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2.
PLoS One ; 15(2): e0229435, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32107491

RESUMEN

A collection of evidence suggests that conjugation of double bonds of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, omega-3 polyunsaturated fatty acids (n-3 PUFAs), increases their anticarcinogenic activity; however, the effect of such conjugation on vascular tone activity remains unknown. We propose that the mixture of conjugated PUFAs exerts higher vasorelaxation activity than the corresponding mixture of nonconjugated PUFAs. The vascular response to different concentrations of conjugated and nonconjugated isomers of EPA and DHA, among other fatty acids (FAs) naturally present in shark oil, and the role of nitric oxide (NO) as a vasorelaxant agent were investigated. Both conjugated EPA (CEPA) and conjugated DHA (CDHA) were prepared by alkaline isomerization of all PUFAs contained in shark oil. Different concentrations of conjugated and nonconjugated PUFAs were placed in contact with precontracted aortic rings of Wistar rats to assess their effect on vascular tone. All tested samples exerted a vasorelaxant effect. Compared to nonconjugated PUFAs, conjugated isomers exhibited an increase in the dilatation of the aortic rings (P<0.001) in a dose-dependent manner (P<0.001). In addition, nonconjugated PUFAs produced nitric oxide (NO) in a dose-dependent manner, while conjugated PUFAs did not, suggesting that their dilatation mechanism is not totally dependent on NO.


Asunto(s)
Aorta Torácica/fisiología , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Aceites de Pescado/farmacología , Óxido Nítrico/metabolismo , Vasodilatación/fisiología , Animales , Aorta Torácica/efectos de los fármacos , Ácidos Docosahexaenoicos/química , Ácido Eicosapentaenoico/química , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Ácidos Grasos/metabolismo , Aceites de Pescado/química , Isomerismo , Masculino , Ratas , Ratas Wistar , Tiburones , Vasodilatación/efectos de los fármacos
3.
Mayo Clin Proc ; 94(12): 2455-2466, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31806099

RESUMEN

OBJECTIVE: To investigate the factors that are associated with the effect of metformin on endothelial dysfunction in polycystic ovary syndrome (PCOS). PATIENTS AND METHODS: From March 24, 2014, to November 18, 2016, 48 women with PCOS were randomly assigned to 1500 mg/d of metformin (N=29) or no treatment (N=13) for 3 months; 42 patients (29 in the initial treatment group and 13 in the no treatment group) completed the study. Study variables were measured at baseline and after 3 months. Participants who did not receive metformin initially were then treated with metformin for another 3 months, and study variables were measured again. Endothelial function was measured as reactive hyperemia-peripheral arterial tonometry (RH-PAT) from the index finger. RESULTS: The age and baseline endothelial function (mean ± SD) of the participants were 32.7±6.9 years and 1.8±0.5, respectively. No notable change was observed in endothelial function after 3 months with metformin compared with no treatment. However, after stratifying participants who received metformin based on baseline endothelial function, there was a significant improvement following metformin treatment in participants with abnormal baseline endothelial function (1.3±0.3 vs 1.7±0.3; P<.001) but not in those with normal baseline endothelial function (2.1±0.4 vs 2.0±0.5; P=.11). CONCLUSION: Metformin improves endothelial function in women with PCOS and endothelial dysfunction independent of changes in glucose metabolism, dyslipidemia, or presence of prediabetes. Metformin has a direct effect on endothelial function in PCOS, and measurement of endothelial function can stratify and follow response to metformin treatment in PCOS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02086526.


Asunto(s)
Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Adulto , Femenino , Humanos , Manometría , Síndrome del Ovario Poliquístico/fisiopatología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología
4.
J Cardiothorac Surg ; 14(1): 200, 2019 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-31752946

RESUMEN

BACKGROUND: Vasoplegia is a severe complication which may occur after cardiac surgery, particularly in patients with heart failure. It is a result of activation of vasodilator pathways, inactivation of vasoconstrictor pathways and the resistance to vasopressors. However, the precise etiology remains unclear. The aim of the Vasoresponsiveness in patients with heart failure (VASOR) study is to objectify and characterize the altered vasoresponsiveness in patients with heart failure, before, during and after heart failure surgery and to identify the etiological factors involved. METHODS: This is a prospective, observational study conducted at Leiden University Medical Center. Patients with and patients without heart failure undergoing cardiac surgery on cardiopulmonary bypass are enrolled. The study is divided in two inclusion phases. During phase 1, 18 patients with and 18 patients without heart failure are enrolled. The vascular reactivity in response to a vasoconstrictor (phenylephrine) and a vasodilator (nitroglycerin) is assessed in vivo on different timepoints. The response to phenylephrine is assessed on t1 (before induction), t2 (before induction, after start of cardiotropic drugs and/or vasopressors), t3 (after induction), t4 (15 min after cessation of cardiopulmonary bypass) and t5 (1 day post-operatively). The response to nitroglycerin is assessed on t1 and t5. Furthermore, a sample of pre-pericardial fat tissue, containing resistance arteries, is collected intraoperatively. The ex vivo vascular reactivity is assessed by constructing concentrations response curves to various vasoactive substances using isolated resistance arteries. Next, expression of signaling proteins and receptors is assessed using immunohistochemistry and mRNA analysis. Furthermore, the groups are compared with respect to levels of organic compounds that can influence the cardiovascular system (e.g. copeptin, (nor)epinephrine, ANP, BNP, NTproBNP, angiotensin II, cortisol, aldosterone, renin and VMA levels). During inclusion phase 2, only the ex vivo vascular reactivity test is performed in patients with (N = 12) and without heart failure (N = 12). DISCUSSION: Understanding the difference in vascular responsiveness between patients with and without heart failure in detail, might yield therapeutic options or development of preventive strategies for vasoplegia, leading to safer surgical interventions and improvement in outcome. TRIAL REGISTRATION: The Netherlands Trial Register (NTR), NTR5647. Registered 26 January 2016.


Asunto(s)
Procedimientos Quirúrgicos Cardíacos/efectos adversos , Insuficiencia Cardíaca/cirugía , Complicaciones Posoperatorias/etiología , Vasodilatación/fisiología , Vasoplejía/etiología , Femenino , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/fisiopatología , Estudios Prospectivos , Vasoplejía/fisiopatología , Vasoplejía/prevención & control
5.
Undersea Hyperb Med ; 46(5): 635-646, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31683362

RESUMEN

We aimed to assess the effects of intermittent hyperbaric oxygenation (HBO2 at 2 bars for 120 minutes a day for four successive days) on acetylcholine-induced vasorelaxation (AChIR) in female Sprague-Dawley (SD) rats (N=80) that were randomized into four groups: healthy controls (CTR); diabetic rats (DM); and control and diabetic rats that underwent hyperbaric oxygenation (CTR+HBO and DM+HBO), respectively. AChIR was measured in vitro in aortic rings, with/without L-NAME, MS-PPOH, HET0016 or indomethacin. mRNA expression of eNOS, iNOS, COX-1, COX-2, thromboxane A synthase 1 (TBXAS1), CYP4A1, CYP4A3 and CYP2J3 was assessed by qPCR. Systemic oxidative stress and plasma antioxidative capacity were determined with the thiobarbituric acid-reactive substances (TBARS) and the ferric reducing ability of plasma (FRAP) assays, respectively. There was no significant difference in AChIR among experimental groups of rats. In CTR and DM group of rats, AChIR was mediated by NO and EETs pathway, while in the CTR+HBO and DM+HBO groups, NO-pathway prevailed. iNOS expression was upregulated in the DM group compared to CTR, while HBO2 upregulated eNOS in CTR group and TBXAS1 in DM group of rats. In both, CTR and DM group of rats, the sensitivity to ACh in the presence of L-NAME or in the presence of MSPPOH was significantly decreased compared to the response to ACh in the absence or presence of indomethacin or HET0016. DM and DM+HBO rats had increased TBARS compared to their respective controls. In conclusion, HBO2 presumably alters vasorelaxation in response to ACh from NO-EETs mediated pathways to solely NO-pathway, without affecting oxidative status of DM rats.


Asunto(s)
Acetilcolina/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Diabetes Mellitus Experimental/fisiopatología , Oxigenación Hiperbárica , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Análisis de Varianza , Animales , Aorta/efectos de los fármacos , Aorta/fisiopatología , Glucemia/análisis , Peso Corporal , Sistema Enzimático del Citocromo P-450/fisiología , Cartilla de ADN , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Oxigenación Hiperbárica/métodos , Estrés Oxidativo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Estreptozocina , Factores de Tiempo , Vasodilatación/fisiología
6.
Plast Reconstr Surg ; 144(4): 669e-681e, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31568315

RESUMEN

BACKGROUND: Physiologic studies show that tissue perfusion increases during moderate amounts of tissue compression. This is attributed to sensory nerves initiating a vasodilatory cascade referred to as pressure-induced vasodilation. METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies investigating perfusion during pressure exposure longer than 10 minutes. Retrieved studies were assessed using the Office of Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal Studies. Results were pooled with random effects models. The body of evidence was rated using the Office of Health Assessment and Translation approach. RESULTS: Twenty-nine articles were included, of which 19 articles were included in meta-analyses. The evidence indicates that moderate amounts of tissue compression have the capacity to increase perfusion in healthy humans by 46 percent (95 percent CI, 30 to 62 percent). Using the Office of Health Assessment and Translation approach, the authors found a high level of confidence in the body of evidence. Pressure-induced vasodilation blockade was associated with increased pressure ulcer formation. Pressure-induced vasodilation was impaired by neuropathy and by the drugs diclofenac and amiloride. CONCLUSIONS: This systematic review and meta-analysis indicates that healthy humans have the capacity to increase local perfusion in response to mechanical stress resulting from tissue compression. Because pressure-induced vasodilation is mediated by sensory nerves, pressure-induced vasodilation emphasizes the importance of sensory innervation for durable tissue integrity. Pressure-induced vasodilation impairment seems to provide a complementary explanation for the susceptibility of neuropathic tissues to pressure-induced lesions.


Asunto(s)
Úlcera por Presión/etiología , Vasodilatación , Humanos , Presión , Vasodilatación/fisiología
7.
Clin Interv Aging ; 14: 1579-1587, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31564840

RESUMEN

Background: Aging leads to structural and functional changes in the vasculature characterized by arterial endothelial dysfunction and stiffening of large elastic arteries and is a predominant risk factor for cardiovascular disease, the leading cause of morbidity and mortality in modern societies. Although exercise reduces the risk of many age-related diseases, including cardiovascular disease, the mechanisms underlying the beneficial effects of exercise on age-related endothelial function fully elucidated. Purpose: The present study explored the effects of exercise on the impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilation in aged arteries and on the involvement of the transient receptor potential vanilloid 4 (TRPV4) channel and the small-conductance calcium-activated potassium (KCa2.3) channel signaling in this process. Methods: Male Sprague-Dawley rats aged 19-21 months were randomly assigned to a sedentary group or to an exercise group. Two-month-old rats were used as young controls. Results: We found that TRPV4 and KCa2.3 isolated from primary cultured rat aortic endothelial cells pulled each other down in co-immunoprecipitation assays, indicating that the two channels could physically interact. Using ex vivo functional arterial tension assays, we found that EDHF-mediated relaxation induced by acetylcholine or by the TRPV4 activator GSK1016790A was markedly decreased in aged rats compared with that in young rats and was significantly inhibited by TRPV4 or KCa2.3 blockers in both young and aged rats. However, exercise restored both the age-related and the TRPV4-mediated and KCa2.3-mediated EDHF responses. Conclusion: These results suggest an important role for the TRPV4-KCa2.3 signaling undergirding the beneficial effect of exercise to ameliorate age-related arterial dysfunction.


Asunto(s)
Factores Biológicos/metabolismo , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Canales de Potasio Calcio-Activados/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Enfermedades Cardiovasculares/fisiopatología , Endotelio Vascular/fisiopatología , Masculino , Ratas , Ratas Sprague-Dawley , Vasodilatación/fisiología
8.
Hypertension ; 74(5): 1104-1112, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31522618

RESUMEN

Sodium bicarbonate has long been used to treat chronic kidney disease. It has been demonstrated to slow the decline in glomerular filtration rate in chronic kidney disease patient; however, the mechanisms are not completely understood. We hypothesized that NaHCO3 dilates afferent arterioles (Af-Art) by stimulating nitric oxide (NO) release mediated by the Na+/HCO3- cotransporter (NBC) contributing to the elevation in glomerular filtration rate. Isolated microperfused mouse renal Af-Art, preconstricted with norepinephrine (1 µmol/L), dilated 45±2% (n=6, P<0.05) in response to NaHCO3 (44 mmol/L). Whereas, NaCl solution containing the same Na+ concentration was not effective. The mRNA for NBCn1 and NBCe1 were detected in microdissected Af-Art using reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction. The Af-Art intracellular pH measured with 2',7'-bis-(2-carboxyethyl)-5-(and-6) carboxyfluorescein, acetoxymethyl ester increased significantly by 0.29±0.02 (n=6; P<0.05) in the presence of NaHCO3, which was blunted by N-cyanosulphonamide compound (S0859) that is an inhibitor of the NBC family. After clamping the intracellular pH with 10 µM nigericin, changing the bath solution pH from 7.4 to 7.8 still dilates the Af-Art by 53±4% (n=7; P<0.005) and increases NO generation by 22±3% (n=7; P<0.005). Both pH-induced NO generation and vasodilation were blocked by L-NG-Nitroarginine Methyl Ester. NaHCO3 increased NO generation in Af-Art by 19±4% (n=5; P<0.005) and elevated glomerular filtration rate in conscious mice by 36% (233 versus 318 ul/min; n=9-10; P<0.0001). S0859 and L-NG-nitroarginine methyl ester blocked NaHCO3-induced increases in NO generation and vasodilation. We conclude that NBCn1 and NBCe1 are expressed in Af-Art and that NaHCO3 dilates Af-Art via NBCs mediated by NO that increases the glomerular filtration rate.


Asunto(s)
Arteriolas/efectos de los fármacos , Glomérulos Renales/efectos de los fármacos , Bicarbonato de Sodio/farmacología , Simportadores de Sodio-Bicarbonato/metabolismo , Vasodilatación/efectos de los fármacos , Animales , Arteriolas/fisiología , Modelos Animales de Enfermedad , Tasa de Filtración Glomerular/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/metabolismo , Perfusión/métodos , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/patología , Sensibilidad y Especificidad , Simportadores de Sodio-Bicarbonato/efectos de los fármacos , Técnicas de Cultivo de Tejidos , Vasodilatación/fisiología
9.
PLoS Comput Biol ; 15(8): e1007231, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31469820

RESUMEN

Capillaries are the prime location for oxygen and nutrient exchange in all tissues. Despite their fundamental role, our knowledge of perfusion and flow regulation in cortical capillary beds is still limited. Here, we use in vivo measurements and blood flow simulations in anatomically accurate microvascular network to investigate the impact of red blood cells (RBCs) on microvascular flow. Based on these in vivo and in silico experiments, we show that the impact of RBCs leads to a bias toward equating the values of the outflow velocities at divergent capillary bifurcations, for which we coin the term "well-balanced bifurcations". Our simulation results further reveal that hematocrit heterogeneity is directly caused by the RBC dynamics, i.e. by their unequal partitioning at bifurcations and their effect on vessel resistance. These results provide the first in vivo evidence of the impact of RBC dynamics on the flow field in the cortical microvasculature. By structural and functional analyses of our blood flow simulations we show that capillary diameter changes locally alter flow and RBC distribution. A dilation of 10% along a vessel length of 100 µm increases the flow on average by 21% in the dilated vessel downstream a well-balanced bifurcation. The number of RBCs rises on average by 27%. Importantly, RBC up-regulation proves to be more effective the more balanced the outflow velocities at the upstream bifurcation are. Taken together, we conclude that diameter changes at capillary level bear potential to locally change the flow field and the RBC distribution. Moreover, our results suggest that the balancing of outflow velocities contributes to the robustness of perfusion. Based on our in silico results, we anticipate that the bi-phasic nature of blood and small-scale regulations are essential for a well-adjusted oxygen and energy substrate supply.


Asunto(s)
Encéfalo/irrigación sanguínea , Eritrocitos/fisiología , Microvasos/fisiología , Animales , Velocidad del Flujo Sanguíneo/fisiología , Capilares/anatomía & histología , Capilares/fisiología , Circulación Cerebrovascular/fisiología , Biología Computacional , Simulación por Computador , Femenino , Hematócrito , Ratones , Ratones Endogámicos C57BL , Microvasos/anatomía & histología , Modelos Cardiovasculares , Modelos Neurológicos , Vasodilatación/fisiología
10.
J Therm Biol ; 84: 228-235, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31466758

RESUMEN

Naked mole-rats are among the most hypoxia-tolerant mammals but have a poor thermoregulatory capacity due to their lack of insulating fur and fat, and small body size. In acute hypoxia, naked mole-rat body temperature (Tb) decreases to ambient temperature (Ta) but the mechanisms that underlie this thermoregulatory response are unknown. We hypothesized 1) that naked mole-rat blood vessels vasodilate during hypoxia to shunt heat toward the body surface and/or 2) that they augment heat loss through evaporative cooling. Using open-flow respirometry (indirect calorimetry) we explored metabolic and thermoregulatory strategies of naked mole-rats exposed to hypoxia (7% O2 for 1 h) at two relative humidities (RH; 50 or 100% water saturation), and in two Ta's (25 and 30 °C), alone, and following treatment with the vasoconstrictor angiotensin II (ANGII). We found that Tb and metabolic rate decreased in hypoxia across all treatment groups but that neither RH nor ANGII effected either variable in hypoxia. Conversely, both Tb and metabolic rate were reduced in 100% RH or by ANGII treatment in normoxia at 25 °C, and therefore the absolute change in both variables with the onset of hypoxia was reduced when vasodilation or evaporative cooling were prevented. We conclude that naked mole-rats employ evaporative cooling and vasodilation to thermoregulate in normoxia and in 25 °C but that neither mechanism is involved in thermoregulatory changes during acute hypoxia. These findings suggest that NMRs may employ passive strategies such as reducing thermogenesis to reduce Tb in hypoxia, which would support metabolic rate suppression.


Asunto(s)
Regulación de la Temperatura Corporal/fisiología , Hipoxia/fisiopatología , Ratas Topo/fisiología , Vasodilatación/fisiología , Animales , Metabolismo Basal , Femenino , Masculino
11.
Hypertension ; 74(4): 817-825, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31422694

RESUMEN

The BBSome-a complex consisting of 8 Bardet-Biedl syndrome proteins-is involved in the regulation of various cellular processes. Recently, the BBSome complex has emerged as an important regulator of cardiovascular function with implications for disease. In this study, we examined the role of the BBSome in vascular smooth muscle and its effects on the regulation of cardiovascular function. Smooth muscle-specific disruption of the BBSome through tamoxifen-inducible deletion of Bbs1 gene-a critical component of the BBSome complex-reduces relaxation and enhances contractility of vascular rings and increases aortic stiffness independent of changes in arterial blood pressure. Mechanistically, we demonstrate that smooth muscle Bbs1 gene deletion increases vascular angiotensinogen gene expression implicating the renin-angiotensin system in these altered cardiovascular responses. Additionally, we report that smooth muscle-specific Bbs1 knockout mice demonstrate enhanced ET-1 (endothelin-1)-induced contractility of mesenteric arteries-an effect reversed by blockade of the AT1 (angiotensin type 1 receptor) with losartan. These findings highlight the importance of the smooth muscle BBSome in the control of vascular function and arterial stiffness through modulation of renin-angiotensin system signaling.


Asunto(s)
Presión Sanguínea/fisiología , Proteínas Asociadas a Microtúbulos/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Rigidez Vascular/fisiología , Angiotensinógeno/genética , Angiotensinógeno/metabolismo , Animales , Aorta/fisiología , Arterias Mesentéricas/fisiología , Ratones , Ratones Transgénicos , Proteínas Asociadas a Microtúbulos/genética , Vasodilatación/fisiología
12.
Hypertension ; 74(4): 936-946, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31378107

RESUMEN

Endothelial cells regulate vascular tone by producing both relaxing and contracting factors to control the local blood flow. Hypertension is a common side effect of mTORC1 (mammalian target of rapamycin complex 1) inhibitors. However, the role of endothelial mTORC1 in hypertension remains elusive. The present study aimed to determine the role of endothelial mTORC1 in Ang II (angiotensin II)-induced hypertension and the underlying mechanism. Endothelial mTORC1 activity was increased by Ang II both in vitro and in vivo. Blood pressure was higher in Tie-2-Cre-mediated regulatory associated protein of mTOR (mammalian target of rapamycin; Raptor) heterozygous-deficient (Tie2Cre-RaptorKD) mice than control mice both before and after Ang II infusion. Acetylcholine-evoked endothelium-dependent relaxation of mesenteric arteries was impaired in Tie2Cre-RaptorKD mice. Treatment with indomethacin or a specific COX (cyclooxygenase)-2 inhibitor, NS-398, but not L-NG-nitroarginine methyl ester reduced endothelium-dependent relaxation in Raptorflox/- mice to a similar extent as in Tie2Cre-RaptorKD mice. Metabolomic profiling revealed that the plasma content of prostaglandin E2 was reduced in Tie2Cre-RaptorKD mice with or without Ang II infusion. In endothelial cells, reduction of the protein level of YAP (yes-associated protein) with siRNA-mediated RPTOR deficiency was autophagy dependent and transcriptionally regulated the expression of COX-2 and mPGES-1 (microsomal prostaglandin E synthase-1). Hence, overexpression of YAP in endothelial cells enhanced the mRNA and protein levels of COX-2 and mPGES-1 and reversed the endothelial dysfunction and hypertension in Tie2Cre-RaptorKD mice. The present results demonstrate that suppression of mTORC1 activity in endothelial cells reduces prostaglandin E2 production and causes hypertension by reducing YAP-mediated COX-2/mPGES-1 expression.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Presión Sanguínea/fisiología , Endotelio Vascular/metabolismo , Hipertensión/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Fosfoproteínas/metabolismo , Transducción de Señal/fisiología , Angiotensina II , Animales , Presión Sanguínea/efectos de los fármacos , Proteínas de Ciclo Celular , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Dinoprostona/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Endotelio Vascular/efectos de los fármacos , Hipertensión/inducido químicamente , Indometacina/farmacología , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/metabolismo , Ratones , Prostaglandina-E Sintasas/metabolismo , Transducción de Señal/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología
13.
Int Heart J ; 60(4): 854-861, 2019 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-31257335

RESUMEN

The aim of this single-arm pilot study was to determine the effects of whole-body vibration training (WBVT) on endothelial function in elderly patients with cardiovascular diseases, as well as its safety. A total of 20 elderly patients with stable cardiovascular diseases underwent WBVT, which consisted of five static resistance training exercises (squats, wide stance squats, toe-stands, squats + band, and front lunges). The parameters of WBVT included vertical vibrations, 30 Hz frequency, and a 3-mm peak-to-peak amplitude. Each vibration session lasted 30 seconds, with 120 seconds of rest between sessions. Before and after WBVT, the reactive hyperemia peripheral arterial tonometry index (RH-PAT index) and transcutaneous oxygen pressure (tcPO2) were recorded as a measure of endothelial function and peripheral blood circulation. Systolic blood pressure, diastolic blood pressure, heart rate, and arterial oxygen saturation of pulse oximetry (SpO2) were measured at each rest interval as well as before and after WBVT. All patients completed our WBVT protocol without adverse events. The RH-PAT index significantly increased following WBVT (1.42 to 2.06, P < 0.001). There were no significant changes in heart rate (P = 0.777), systolic blood pressure (P = 0.183), diastolic blood pressure (P = 0.925), or SpO2 (P = 0.248) during WBVT. In conclusion, we demonstrated the acute effects of WBVT on endothelial function, with no reports of adverse events. These findings support the need for further randomized controlled studies to investigate the long-term effects of WBVT.


Asunto(s)
Arterias/fisiopatología , Enfermedades Cardiovasculares/terapia , Endotelio Vascular/fisiopatología , Modalidades de Fisioterapia/instrumentación , Vasodilatación/fisiología , Anciano , Presión Sanguínea/fisiología , Enfermedades Cardiovasculares/fisiopatología , Diseño de Equipo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Fuerza Muscular/fisiología , Proyectos Piloto , Pletismografía , Estudios Retrospectivos , Resultado del Tratamiento , Vibración
14.
Graefes Arch Clin Exp Ophthalmol ; 257(10): 2095-2101, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31273510

RESUMEN

PURPOSE: Remote ischemic conditioning (RIC) implies that transient ischemia in one organ can affect blood flow and protect from ischemia in another remote organ such as the retina. The purpose of the present study was to investigate the effect of RIC on the diameter of retinal arterioles in patients with diabetic retinopathy and whether this effect differs among peripheral and macular vessels. METHODS: In twenty type 1 diabetes patients aged 20-31 years, the Dynamic Vessel Analyzer (DVA) was used to measure diameters of peripheral and macular arterioles during rest, isometric exercise, and flicker stimulation. Measurements were obtained before, immediately after, and 1 h after RIC, and were compared to responses obtained from normal persons. RESULTS: The reduced baseline diameter (p < 0.009) and contraction of peripheral retinal arterioles during isometric exercise (p = 0.025) observed immediately after RIC in normal persons were absent in the studied diabetic patients. CONCLUSIONS: RIC affects the diameter of peripheral but not macular arterioles in normal persons, but the response is abolished in diabetic patients. TRIAL REGISTRATION: NCT03906383.


Asunto(s)
Diabetes Mellitus Tipo 1/complicaciones , Retinopatía Diabética/diagnóstico , Isquemia/diagnóstico , Flujo Sanguíneo Regional/fisiología , Arteria Retiniana/diagnóstico por imagen , Tomografía de Coherencia Óptica/métodos , Vasodilatación/fisiología , Adulto , Arteriolas/patología , Arteriolas/fisiopatología , Retinopatía Diabética/complicaciones , Retinopatía Diabética/fisiopatología , Femenino , Humanos , Isquemia/etiología , Isquemia/fisiopatología , Precondicionamiento Isquémico/métodos , Masculino , Arteria Retiniana/fisiopatología , Adulto Joven
15.
Skin Pharmacol Physiol ; 32(5): 235-243, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31220834

RESUMEN

BACKGROUND: Protease-activated receptor 2 (PAR2) exists in the cutaneous vasculature and eccrine sweat glands. We previously showed that in young habitually active men, exogenous PAR2 activation via the agonist SLIGKV-NH2 had no effect on heat loss responses of cutaneous vasodilatation and sweating during rest or exercise in the heat. However, ageing is associated with altered mechanisms governing these responses. Thus, the effect of exogenous PAR2 activation on cutaneous vasodilatation and sweating in older individuals may differ from that in young adults. METHODS: Local cutaneous vascular conductance (CVC) and sweat rate were measured in 9 older males (62 ± 4 years) at four forearm skin sites treated with the following: (1) lactated Ringer solution (control), (2) 0.05 mM, (3) 0.5 mM, or (4) 5 mM SLIGKV-NH2. Measurements were performed while participants rested in a non-heat-stress environment (25°C) for ∼60 min and an additional 50 min thereafter in the heat (40°C). Participants then performed 50 min of cycling at a fixed metabolic heat load of 200 W/m2 (to maintain the same thermal drive for heat loss between participants) followed by a 30-min recovery. RESULTS: CVC during non-heat-stress resting was elevated from the control site with 5 mM SLIGKV-NH2 (p ≤ 0.05), but this response was not observed during ambient heat exposure. By contrast, 5 mM SLIGKV-NH2 lowered CVC during the early stage (10 and 20 min) of exercise compared to the control site (all p ≤ 0.05). Although sweating during non-heat-stressed and heat-stressed resting was not affected by any dose of SLIGKV-NH2, it was reduced with all SLIGKV-NH2 doses relative to the control site during and following exercise (all p ≤ 0.05). CONCLUSION: We show that while exogenous PAR2 activation induces cutaneous vasodilatation at rest under non-heat-stressed conditions, it attenuates cutaneous vasodilatation and sweating during and following an exercise-induced heat stress in older men.


Asunto(s)
Ejercicio Físico/fisiología , Receptor PAR-2/fisiología , Sudoración/fisiología , Vasodilatación/fisiología , Anciano , Calor , Humanos , Masculino , Persona de Mediana Edad , Oligopéptidos/farmacología , Receptor PAR-2/agonistas , Fenómenos Fisiológicos de la Piel , Sudoración/efectos de los fármacos , Vasodilatación/efectos de los fármacos
16.
Redox Biol ; 26: 101238, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31200239

RESUMEN

L-NG-Nitro arginine methyl ester (L-NAME) has been widely applied for several decades in both basic and clinical research as an antagonist of nitric oxide synthase (NOS). Herein, we show that L-NAME slowly releases NO from its guanidino nitro group. Daily pretreatment of rats with L-NAME potentiated mesenteric vasodilation induced by nitrodilators such as nitroglycerin, but not by NO. Release of NO also occurred with the NOS-inactive enantiomer D-NAME, but not with L-arginine or another NOS inhibitor L-NMMA, consistent with the presence or absence of a nitro group in their structure and their nitrodilator-potentiating effects. Metabolic conversion of the nitro group to NO-related breakdown products was confirmed using isotopically-labeled L-NAME. Consistent with Fenton chemistry, transition metals and reactive oxygen species accelerated the release of NO from L-NAME. Both NO production from L-NAME and its nitrodilator-potentiating effects were augmented under inflammation. NO release by L-NAME can confound its intended NOS-inhibiting effects, possibly by contributing to a putative intracellular NO store in the vasculature.


Asunto(s)
Inhibidores Enzimáticos/farmacología , NG-Nitroarginina Metil Éster/farmacología , Nitroglicerina/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Arginina/farmacología , Femenino , Arterias Mesentéricas/efectos de los fármacos , Ratones , Miografía , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Células RAW 264.7 , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Ovinos , Estereoisomerismo , Vasodilatación/fisiología , omega-N-Metilarginina/farmacología
17.
Nutrients ; 11(6)2019 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-31207908

RESUMEN

Obesity is associated with microvascular dysfunction. While low-fat diet improves cardiovascular risk, its contributions on microvascular function, independent of weight loss, is unknown. We tested the hypothesis that nitric oxide (NO)-dependent vasodilation in microvessels is improved by low-fat diets designed for weight loss (LFWL) compared to low-fat weight maintenance (LFWM) diet. Obese adults were randomly assigned to either a LFWL diet (n = 11) or LFWM diet (n = 10) for six weeks. Microvessels were obtained from gluteal subcutaneous fat biopsies before and after the intervention for vascular reactivity measurements to acetylcholine (Ach) and flow, with and without L-NAME or indomethacin. Vascular and serum NO and C-reactive protein (CRP) were also measured. LFWL diet increased flow-induced (FID) and ACh-induced dilation (AChID); an effect that was inhibited by L-NAME. Conversely, LFWM diet did not affect FID or AChID. Indomethacin improved FID and AChID in the baseline and this effect was minimized in response to both diets. Serum NO or CRP did not change in response to either diet. In conclusion, LFWL diet improves microvascular reactivity compared to LFWM diet and increased vascular NO contribution to the improved microvascular dilation. These data suggest that weight reduction on low fat diet is critical for microvascular health.


Asunto(s)
Dieta con Restricción de Grasas , Óxido Nítrico/metabolismo , Obesidad , Vasodilatación/fisiología , Pérdida de Peso/fisiología , Adolescente , Adulto , Mantenimiento del Peso Corporal/fisiología , Femenino , Humanos , Masculino , Microvasos/metabolismo , Microvasos/fisiología , Persona de Mediana Edad , Óxido Nítrico/análisis , Obesidad/dietoterapia , Obesidad/fisiopatología , Grasa Subcutánea/irrigación sanguínea , Adulto Joven
18.
Respir Res ; 20(1): 111, 2019 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-31170998

RESUMEN

BACKGROUND: Tyrosine kinase inhibitors (TKIs) inhibit the platelet derived growth factor receptor (PDGFR) and gain increasing significance in the therapy of proliferative diseases, e.g. pulmonary arterial hypertension (PAH). Moreover, TKIs relax pulmonary vessels of rats and guinea pigs. So far, it is unknown, whether TKIs exert relaxation in human and murine pulmonary vessels. Thus, we studied the effects of TKIs and the PDGFR-agonist PDGF-BB in precision-cut lung slices (PCLS) from both species. METHODS: The vascular effects of imatinib (mice/human) or nilotinib (human) were studied in Endothelin-1 (ET-1) pre-constricted pulmonary arteries (PAs) or veins (PVs) by videomicroscopy. Baseline initial vessel area (IVA) was defined as 100%. With regard to TKI-induced relaxation, K+-channel activation was studied in human PAs (PCLS) and imatinib/nilotinib-related changes of cAMP and cGMP were analysed in human PAs/PVs (ELISA). Finally, the contractile potency of PDGF-BB was explored in PCLS (mice/human). RESULTS: Murine PCLS: Imatinib (10 µM) relaxed ET-1-pre-constricted PAs to 167% of IVA. Vice versa, 100 nM PDGF-BB contracted PAs to 60% of IVA and pre-treatment with imatinib or amlodipine prevented PDGF-BB-induced contraction. Murine PVs reacted only slightly to imatinib or PDGF-BB. Human PCLS: 100 µM imatinib or nilotinib relaxed ET-1-pre-constricted PAs to 166% or 145% of IVA, respectively, due to the activation of KATP-, BKCa2+- or Kv-channels. In PVs, imatinib exerted only slight relaxation and nilotinib had no effect. Imatinib and nilotinib increased cAMP in human PAs, but not in PVs. In addition, PDGF-BB contracted human PAs/PVs, which was prevented by imatinib. CONCLUSIONS: TKIs relax pre-constricted PAs/PVs from both, mice and humans. In human PAs, the activation of K+-channels and the generation of cAMP are relevant for TKI-induced relaxation. Vice versa, PDGF-BB contracts PAs/PVs (human/mice) due to PDGFR. In murine PAs, PDGF-BB-induced contraction depends on intracellular calcium. So, PDGFR regulates the tone of PAs/PVs. Since TKIs combine relaxant and antiproliferative effects, they may be promising in therapy of PAH.


Asunto(s)
Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Arteria Pulmonar/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Pulmón/fisiología , Ratones , Ratones Endogámicos BALB C , Arteria Pulmonar/fisiología , Especificidad de la Especie , Vasodilatación/fisiología
19.
Bull Exp Biol Med ; 167(2): 247-249, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31243672

RESUMEN

NO-mediated vasodilatation can be realized via two pathways: dependent and independent on soluble guanylate cyclase; the latter is implemented through NO interaction with ionic channels. We evaluated the contribution of these pathways into NO-induced relaxation of isolated pulmonary arteries in rats. In pulmonary arteries, in contrast to systemic vessels, soluble guanylate cyclase-independent mechanisms is more important, because it mediates relaxation in response to low concentrations of NO donor. The role of soluble guanylate cyclase-dependent mechanisms in the mechanisms of vasodilatation increases with increasing NO donor concentrations.


Asunto(s)
Óxido Nítrico/metabolismo , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiología , Animales , GMP Cíclico/metabolismo , Guanilato Ciclasa/metabolismo , Masculino , Donantes de Óxido Nítrico/metabolismo , Canales de Potasio/metabolismo , Ratas , Guanilil Ciclasa Soluble/metabolismo , Vasodilatación/fisiología
20.
J Headache Pain ; 20(1): 47, 2019 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-31053059

RESUMEN

BACKGROUND: Racemic isometheptene [(RS)-isometheptene] is an antimigraine drug that due to its cardiovascular side-effects was separated into its enantiomers, (R)- and (S)-isometheptene. This study set out to characterize the contribution of each enantiomer to its vasoactive profile. Moreover, rat neurogenic dural vasodilatation was used to explore their antimigraine mechanism of action. METHODS: Human blood vessel segments (middle meningeal artery, proximal and distal coronary arteries, and saphenous vein) were mounted in organ baths and concentration response curves to isometheptene were constructed. Calcitonin gene-related peptide (CGRP)-induced neurogenic dural vasodilation was elicited in the presence of the enantiomers using a rat closed cranial window model. RESULTS: The isometheptene enantiomers did not induce any significant contraction in human blood vessels, except in the middle meningeal artery, when they were administered at the highest concentration (100 µM). Interestingly in rats, (S)-isometheptene induced more pronounced vasopressor responses than (R)-isometheptene. However, none of these compounds affected the CGRP-induced vasodilator responses. CONCLUSION: The isometheptene enantiomers displayed a relatively safe peripheral vascular profile, as they failed to constrict the human coronary artery. These compounds do not appear to modulate neurogenic dural CGRP release, therefore, their antimigraine site of action remains to be determined.


Asunto(s)
Vasos Coronarios/efectos de los fármacos , Arterias Meníngeas/efectos de los fármacos , Metilaminas/farmacología , Trastornos Migrañosos , Vena Safena/efectos de los fármacos , Adulto , Animales , Péptido Relacionado con Gen de Calcitonina/farmacología , Vasos Coronarios/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Arterias Meníngeas/fisiología , Metilaminas/química , Metilaminas/uso terapéutico , Persona de Mediana Edad , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/fisiopatología , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-Dawley , Vena Safena/fisiología , Estereoisomerismo , Vasoconstrictores/química , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Vasodilatadores/química , Vasodilatadores/farmacología
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