from the body core to the peripheral regions solely by determining the heat-transfer exchange between the skin and the surrounding environment, and deactivated it when the core body temperature decreased to 36.5 °C. In total, we calibrated and validated the model using eight distinct studies involving 153 unique male subjects exposed to 10 diverse experimental conditions, including cold-air exposure of the whole body as well as air exposure and cold-water immersion of the hand or the foot. With CIVD incorporated, the model predictions generally yielded root mean square errors (RMSEs) of <3.0 °C for skin temperature, which represented a reduction of up to 3.6 °C compared to when we did not consider CIVD. Similarly, the incorporation of CIVD increased the fraction of predictions within two standard errors of the measured data by up to 63 %. The model predictions yielded RMSEs for core body temperature of <0.2 °C. The model can be used to provide guidelines to reduce the risk of cold-related injuries during prolonged exposures to very-cold environments.
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Regulación de la Temperatura Corporal , Frío , Pie , Mano , Vasodilatación , Humanos , Masculino , Vasodilatación/fisiología , Pie/fisiología , Pie/irrigación sanguínea , Regulación de la Temperatura Corporal/fisiología , Mano/fisiología , Mano/irrigación sanguínea , Adulto , Modelos Biológicos , Temperatura Cutánea/fisiologíaRESUMEN
Cantú syndrome is a multisystem disorder caused by gain-of-function (GOF) mutations in KCNJ8 and ABCC9, the genes encoding the pore-forming inward rectifier Kir6.1 and regulatory sulfonylurea receptor SUR2B subunits, respectively, of vascular ATP-sensitive K+ (KATP) channels. In this study, we investigated changes in the vascular endothelium in mice in which Cantú syndrome-associated Kcnj8 or Abcc9 mutations were knocked in to the endogenous loci. We found that endothelium-dependent dilation was impaired in small mesenteric arteries from Cantú mice. Loss of endothelium-dependent vasodilation led to increased vasoconstriction in response to intraluminal pressure or treatment with the adrenergic receptor agonist phenylephrine. We also found that either KATP GOF or acute activation of KATP channels with pinacidil increased the amplitude and frequency of wave-like Ca2+ events generated in the endothelium in response to the vasodilator agonist carbachol. Increased cytosolic Ca2+ signaling activity in arterial endothelial cells from Cantú mice was associated with elevated mitochondrial [Ca2+] and enhanced reactive oxygen species (ROS) and peroxynitrite levels. Scavenging intracellular or mitochondrial ROS restored endothelium-dependent vasodilation in the arteries of mice with KATP GOF mutations. We conclude that mitochondrial Ca2+ overload and ROS generation, which subsequently leads to nitric oxide consumption and peroxynitrite formation, cause endothelial dysfunction in mice with Cantú syndrome.
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Endotelio Vascular , Hipertricosis , Mitocondrias , Osteocondrodisplasias , Ácido Peroxinitroso , Especies Reactivas de Oxígeno , Vasodilatación , Animales , Ratones , Hipertricosis/genética , Hipertricosis/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Ácido Peroxinitroso/metabolismo , Osteocondrodisplasias/genética , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/patología , Mitocondrias/metabolismo , Vasodilatación/genética , Receptores de Sulfonilureas/metabolismo , Receptores de Sulfonilureas/genética , Calcio/metabolismo , Masculino , Vasoconstricción , Arterias Mesentéricas/metabolismo , Arterias Mesentéricas/fisiopatología , Canales KATP/metabolismo , Canales KATP/genética , Humanos , Modelos Animales de Enfermedad , Mutación con Ganancia de Función , Canales de Potasio de Rectificación Interna/genética , Canales de Potasio de Rectificación Interna/metabolismo , Cardiomegalia/metabolismo , Cardiomegalia/genéticaRESUMEN
OBJECTIVE: This study tested the hypothesis that administration of the KCa channel activator SKA-31 restores endothelium-dependent vasodilation in vivo in Type 2 Diabetic (T2D) rats. BACKGROUND: Acute treatment of isolated resistance arteries from T2D rats and humans with SKA-31 significantly improved endothelium-dependent vasodilation. However, it is unknown whether these in situ actions translate to intact vascular beds in vivo. METHODS: Male Sprague Dawley (SD) and T2D Goto-Kakizaki (GK) rats (26-32 weeks of age) were injected intraperitoneally with either drug vehicle or 10 mg/kg SKA-31. Doppler ultrasound imaging was used to record reactive hyperemia/flow-mediated dilation (FMD) in the femoral artery following release of an occlusion cuff on the distal hind limb, along with diameter changes in the left main coronary artery in response to inhaled isoflurane (2 % â 5 %). RESULTS: Vehicle treated SD rats exhibited a robust and reversible FMD response, the magnitude and time course of which did not differ in SD rats treated with SKA-31. In contrast, only a weak FMD response was observed in vehicle-treated T2D GK rats, whereas prior SKA-31 administration restored FMD to the level observed in control SD rats. Exposure of SD rats to 5 % isoflurane caused robust coronary artery dilation, which was not altered by prior treatment with SKA-31. In T2D GK rats, 5 % isoflurane inhalation alone did not increase coronary artery diameter, however, a strong vasodilatory response was observed following SKA-31 treatment. SKA-31 administration did not modify intrinsic heart rate responses in either protocol. CONCLUSIONS: Enhancement of KCa channel activity in vivo restores endothelium-dependent vasodilation in T2D rats that exhibit peripheral endothelial dysfunction.
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Diabetes Mellitus Tipo 2 , Endotelio Vascular , Ratas Sprague-Dawley , Vasodilatación , Animales , Masculino , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Ratas , Vasodilatación/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Arteria Femoral/efectos de los fármacos , BenzotiazolesRESUMEN
BACKGROUND: Genetic variants in COL4A1 and COL4A2 (encoding collagen IV alpha chain 1/2) occur in genetic and sporadic forms of cerebral small vessel disease (CSVD), a leading cause of stroke, dementia and intracerebral haemorrhage (ICH). However, the molecular mechanisms of CSVD with ICH and COL4A1/COL4A2 variants remain obscure. METHODS: Vascular function and molecular investigations in mice with a Col4a1 missense mutation and heterozygous Col4a2 knock-out mice were combined with analysis of human brain endothelial cells harboring COL4A1/COL4A2 mutations, and brain tissue of patients with sporadic CSVD with ICH. FINDINGS: Col4a1 missense mutations cause early-onset CSVD independent of hypertension, with enhanced vasodilation of small arteries due to endothelial dysfunction, vascular wall thickening and reduced stiffness. Mechanistically, the early-onset dysregulated endothelium-dependent hyperpolarization (EDH) is due to reduced collagen IV levels with elevated activity and levels of endothelial Ca2+-sensitive K+ channels. This results in vasodilation via the Na/K pump in vascular smooth muscle cells. Our data support this endothelial dysfunction preceding development of CSVD-associated ICH is due to increased cytoplasmic Ca2+ levels in endothelial cells. Moreover, cerebral blood vessels of patients with sporadic CSVD show genotype-dependent mechanisms with wall thickening and lower collagen IV levels in those harboring common non-coding COL4A1/COL4A2 risk alleles. INTERPRETATION: COL4A1/COL4A2 variants act in genetic and sporadic CSVD with ICH via dysregulated EDH, and altered vascular wall thickness and biomechanics due to lower collagen IV levels and/or mutant collagen IV secretion. These data highlight EDH and collagen IV levels as potential treatment targets. FUNDING: MRC, Wellcome Trust, BHF.
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Hemorragia Cerebral , Enfermedades de los Pequeños Vasos Cerebrales , Colágeno Tipo IV , Colágeno Tipo IV/metabolismo , Colágeno Tipo IV/genética , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patología , Hemorragia Cerebral/genética , Enfermedades de los Pequeños Vasos Cerebrales/genética , Enfermedades de los Pequeños Vasos Cerebrales/metabolismo , Enfermedades de los Pequeños Vasos Cerebrales/patología , Enfermedades de los Pequeños Vasos Cerebrales/etiología , Humanos , Animales , Ratones , Ratones Noqueados , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Mutación Missense , Masculino , Vasodilatación , Femenino , HipertrofiaRESUMEN
Tanshinone IIA (TSA), the main lipo-soluble component from the dried rhizome of Salvia miltiorrhiza, has been shown to induce vasodilation. However, the underlying mechanisms remains unclear. This study aimed to investigate the effect of TSA on the vasodilation of small resistant arteries ex vivo. Vascular myography revealed that endothelial denudation reduced significantly the vasodilatory effect of TSA. Blocking transient receptor potential vanilloid 4 (TRPV4) channels prevented TSA-induced vasodilation. Whole-cell patch-clamp analysis revealed that the current passing through TRPV4 channels increased after TSA treatment in endothelial cells (ECs). This was attributed to reduced TRPV4 protein degradation along with its increased expression. The TRPV4 inhibitor HC-067047 lowed nitric oxide (NO) production and TSA-induced expression of endothelial nitric oxide synthase (eNOS). Moreover, it increased the production of cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG). The present results indicate that TSA induces endothelium-dependent vasodilation, which is mediated by the TRPV4-NO-PKG signaling pathway. These findings highlight the potential of TSA, a compound known in traditional Chinese medicine as Danshen (Salvia miltiorrhiza), for future cardiovascular therapeutic strategies.
Asunto(s)
Abietanos , GMP Cíclico , Óxido Nítrico Sintasa de Tipo III , Canales Catiónicos TRPV , Vasodilatación , Abietanos/farmacología , Canales Catiónicos TRPV/metabolismo , Vasodilatación/efectos de los fármacos , Animales , Óxido Nítrico Sintasa de Tipo III/metabolismo , Masculino , GMP Cíclico/metabolismo , Óxido Nítrico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Transducción de Señal/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Ratas Sprague-Dawley , Morfolinas/farmacología , Humanos , Ratas , Vasodilatadores/farmacología , PirrolesRESUMEN
Vasodilation in response to low oxygen (O2) tension (hypoxic vasodilation) is an essential homeostatic response of systemic arteries that facilitates O2 supply to tissues according to demand. However, how blood vessels react to O2 deficiency is not well understood. A common belief is that arterial myocytes are O2-sensitive. Supporting this concept, it has been shown that the activity of myocyte L-type Ca2+channels, the main ion channels responsible for vascular contractility, is reversibly inhibited by hypoxia, although the underlying molecular mechanisms have remained elusive. Here, we show that genetic or pharmacological disruption of mitochondrial electron transport selectively abolishes O2 modulation of Ca2+ channels and hypoxic vasodilation. Mitochondria function as O2 sensors and effectors that signal myocyte Ca2+ channels due to constitutive Hif1α-mediated expression of specific electron transport subunit isoforms. These findings reveal the acute O2-sensing mechanisms of vascular cells and may guide new developments in vascular pharmacology.