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1.
Biol Pharm Bull ; 42(10): 1741-1745, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582662

RESUMO

Our previous studies have shown that phenylephrine-induced contraction of cutaneous arteries is primarily mediated via α1A-adrenoceptors, but not α1D-adrenoceptors that generally mediate vascular contraction, and that the larger part of the contraction is induced in a voltage-dependent Ca2+ channel (VDCC)-independent manner. Here, we investigated the mechanism underlying the smaller part of the α1A-adrenoceptor-mediated contraction, i.e., VDCC-dependent one, in cutaneous arteries. Isometric contraction was measured with wire myograph in endothelium-denuded tail and iliac arterial rings isolated from male Wistar rats. LOE908 (10 µM), a cation channel blocker, partially inhibited the contraction induced by phenylephrine in tail and iliac arteries. Nifedipine (10 µM) further suppressed the phenylephrine-induced contraction that remained in the presence of LOE908 (10 µM) in iliac arteries but barely in tail arteries, suggesting that phenylephrine-induced depolarization in tail arteries is due to the activation of LOE908-sensitive cation channels. In iliac arteries, the contraction induced by A-61603, a specific α1A-adrenoceptor agonist, was also partially inhibited by LOE908 (10 µM); however, nifedipine had little effect on the A-61603-induced contraction that remained in the presence of LOE908 (10 µM), suggesting that depolarization mediated via α1A-adrenoceptors is due to the activation of LOE908-sensitive cation channels even in iliac arteries. These results suggest that membrane depolarization mediated via α1Α-adrenoceptors is caused by cation influx through LOE908-sensitive cation channels. Less contribution of VDCC to phenylephrine-induced contraction in tail arteries compared to in iliac arteries is likely due to that α1Α-adrenoceptor-mediated activation of VDCC is caused only by depolarization via cation influx through LOE908-sensitive cation channels.


Assuntos
Canais de Cálcio/fisiologia , Artéria Ilíaca/fisiologia , Receptores Adrenérgicos alfa 1/fisiologia , Cauda/irrigação sanguínea , Acetamidas/farmacologia , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/fisiologia , Imidazóis/farmacologia , Isoquinolinas/farmacologia , Masculino , Nifedipino/farmacologia , Fenilefrina/farmacologia , Ratos Wistar , Cauda/fisiologia , Tetra-Hidronaftalenos/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
2.
J Vasc Res ; 56(6): 320-332, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31550717

RESUMO

BACKGROUND: Perivascular adipose tissue (PVAT) reduces vascular tone in isolated arteries in vitro, however there are no studies of PVAT effects on vascular tone in vivo. In vitro adipocyte ß3-adrenoceptors play a role in PVAT function via secretion of the vasodilator adiponectin. OBJECTIVE: We have investigated the effects of PVAT on vessel diameter in vivo, and the contributions of ß3-adrenoceptors and adiponectin. METHOD: In anaesthetised rats, sections of the intact mesenteric bed were visualised and the diameter of arteries was recorded. Arteries were stimulated with electrical field stimulation (EFS), noradrenaline (NA), arginine-vasopressin (AVP), and acetylcholine (Ach). RESULTS: We report that in vivo, stimulation of PVAT with EFS, NA, and AVP evokes a local anti-constrictive effect on the artery, whilst PVAT exerts a pro-contractile effect on arteries subjected to Ach. The anti-constrictive effect of PVAT stimulated with EFS and NA was significantly reduced using ß3-adrenoceptor inhibition, and activation of ß3-adrenoceptors potentiated the anti-constrictive effect of vessels stimulated with EFS, NA, and AVP. The ß3-adrenoceptor agonist had no effect on mesenteric arteries with PVAT removed. A blocking peptide for adiponectin receptor 1 polyclonal antibody reduced the PVAT anti-constrictive effect in arteries stimulated with EFS and NA, indicating that adiponectin may be the anti-constrictive factor released upon ß3-adrenoceptor activation. CONCLUSIONS: These results clearly demonstrate that PVAT plays a paracrine role in regulating local vascular tone in vivo, and therefore may contribute to the modulation of blood pressure. This effect is mediated via adipocyte ß3-adrenoceptors, which may trigger release of the vasodilator adiponectin.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Artérias Mesentéricas/metabolismo , Comunicação Parácrina , Receptores Adrenérgicos beta 3/metabolismo , Vasoconstrição , Vasodilatação , Tecido Adiposo/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Estimulação Elétrica , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Comunicação Parácrina/efeitos dos fármacos , Ratos Wistar , Receptores Adrenérgicos beta 3/efeitos dos fármacos , Transdução de Sinais , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
3.
Blood Press Monit ; 24(5): 213-220, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31490245

RESUMO

BACKGROUND: Before arterial cannulation for invasive blood pressure monitoring, clinical decision-making depends on non-invasive blood pressure in critically ill patients. Whether non-invasive blood pressure is comparable to invasive measurement is not clearly elucidated. We address this issue as it relates to the use of norepinephrine in patients with cardiogenic shock. METHODS: We analysed invasive and non-invasive blood pressure in 85 patients admitted to the Coronary-Care Unit for cardiogenic shock. We compared initial blood pressure measurement (just after radial artery cannulation) and blood pressure taken during the first 72 hours after admission. Invasive blood pressure was used as the reference method. RESULTS: Initial invasive mean and systolic arterial pressures were in a good agreement with oscillometric blood pressure; mean differences were -0.4 ± 8.8 and +6.1 ± 14.4 mmHg with correlation coefficients of 0.76 and 0.74. Doses of norepinephrine were significant negative determinants of invasive/oscillometric blood pressure differences. The invasive/oscillometric mean arterial pressures and SBP differences were +0.1 ± 3.4 and 7.6 ± 1.6 mmHg in patients treated with nothing or a maximum norepinephrine dose of 0.6 µg/kg/min. However, treatment with very high doses of norepinephrine was associated with a steep rise in mean arterial pressures and SBP invasive/oscillometric differences (-9.5 ± 3.3 and -8.5 ± 5.2 mmHg). In a total of 967 sets of blood pressure measurements, invasive/oscillometric differences were relatively stable across blood pressure categories, with the exception of measurements assessed after very high norepinephrine doses. CONCLUSIONS: Non-invasive BP is a sufficient substitute for invasive measurement in cardiogenic shock patients, with the exception of those receiving very high doses of norepinephrine.


Assuntos
Determinação da Pressão Arterial/métodos , Pressão Sanguínea/efeitos dos fármacos , Norepinefrina/farmacologia , Choque Cardiogênico/fisiopatologia , Vasoconstritores/farmacologia , Idoso , Idoso de 80 Anos ou mais , Pressão Arterial , Cateterismo , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Norepinefrina/administração & dosagem , Oscilometria/métodos , Estudos Prospectivos , Vasoconstritores/administração & dosagem
4.
J Vasc Res ; 56(4): 191-203, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31390638

RESUMO

BACKGROUND: Ca2+ plays an important role in the regulation of vasoconstriction. Ca2+ signaling is regulated by a number of Ca2+-handling proteins. However, whether differences in Ca2+ handling affect the regulation of vasoconstriction in different arteries remains elusive. OBJECTIVE: To determine whether differences in Ca2+ handling affect the response to vasoconstrictors in different arteries. METHODS: Arterial ring contraction was measured using a Multi Myograph System. Vascular smooth muscle cells (VSMCs) were digested with type 2 collagenase in DMEM, then intracellular calcium concentration was measured with the Ca2+ probe fluo-4/AM in the isolated cells. Calcium-related proteins were assayed by Western blotting. RESULTS: Phenylephrine did not induce -coronary arterial contraction. There were differences in -5-hydroxytryptamine, 9,11-dideoxy-11a,9a-epoxymethano-prostaglandin F2a, and endothelin 1-induced vasoconstriction in different solutions between coronary and renal arteries. Vasoconstrictions in the presence of Bay K8644 were stronger in coronary than in renal arteries. Store-operated calcium (SOC) channels could mediate Ca2+ influx in VSMCs of both groups. SOC channels did not participate in the contraction of coronary arteries. In addition, there were significant differences in the expressions of receptors and ion channels between the two groups. CONCLUSIONS: Ca2+ handling contributed to the different responses to vasoconstrictors between coronary and renal arteries.


Assuntos
Sinalização do Cálcio , Cálcio , Vasos Coronários/metabolismo , Artéria Renal/metabolismo , Vasoconstrição , Animais , Sinalização do Cálcio/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Técnicas In Vitro , Masculino , Ratos Wistar , Artéria Renal/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
5.
Kidney Blood Press Res ; 44(4): 792-809, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430751

RESUMO

OBJECTIVE: We evaluated the hypothesis that the development of renal dysfunction and congestive heart failure (CHF) caused by volume overload in rats with angiotensin II (ANG II)-dependent hypertension is associated with altered renal vascular responsiveness to ANG II and to epoxyeicosatrienoic acids (EETs). METHODS: Ren-2 transgenic rats (TGRs) were used as a model of ANG II-dependent hypertension. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF). Renal blood flow (RBF) responses were determined to renal arterial administration of ANG II, native 11,12-EET, an analog of 14,15-EETs (EET-A), norepinephrine (NE), acetylcholine (Ach) and bradykinin (Bk) in healthy (i.e., sham-operated) TGR and ACF TGR (5 weeks after ACF creation). RESULTS: Selective intrarenal administration of neither vasoactive drug altered mean arterial pressure in any group. Administration of ANG II caused greater decreases in RBF in ACF TGR than in sham-operated TGR, whereas after administration of NE the respective decreases were comparable in the 2 groups. Administration of Ach and Bk elicited significantly higher RBF increases in ACF TGR as compared with sham-operated TGR. In contrast, administration of 11,12-EET and EET-A caused significantly smaller RBF increases in ACF TGR than in sham-operated TGR. CONCLUSION: The findings show that 5 weeks after creation of ACF, the TGR exhibit exaggerated renal vasoconstrictor responses to ANG II and reduced renal vasodilatory responses to EETs, suggesting that both these alterations might play an important role in the development of renal dysfunction in this model of CHF.


Assuntos
Angiotensina II/efeitos adversos , Insuficiência Cardíaca/complicações , Hipertensão/induzido quimicamente , Circulação Renal/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Fístula Artério-Arterial/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Hipertensão/complicações , Artéria Pulmonar/anormalidades , Artéria Pulmonar/fisiopatologia , Ratos , Ratos Transgênicos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
6.
Cir Cir ; 87(5): 580-586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31448774

RESUMO

Monitoring of the neurocritical in the perioperatory is in constant evolution. There are essentially two ultrasonographic application of neuromonitoring: the diameter of the sheath of the optic nerve and transcranial Doppler. Ultrasound-guided neuromonitoring can detect stenosis or occlusion of intracranial arteries, monitor the evolution of patients with vasospasm after subarachnoid hemorrhage, detect cerebral embolism, evaluate the cerebral collateral system, determine brain death, calculate indirectly Intracranial pressure and cerebral perfusion and helps in clinical decisions and early therapeutic interventions in neurocritical care. The purpose of this review is to present the applications of ultrasonography to the head of the patient in neuromonitoring.


Assuntos
Transtornos Cerebrovasculares/diagnóstico por imagem , Monitorização Neurofisiológica Intraoperatória/métodos , Neuroimagem/métodos , Nervo Óptico/diagnóstico por imagem , Assistência Perioperatória/métodos , Ultrassonografia Doppler Transcraniana , Morte Encefálica/diagnóstico por imagem , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Circulação Cerebrovascular/efeitos dos fármacos , Tomada de Decisão Clínica , Humanos , Pressão Intracraniana , Órbita/diagnóstico por imagem , Fluxo Pulsátil , Hemorragia Subaracnóidea/diagnóstico por imagem , Vasoconstritores/farmacologia , Vasoespasmo Intracraniano/diagnóstico por imagem
7.
Life Sci ; 234: 116792, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31465733

RESUMO

AIMS: Assisted reproductive technologies (ART) have been widely used to treat infertility, which may impact on fetuses and offspring. This study investigated the effects of in vitro fertilization-embryo transfer (IVF-ET) on angiotensin II (AII)-mediated vasoconstrictions in umbilical cord vein, and explored possible reprogrammed methylation mechanism. MATERIALS AND METHODS: Human umbilical cords were randomly divided into ordinary pregnancy and IVF-ET pregnancy. Vascular studies with AII as well as its specific receptor antagonists losartan and PD123,319 were conducted. Real-time quantitative PCR, Western blotting, and methylation analysis by bisulfite sequencing were performed with the cord vessel samples. KEY FINDINGS: In IVF-ET group, the maximal response to AII in umbilical vessels was significantly greater than that in the ordinary pregnancy. Using losartan and PD123,319, angiotensin receptor subtype 1 (AT1R) was found mainly responsible for the enhanced contraction in the umbilical vein of IVF-ET pregnancy. Decreased mRNA expression of DNMT3A was found in umbilical vein of IVF-ET group. Hypomethylation of the AGTR1 gene (gene encoding AT1R) in the umbilical veins of the IVF group was found. The data suggested that the IVF-ET treatments altered AII-mediated vasoconstrictions in umbilical veins, which could be partially attributed to the increased expression of AT1R. SIGNIFICANCE: The hypo-methylation of the AGTR1 gene caused by IVF-ET might play important roles in altered vasoconstrictions, impacting on cardiovascular systems in the long run.


Assuntos
Angiotensina II/metabolismo , Metilação de DNA , Transferência Embrionária/métodos , Fertilização In Vitro/métodos , Receptor Tipo 1 de Angiotensina/genética , Cordão Umbilical/irrigação sanguínea , Vasoconstrição , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Transferência Embrionária/efeitos adversos , Feminino , Fertilização In Vitro/efeitos adversos , Humanos , Imidazóis/farmacologia , Losartan/farmacologia , Gravidez , Piridinas/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
8.
Int Braz J Urol ; 45(5): 1033-1042, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31408283

RESUMO

Cinnamomum cassia (Cinnamon) is a well-known traditional medicine with therapeutic benefits for centuries. We evaluated the effects of cinnamon essential oil (CEO) and its main component cinnamaldehyde (CA) on human corpus cavernosum (HCC) and rat CC. The essential oil of cinnamon was analyzed for the confirmation of the oil profile. HCC specimens from patients undergoing penile prosthesis surgery (age 48-69 years) were utilized for functional studies. In addition, erectile responses in anesthetized control and diabetic rats were evaluated in vivo after intracavernosal injection of CEO and CA, and rat CC strips were placed in organ baths. After precontraction with phenylephrine (10µM), relaxant responses to CEO and CA were investigated. CA (96.9%) was found as the major component. The maximum relaxation responses to CEO and CA were 96.4±3.5% and 96.0±5.0% in HCC and 97.5±5.5% and 96.8±4.8% in rat CC, respectively. There was no difference between control and diabetic rats in relaxation responses to CEO and CA. The relaxant responses obtained with essential oil and CA were not attenuated in the presence of nitric oxide synthase (NOS) inhibitor, and soluble guanylate cyclase inhibitor (sGS) in CC. In vivo, erectile responses in diabetic rats were lower than in control rats, which was restored after intracavernosal injection of CEO and CA. CEO and CA improved erectile function and relaxation of isolated strips of rat CC and HCC by a NO/cGMP-independent mechanism. Further investigations are warranted to fully elucidate the restorative effects of CEO and CA on diabetic erectile dysfunction.


Assuntos
Acroleína/análogos & derivados , Cinnamomum zeylanicum/química , Relaxamento Muscular/efeitos dos fármacos , Óleos Voláteis/farmacologia , Pênis/efeitos dos fármacos , Acroleína/farmacologia , Idoso , Análise de Variância , Animais , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/fisiologia , Ereção Peniana/efeitos dos fármacos , Ereção Peniana/fisiologia , Pênis/fisiopatologia , Fenilefrina/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Citrato de Sildenafila/farmacologia , Vasoconstritores/farmacologia
9.
J Pharmacol Sci ; 140(2): 205-209, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262461

RESUMO

The cardio-ankle vascular index (CAVI) has been established as a stiffness indicator from thoracic aorta to tibial arteries. To better understand physiological regulatory factors for the arterial stiffness, we assessed effects of angiotensin II and adrenaline on the CAVI in anesthetized rabbits. A hypertensive dose of angiotensin II (300 ng/kg, i.v.) increased the CAVI as well as the heart-ankle pulse wave velocity (haPWV). On the other hand, although a hypertensive dose of adrenaline (1000 ng/kg, i.v.) increased the haPWV, it did not affect the CAVI. These results suggest that angiotensin II may act as a regulatory factor for arterial stiffness.


Assuntos
Angiotensina II/farmacologia , Monitorização Fisiológica , Rigidez Vascular/efeitos dos fármacos , Vasoconstritores/farmacologia , Anestesia , Angiotensina II/fisiologia , Animais , Relação Dose-Resposta a Droga , Epinefrina/farmacologia , Masculino , Análise de Onda de Pulso , Coelhos
10.
Biomed Res Int ; 2019: 6539050, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31309111

RESUMO

Objective: To determine whether the administration of intra-arrest cyclosporine (CCY) and methylprednisolone (MP) preserves left ventricular ejection fraction (LVEF) and cardiac output (CO) after return of spontaneous circulation (ROSC). Methods: Eleven, 25-30kg female swine were randomized to receive 10mg/kg CCY + 40mg MP or placebo, anesthetized and given a transthoracic shock to induce ventricular fibrillation. After 8 minutes, standard CPR was started. After two additional minutes, the experimental agent was administered. Animals with ROSC were supported for up to 12h with norepinephrine as needed. Echocardiography was performed at baseline, and 1, 2, 6 and 12h post-ROSC. Analysis was performed using generalized estimating equations (GEE) after downsampling continuously sampled data to 5 minute epochs. Results: Eight animals (64%) achieved ROSC after a median of 7 [IQR 5-13] min of CPR, 2 [ IQR 1-3] doses of epinephrine and 2 [IQR 1-5] defibrillation shocks. Animals receiving CCY+MP had higher post ROSC MAP (GEE coefficient -10.2, P = <0.01), but reduced cardiac output (GEE coefficient 0.8, P = <0.01) compared to placebo. There was no difference in LVEF or vasopressor use between arms. Conclusions: Intra-arrest cyclosporine and methylprednisolone decreased post-arrest cardiac output and increased mean arterial pressure without affecting left ventricular ejection fraction.


Assuntos
Cardiomiopatias/tratamento farmacológico , Ciclosporina/farmacologia , Parada Cardíaca/tratamento farmacológico , Metilprednisolona/farmacologia , Animais , Débito Cardíaco/efeitos dos fármacos , Reanimação Cardiopulmonar/métodos , Ecocardiografia/métodos , Cardioversão Elétrica/métodos , Epinefrina/farmacologia , Feminino , Ventrículos do Coração/efeitos dos fármacos , Suínos , Vasoconstritores/farmacologia , Fibrilação Ventricular/tratamento farmacológico
11.
Int J Mol Sci ; 20(14)2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31336656

RESUMO

Brain natriuretic peptide (BNP) is an important biomarker for patients with heart failure, hypertension and cardiac hypertrophy. Although it is known that BNP levels are relatively higher in patients with chronic kidney disease and no heart disease, the mechanism remains unknown. Here, we review the functions and the roles of BNP in the heart-kidney interaction. In addition, we discuss the relevant molecular mechanisms that suggest BNP is protective against chronic kidney diseases and heart failure, especially in terms of the counterparts of the renin-angiotensin-aldosterone system (RAAS). The renal medulla has been reported to express depressor substances. The extract of the papillary tips from kidneys may induce the expression and secretion of BNP from cardiomyocytes. A better understanding of these processes will help accelerate pharmacological treatments for heart-kidney disease.


Assuntos
Coração/fisiologia , Rim/fisiologia , Peptídeo Natriurético Encefálico/metabolismo , Transdução de Sinais , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Animais , Suscetibilidade a Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Peptídeo Natriurético Encefálico/genética , Neprilisina/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasoconstritores/uso terapêutico
12.
Life Sci ; 231: 116580, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31216440

RESUMO

AIMS: Chemerin has been recently identified as a vasoactive adipokine implicated in blood pressure regulation. In this context, we evaluated whether chemerin could influence pulmonary vasoreactive response. MATERIALS AND METHODS: Vascular reactivity to chemerin and to phenylephrine, serotonin and endothelin-1 after chemerin pretreatment was evaluated in rat isolated pulmonary artery versus thoracic aorta with and without endothelium. Vasoreactivity to acetylcholine in presence of nitric oxide (NO)-synthase inhibitor (L-NAME) and to NO donor sodium nitroprusside (SNP) was evaluated in chemerin-pretreated pulmonary artery versus thoracic aorta with endothelium. Pretreatment with ODQ, a soluble guanylate cyclase inhibitor and apocynin, a ROS production inhibitor, were also tested. Arteries and lung tissue were harvested for pathobiological evaluation. KEY FINDINGS: Chemerin contracted endothelium-denuded pulmonary artery, while no response was observed in arteries with endothelium. Chemerin potentiated phenylephrine-, endothelin-1- and serotonin-induced vasoconstriction, which was further enhanced by endothelium removal. Chemerin decreased acetylcholine-induced vasorelaxation in arteries with endothelium, while it did not affect SNP-induced relaxation. In presence of L-NAME, there remained a vasorelaxation in chemerin-pretreated arteries. Chemerin or ODQ alone partly decreased acetylcholine-induced vasorelaxation in pulmonary artery and thoracic aorta, while combined chemerin and ODQ incubation abolished it. Treatment with apocynin partly or totally reversed chemerin effects. In both types of arteries, chemerin reduced acetylcholine-induced NO production, as well as endothelial and inducible NO-synthase expression. SIGNIFICANCE: Chemerin potentiates vascular responses to vasoconstrictors in pulmonary artery and thoracic aorta and, impairs acetylcholine-induced pulmonary artery vasodilatation, by mechanisms involving at least partly NO signaling and oxidative stress.


Assuntos
Quimiocinas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Artéria Pulmonar/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Acetilcolina/farmacologia , Adipocinas/metabolismo , Animais , Quimiocinas/metabolismo , Endotelina-1/metabolismo , Endotelinas/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Nitroprussiato/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenilefrina/farmacologia , Artéria Pulmonar/metabolismo , Ratos , Ratos Wistar , Serotonina/metabolismo , Artérias Torácicas/efeitos dos fármacos , Artérias Torácicas/metabolismo , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos
13.
EBioMedicine ; 44: 574-581, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31175056

RESUMO

BACKGROUND: Pre-eclampsia is a leading cause of maternal mortality and morbidity. Although the exact mechanisms that cause pre-eclampsia remain unclear, it is undeniable that abnormal placental function and circulation are a center for initiation pre-eclampsia. As a potent vasoconstrictor, arginine vasopressin (AVP) has long been implicated in controlling placental vascular tone and circulation; its secretion is grossly elevated in pre-eclamptic circulation. However, little is known about the reactivity of AVP in pre-eclamptic placental vasculature. METHODS: To reveal the special features of placental vascular regulations with placental pathophysiological changes, as well as the corresponding molecular mechanisms under pre-eclamptic conditions, vascular function and molecular assays were conducted with placental vessel samples from normal and pre-eclamptic pregnancies. FINDINGS: The present study found that vasoconstriction responses of placental vessels to AVP were attenuated in pre-eclampsia as compared to in normal pregnancy. The insensitivity of AVP was correlated with the down-regulated AVP receptor 1a (AVPR1A, AVPR1A gene) and protein kinase C isoform ß (PKCß, PKCΒ gene), particularly the hyper-methylation-mediated AVPR1A and PKCΒ gene down-regulation, respectively. INTERPRETATION: The findings collectively revealed that aberrant DNA methylation-mediated gene expressions are correlated with vascular dysfunction in pre-eclamptic placental circulation. FUND: This work was supported by National Nature & Science Foundation of China. "333 Project", "Six one project", "Shuang Chuang Tuan Dui" and Key Discipline "Fetal medicine" of Jiangsu Province, and the Suzhou city "Wei Sheng Ren Cai" program.


Assuntos
Arginina Vasopressina/farmacologia , Metilação de DNA , Resistência a Medicamentos/genética , Placenta/irrigação sanguínea , Placenta/efeitos dos fármacos , Pré-Eclâmpsia/etiologia , Proteína Quinase C beta/genética , Receptores de Vasopressinas/genética , Arginina Vasopressina/uso terapêutico , Ilhas de CpG , Feminino , Humanos , Placenta/metabolismo , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/metabolismo , Gravidez , Regiões Promotoras Genéticas , Proteína Quinase C beta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasoconstritores/uso terapêutico
14.
J Steroid Biochem Mol Biol ; 192: 105413, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31202858

RESUMO

In steroid-producing cells, cholesterol transport from the outer to the inner mitochondrial membrane is the first and rate-limiting step for the synthesis of all steroid hormones. Cholesterol can be transported into mitochondria by specific mitochondrial protein carriers like the steroidogenic acute regulatory protein (StAR). StAR is phosphorylated by mitochondrial ERK in a cAMP-dependent transduction pathway to achieve maximal steroid production. Mitochondria are highly dynamic organelles that undergo replication, mitophagy and morphology changes, all processes allowed by mitochondrial fusion and fission, known as mitochondrial dynamics. Mitofusin (Mfn) 1 and 2 are GTPases involved in the regulation of fusion, while dynamin-related protein 1 (Drp1) is the major regulator of mitochondrial fission. Despite the role of mitochondrial dynamics in neurological and endocrine disorders, little is known about fusion/fission in steroidogenic tissues. In this context, the present work aimed to study the role of angiotensin II (Ang II) in protein subcellular compartmentalization, mitochondrial dynamics and the involvement of this process in the regulation of aldosterone synthesis. We demonstrate here that Ang II stimulation promoted the recruitment and activation of PKCε, ERK and its upstream kinase MEK to the mitochondria, all of them essential for steroid synthesis. Moreover, Ang II prompted a shift from punctate to tubular/elongated (fusion) mitochondrial shape, in line with the observation of hormone-dependent upregulation of Mfn2 levels. Concomitantly, mitochondrial Drp1 was diminished, driving mitochondria toward fusion. Moreover, Mfn2 expression is required for StAR, ERK and MEK mitochondrial localization and ultimately for aldosterone synthesis. Collectively, this study provides fresh insights into the importance of hormonal regulation in mitochondrial dynamics as a novel mechanism involved in aldosterone production.


Assuntos
Neoplasias das Glândulas Suprarrenais/metabolismo , Carcinoma Adrenocortical/metabolismo , Angiotensina II/farmacologia , Colesterol/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas Quinases/metabolismo , Vasoconstritores/farmacologia , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/patologia , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Transporte Biológico , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fosforilação , Células Tumorais Cultivadas
15.
J Headache Pain ; 20(1): 47, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053059

RESUMO

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.


Assuntos
Vasos Coronários/efeitos dos fármacos , Artérias Meníngeas/efeitos dos fármacos , Metilaminas/farmacologia , Transtornos de Enxaqueca , Veia Safena/efeitos dos fármacos , Adulto , Animais , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Vasos Coronários/fisiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Artérias Meníngeas/fisiologia , Metilaminas/química , Metilaminas/uso terapêutico , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/fisiopatologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Veia Safena/fisiologia , Estereoisomerismo , Vasoconstritores/química , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/química , Vasodilatadores/farmacologia
16.
Pharmacol Rep ; 71(4): 565-572, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132686

RESUMO

BACKGROUND: Transient receptor potential ankyrin 1 (TRPA1) channels may have a role in migraine as some substances known to cause headache activate the channel. In the craniovascular system such activation causes a calcitonin gene-related peptide (CGRP)-dependent increase in meningeal blood flow. TRPA1 channels in the endothelium of cerebral arteries cause vasodilation when activated. The headache preventive substance feverfew inhibits activation of TRPA1 channels. In this study we aim to compare and characterize the effect of the TRPA1 agonist allyl isothiocyanate (AITC) on the diameter of rat dural and pial arteries in vivo. METHODS: The genuine closed-cranial window technique in rats was used to examine changes in dural and pial artery diameter and mean arterial blood pressure (MABP) after intracarotid infusion of AITC. Blockade experiments were performed by intravenous infusion of olcegepant, HC-030031, sumatriptan or capsazepine immediately after infusion of AITC, in four different groups of rats. RESULTS: AITC caused a significant dilation of dural arteries, which was inhibited by HC-030031, olcegepant and sumatriptan, but not by capsazepine. In pial arteries AITC caused a significant dilation, which was not inhibited by any of the pre-treatments, suggesting a poor penetration of the blood-brain barrier or autoregulation due to dimethyl sulfoxide (DMSO) mediated decrease in MABP during HC-030031 infusion. AITC did not cause a significant change in MABP. CONCLUSION: AITC causes dilation of dural arteries via a mechanism dependent on CGRP and TRPA1 that is sensitive to sumatriptan. AITC causes a small but significant dilation of pial arteries.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Artérias Cerebrais/efeitos dos fármacos , Isotiocianatos/farmacologia , Canal de Cátion TRPA1/agonistas , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Artérias Cerebrais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Infusões Intra-Arteriais , Isotiocianatos/administração & dosagem , Masculino , Ratos Sprague-Dawley , Vasoconstritores/farmacologia , Vasodilatadores/administração & dosagem
17.
Anesth Analg ; 128(6): 1081-1088, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31094772

RESUMO

BACKGROUND: Near-infrared spectroscopy (NIRS) is used worldwide to monitor regional cerebral oxygenation (rScO2) during cardiopulmonary bypass (CPB). Intervention protocols meant to mitigate cerebral desaturation advocate to increase mean arterial pressure (MAP) when cerebral desaturation occurs. However, the isolated effect of MAP on rScO2 is uncertain. The aim of the present study was in a randomized, blinded design to elucidate the effect of 2 distinct levels of MAP on rScO2 values during CPB.We hypothesized that a higher MAP would be reflected in higher rScO2 values, lower frequency of patients with desaturation, and a less pronounced cerebral desaturation load. METHODS: This is a substudy of the Perfusion Pressure Cerebral Infarct trial, in which we investigated the impact of MAP levels during CPB on ischemic brain injury after cardiac surgery. Deviation in rScO2 was a predefined outcome in the Perfusion Pressure Cerebral Infarct trial. Patients were randomized to low MAP (LMAP; 40-50 mm Hg) or high MAP (HMAP; 70-80 mm Hg) during CPB. CPB pump flow was fixed at 2.4 L/min/m, and MAP levels were targeted using norepinephrine. Intraoperatively, NIRS monitoring was performed in a blinded fashion, with sensors placed on the left and right side of the patient's forehead. NIRS recordings were extracted for offline analysis as the mean value of left and right signal during prespecified periods. Mean rScO2 during CPB was defined as the primary outcome in the present study. RESULTS: The average MAP level during CPB was 67 mm Hg ± SD 5.0 in the HMAP group (n = 88) and 45 mm Hg ± SD 4.4 in the LMAP group (n = 88). Mean rScO2 was significantly lower in the HMAP group during CPB (mean difference, 3.5; 95% confidence interval, 0.9-6.1; P = .010). There was no difference in rScO2 values at specified time points during the intraoperative period between the 2 groups. Significantly more patients experienced desaturation below 10% and 20% relative to rScO2 baseline in the HMAP group (P = .013 and P = .009, respectively), and the cerebral desaturation load below 10% relative to rScO2 baseline was more pronounced in the HMAP group (P = .042). CONCLUSIONS: In a randomized blinded study, we observed that a higher MAP induced by vasopressors, with a fixed CPB pump flow, leads to lower mean rScO2 and more frequent and pronounced cerebral desaturation during CPB. The mechanism behind these observations is not clear. We cannot exclude extracranial contamination of the NIRS signal as a possible explanation. However, we cannot recommend increasing MAP by vasoconstrictors during cerebral desaturation because this is not supported by the findings of the present study.


Assuntos
Pressão Arterial , Procedimentos Cirúrgicos Cardíacos , Ponte Cardiopulmonar , Monitorização Intraoperatória/métodos , Oximetria/métodos , Espectroscopia de Luz Próxima ao Infravermelho , Adulto , Idoso , Algoritmos , Circulação Cerebrovascular , Interpretação Estatística de Dados , Método Duplo-Cego , Feminino , Lobo Frontal/patologia , Humanos , Hipóxia , Masculino , Pessoa de Meia-Idade , Oxigênio , Consumo de Oxigênio , Perfusão , Projetos de Pesquisa , Resultado do Tratamento , Vasoconstritores/farmacologia
18.
Intensive Care Med ; 45(6): 844-855, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31062052

RESUMO

PURPOSE: We performed an individual patient data meta-analysis to investigate the possible benefits and harms of vasopressin therapy in adults with septic shock both overall and in pre-defined subgroups. METHODS: Our pre-specified study protocol is published on PROSPERO, CRD42017071698. We identified randomised clinical trials up to January 2019 investigating vasopressin therapy versus any other vasoactive comparator in adults with septic shock. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed as well as one-stage regression models with single treatment covariate interactions for subgroup analyses. RESULTS: Four trials were included with a total of 1453 patients. For the primary outcomes, there was no effect of vasopressin on 28-day mortality [relative risk (RR) 0.98, 95% CI 0.86-1.12] or serious adverse events (RR 1.02, 95% CI 0.82-1.26). Vasopressin led to more digital ischaemia [absolute risk difference (ARD) 1.7%, 95% CI 0.3%-3.2%] but fewer arrhythmias (ARD - 2.8%, 95% CI - 0.2% to - 5.3%). Mesenteric ischaemia and acute coronary syndrome events were similar between groups. Vasopressin reduced the requirement for renal replacement therapy (RRT) (RR 0.86, 95% CI 0.74-0.99), but this finding was not robust to sensitivity analyses. There were no statistically significant interactions in the pre-defined subgroups (baseline kidney injury severity, baseline lactate, baseline norepinephrine requirement and time to study inclusion). CONCLUSIONS: Vasopressin therapy in septic shock had no effect on 28-day mortality although the confidence intervals are wide. It appears safe but with a different side effect profile from norepinephrine. The finding on reduced RRT should be interpreted cautiously. Future trials should focus on long-term outcomes in select patient groups as well as incorporating cost effectiveness analyses regarding possible reduced RRT use.


Assuntos
Choque Séptico/tratamento farmacológico , Vasopressinas/farmacologia , APACHE , Idoso , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Choque Séptico/epidemiologia , Choque Séptico/mortalidade , Sobreviventes , Vasoconstritores/farmacologia , Vasoconstritores/uso terapêutico , Vasopressinas/uso terapêutico
19.
Molecules ; 24(7)2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934724

RESUMO

A single herb can contain multiple constituents with diverse bioactivities. We found that the extract of Citrus unshiu peel (CUP), induced abnormal vasoconstriction responses on the freshly isolated rat aortic rings in vitro. CUP stimulated the vasoconstriction alone, and it suppressed the phenylephrine-stimulated vasoconstriction. We studied the reasons behind this abnormal vasoconstriction pattern. Major constituents of CUP were determined and evaluated for their vaso-activities. Notably, synephrine, a contractile agonist, and nobiletin, newly identified to have anti-contractile activity co-existed in CUP. Synephrine and nobiletin competitively blocked or activated the same contractile targets resulting in contradicting and abnormal vasoconstriction responses. Accordingly, the vasoconstriction pattern varies significantly depending on the relative contents of synephrine and nobiletin in CUP. Interestingly, this response pattern could be observed with another plant extract, Acorus gramineus Sol. Collectively, we demonstrated that active ingredients with contradicting bioactivities could co-exist in a single plant extract, interact and produce abnormal response patterns in bioassay, which would give an important insight into the interpretation of unusual activity patterns induced by plant extracts.


Assuntos
Anti-Hipertensivos/farmacologia , Citrus/química , Flavonas/farmacologia , Extratos Vegetais/farmacologia , Sinefrina/farmacologia , Vasoconstritores/farmacologia , Anti-Hipertensivos/química , Flavonas/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Sinefrina/química , Vasoconstritores/química
20.
Transfusion ; 59(S2): 1568-1577, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30980740

RESUMO

BACKGROUND: We set out to define the impact of collection, processing, and storage on plasma product microparticle (MP) abundance, potential for nitric oxide (NO) scavenging, and vasoactivity. STUDY DESIGN AND METHODS: Three currently US licensed products were tested: liquid plasma (LP), fresh frozen plasma (FFP), and solvent detergent plasma (SDP), along with a product under development, spray-dried solvent detergent plasma (SD-SDP) with/without beads. Vasoactivity was assessed in vitro using rabbit aortic vascular rings; MP abundance was determined by flow cytometry; and NO scavenging capacity/rate was determined using a biochemical NO consumption assay. All samples were analyzed unprocessed and following centrifugation at two speeds (2,500× g to remove platelets, and 25,000× g to remove microparticles). RESULTS: Significant differences in vasoactivity were observed, with SD-SDP minus beads demonstrating the greatest constriction and FFP the lowest constriction response. All products exhibited the same total NO scavenging capacity; however, significant differences were observed in the maximal rate of scavenging, with SD-SDP minus beads and FFP reacting fastest and SDP the slowest. Across all products, platelet and microparticle depletion had no effect on vasoactivity or NO scavenging (total or rate). Microparticles (RBC derived) were found only in FFP and LP, with relative abundance (LP > FFP). Additionally, storage had no effect on total or RBC-derived MP abundance, NO scavenging, or vasoactivity. CONCLUSION: Although vasoactivity differed between plasma products, we did not find similar differences in either total or RBC-derived MP abundance or NO scavenging capacity/rate.


Assuntos
Aorta/metabolismo , Preservação de Sangue , Micropartículas Derivadas de Células/química , Eritrócitos/química , Depuradores de Radicais Livres , Plasma/química , Vasoconstritores , Animais , Aorta/fisiopatologia , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/farmacologia , Humanos , Óxido Nítrico/metabolismo , Coelhos , Vasoconstritores/química , Vasoconstritores/farmacologia
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