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1.
World J Gastroenterol ; 25(39): 5953-5960, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31660032

RESUMO

BACKGROUND: Portal hypertension (PHT) is primarily caused by an increase in resistance to portal outflow and secondarily by an increase in splanchnic blood flow. Vascular hyporeactivity both in systemic circulation and in the mesenteric artery plays a role in the hyperdynamic circulatory syndrome. AIM: To explore gender differences and the role of endogenous sex hormones in PHT and vascular reactivity of mesenteric arterioles in rats. METHODS: Cirrhosis and PHT were established by subcutaneous injection of carbon tetrachloride (CCl4) in both male and female integral and castrated rats (ovariectomized [OVX] in female rats, orchiectomy [ORX] in male rats). The third-order branch of the mensenteric artery was divided and used to measure vascular reactivity to vasoconstrictors. RESULTS: No significant difference in portal pressure was observed between integral and castrated male PHT rats (15.2 ± 2.1 mmHg vs 16.7 ± 2.7 mmHg, P > 0.05). The portal pressure in integral female PHT rats was lower than that in OVX female PHT rats (12.7 ± 2.7 mmHg vs 16.5 ± 2.4 mmHg, P < 0.05). In PHT rats, the concentration response curves of the mesenteric arterioles to norepinephrine were shifted to the right, and the maximal responses (Emax) values were decreased and effective concentrations causing half maximum responses (EC50) values were increased, compared to those of non-PHT rats, both in male and female rats. Compared to non-PHT integral male rats, the sensitivity of the mesenteric arterioles of non-PHT ORX male rats to norepinephrine was decreased (P > 0.05). However, there was no difference between integral and ORX male rats with PHT. In integral female PHT rats, the concentration response curves were shifted to the left (P < 0.05), and the Emax values were increased and EC50 values were decreased compared to OVX female PHT rats. CONCLUSION: Clear gender differences were observed in mesenteric vascular reactivity in CCl4-induced cirrhotic and PHT rats. Conservation of estrogen can retain the sensitivity of the mesenteric arterioles to vasoconstrictors and has a protective effect on splanchnic vascular function in PHT.


Assuntos
Arteríolas/fisiologia , Hormônios Esteroides Gonadais/metabolismo , Hipertensão Portal/fisiopatologia , Cirrose Hepática Experimental/fisiopatologia , Resistência Vascular/fisiologia , Animais , Arteríolas/efeitos dos fármacos , Tetracloreto de Carbono/toxicidade , Feminino , Humanos , Hipertensão Portal/induzido quimicamente , Hipertensão Portal/metabolismo , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Pressão na Veia Porta/efeitos dos fármacos , Pressão na Veia Porta/fisiologia , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Circulação Esplâncnica/efeitos dos fármacos , Circulação Esplâncnica/fisiologia , Resistência Vascular/efeitos dos fármacos , Vasoconstritores/administração & dosagem
2.
Med Arch ; 73(3): 157-162, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31391706

RESUMO

Introduction: Hypertension is significantly contributing to global mortality and morbidity and has been identified as the most important modifiable risk factor for early development of cardiovascular diseases (CVD). Aim: The aim of this study was to investigate the efficacy of different combinations of antihypertensive therapy on blood pressure, arterial stiffness and peripheral resistance in patients with essential hypertension using the brachial oscillometric ambulatory blood pressure monitor. Methods: This study was designed as an observational, prospective, multi centric study conducted in eight primary care centers of the Health Center of Canton Sarajevo during the period of six months. The study included 655 participants, both genders, aged between 30 and 75, who were diagnosed with hypertension according to the ESC/ESH guidelines. Participants were divided into six treatment groups based on the hypertensive drug therapy they were using; lisinopril, losartan or valsartan alone or in combination with hydrochlorothiazide (A, B and C group respectively) or combination of lisinopril, losartan or valsartan with/without hydrochlorothiazide together with amlodipine (D, E and F respectively). The participants were monitored at baseline, after 3 and 6 months (1st and 2nd follow-up). Brachial oscillometric ambulatory blood pressure monitor was used for measuring systolic (SBP), diastolic (DBP), pulse pressure (PP), pulse wave velocity (PWV) and peripheral resistance (PR). Results: SBP, DPB, PP, and PWV significantly decreased from baseline to 2nd follow-up in all treatment groups. The mean reductions in SBP were from -11.7 (95%CI; 9.3- 14.1) to -23.2 (95%CI; 18.3-28.1) mmHg and DBP reductions varied from -5.5 (95%CI; 3.9- 7.1) to -13.4 (95%CI; 7.7-19.1) mmHg. PWV decreased in all treatment groups (from -3.3% to -8.2%). Treatment regiment was not associated with significant differences in SBP, DBP, PP or PWV reductions or their values measured at 2nd follow-up. Peripheral resistance significantly decreased only in group C (p=0.011), group D (p=0.009) and group F (p=0.027). Conclusion: These data suggest that lisinopril/lisinopril + hydrochlorothiazide, losartan/losartan + hydrochlorothiazide and valsartan/valsartan + hydrochlorothiazide alone or in combination with amlodipine are equally effective and well tolerated for the reduction of both systolic and diastolic blood pressure and improve arterial stiffness in patients with essential hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Rigidez Vascular/efeitos dos fármacos , Idoso , Anlodipino/farmacologia , Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Artérias , Diástole/efeitos dos fármacos , Combinação de Medicamentos , Hipertensão Essencial/tratamento farmacológico , Feminino , Humanos , Hidroclorotiazida/farmacologia , Hidroclorotiazida/uso terapêutico , Lisinopril/farmacologia , Lisinopril/uso terapêutico , Losartan/farmacologia , Losartan/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Onda de Pulso , Sístole/efeitos dos fármacos , Valsartana/farmacologia , Valsartana/uso terapêutico
3.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31443094

RESUMO

Urocortin 2 (Ucn2) - corticotropin-releasing hormone receptor 2 signalling has favourable effects in the cardiovascular system, including vasodilation, lowering of blood pressure and systemic peripheral resistance, increase in cardiac output and cardiac contractility, as well as cardioprotection against ischemia-reperfusion injury. Vasodilation and lowering of blood pressure seem to be very interesting and important effects, but their mechanism and interaction with the antihypertensive drugs have not been evaluated. The aim of the present study was to assess the relationship between Ucn2 concentration and antihypertensive therapy in patients with primary hypertension. We examined a group of 65 patients with primary hypertension receiving at least 3 antihypertensive drugs. In all of them plasma level of Ucn2, anthropometric measurements, biochemical tests, ambulatory blood pressure monitoring (ABPM), and echocardiography were performed. There were no differences in Ucn2 level related to beta-blockers, calcium channel blockers or diuretics, but we observed that in patients treated with angiotensin converting enzyme inhibitors (ACEI) (n = 52) serum Ucn2 levels were significantly higher than in patients treated with angiotensin-receptor blockers (ARBs) (n = 13) (10.93 versus 5.56 ng/mL; P < 0.05). Moreover, we did not observe any differences in terms of blood pressure on ABPM, biochemical measurements, left ventricular mass index, or presence of diabetes. In addition, in a small subgroup receiving alpha-blockers we also found a lower level of Ucn2, with coexisting higher systolic blood pressure at night, higher left ventricle mass index (LVMI) and more frequent occurrences of diabetes compared to non-alpha-blockers. Our findings suggest that the hypotensive action of renin-angiotensin-aldosterone system blockade may be related to the urocortin system. Ucn2 may be an important element in the mosaic of blood pressure-lowering factors in patients treated for essential hypertension.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Hormônio Liberador da Corticotropina/metabolismo , Hipertensão/tratamento farmacológico , Urocortinas/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Monitorização Ambulatorial da Pressão Arterial/métodos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Feminino , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Humanos , Hipertensão/metabolismo , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos
4.
PLoS One ; 14(7): e0213414, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291253

RESUMO

In acidosis, catecholamines are attenuated, and higher doses are often required to improve cardiovascular function. Colforsin activates adenylate cyclase in cardiomyocytes without beta-adrenoceptor. Here, six beagles were administered colforsin or dobutamine four times during eucapnia (partial pressure of arterial carbon dioxide 35-40 mm Hg; normal) and hypercapnia (ibid 90-110 mm Hg; acidosis) conditions. The latter was induced by CO2 inhalation. Anesthesia was induced with propofol and maintained with isoflurane. Cardiovascular function was measured by thermodilution and a Swan-Ganz catheter at baseline and 60 min after 0.3 µg/kg/min (low), 0.6 µg/kg/min (middle), and 1.2 µg/kg/min (high) colforsin administration. The median pH was 7.38 [range 7.33-7.42] and 7.01 [range 6.96-7.08] at baseline in the Normal and Acidosis conditions, respectively. Endogenous adrenaline and noradrenaline levels at baseline were significantly (P < 0.05) higher in the Acidosis than in the Normal condition. Colforsin induced cardiovascular effects similar to those caused by dobutamine. Colforsin increased cardiac output in the Normal condition (baseline: 3.9 ± 0.2 L/kg/m2 [mean ± standard error], low: 5.2 ± 0.4 L/kg/min2, middle: 7.0 ± 0.4 L/kg/m2, high: 9.4 ± 0.2 L/kg/m2; P < 0.001) and Acidosis condition (baseline: 6.1 ± 0.3 L/kg/m2, low: 6.2 ± 0.2 L/kg/m2, middle: 7.2 ± 0.2 L/kg/m2, high: 8.3 ± 0.2 L/kg/m2; P < 0.001). Colforsin significantly increased heart rate and decreased systemic vascular resistance compared to values at baseline. Both drugs increased pulmonary artery pressure, but colforsin (high: 13.3 ± 0.6 mmHg in Normal and 20.1 ± 0.2 mmHg in Acidosis) may have lower clinical impact on the pulmonary artery than dobutamine (high: 19.7 ± 0.6 in Normal and 26.7 ± 0.5 in Acidosis). Interaction between both drugs and experimental conditions was observed in terms of cardiovascular function, which were similarly attenuated with colforsin and dobutamine under acute respiratory acidosis.


Assuntos
Acidose Respiratória/tratamento farmacológico , Cardiotônicos/administração & dosagem , Colforsina/análogos & derivados , Acidose Respiratória/fisiopatologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Catecolaminas/sangue , Colforsina/administração & dosagem , Modelos Animais de Doenças , Dobutamina/administração & dosagem , Cães , Relação Dose-Resposta a Droga , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Resistência Vascular/efeitos dos fármacos
5.
Hypertension ; 74(1): 201-207, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31188673

RESUMO

Approximately 60% of patients with type 2 diabetes mellitus (T2D) develop hypertension. Recent work also indicates greater blood pressure (BP) excursions throughout the day in T2D. Collectively, these findings suggest altered BP control in T2D. Although muscle sympathetic nerve activity (MSNA) recordings in T2D have provided equivocal results, quantification of MSNA alone does not account for ensuing vasoconstriction and BP responses elicited by MSNA. Thus, we tested the hypothesis that patients with T2D exhibit enhanced sympathetic transduction to BP. MSNA (microneurography) and beat-to-beat BP (Finometer) were measured at rest in 21 T2D and 13 age-matched and body mass index-matched control subjects and, signal-averaging was performed to quantify the mean arterial pressure and total vascular conductance responses to spontaneous bursts of MSNA. The peak mean arterial pressure and total vascular conductance responses to spontaneous MSNA were similar between T2D and control (both P>0.05). However, further analysis, separating T2D into those taking statins (n=13, T2D +statin) and not taking statins (n=8, T2D -statin), indicated that T2D -statin patients (4.2±0.6 mm Hg) exhibited greater peak mean arterial pressure responses compared with both T2D +statin patients (2.5±0.3 mm Hg, P=0.01) and control (control: 2.8±0.3 mm Hg, P=0.02). Likewise, nadir total vascular conductance responses to spontaneous MSNA bursts were greater in T2D -statin patients (T2D -statin: -3.3±0.6 mL/(min·mm Hg), T2D +statin: -1.6±0.3 mL/(min·mm Hg), P=0.03; control -2.2±0.3 mL/(min·mm Hg), P=0.08). Notably, T2D +statin patients exhibited similar peak mean arterial pressure and total vascular conductance responses to MSNA compared with control. Collectively, these findings demonstrate, for the first time, that patients with T2D exhibit augmented sympathetic transduction and this effect seems to be offset by statin therapy.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão/epidemiologia , Sistema Nervoso Simpático/fisiopatologia , Adulto , Fatores Etários , Análise de Variância , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Seguimentos , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Pessoa de Meia-Idade , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença , Sistema Nervoso Simpático/efeitos dos fármacos , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos , Resistência Vascular/fisiologia
6.
Congenit Heart Dis ; 14(4): 645-650, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31166081

RESUMO

OBJECTIVE: The optimal dose of Fasudil is still controversial in congenital heart disease accompanied with severe pulmonary hypertension (CHD-PAH). This study aimed to compare acute hemodynamic changes after different doses of Fasudil in 60 consecutive adult patients with CHD-PAH. DESIGN: Prospective randomized controlled trial. SETTING: Tertiary cardiology center. PATIENTS: Adult patients with CHD-PAH. INTERVENTIONS: Patients were randomized to Fasudil 30 or 60 mg. OUTCOME MEASURES: The hemodynamic parameters were measured at baseline and after 30 minutes of Fasudil through right cardiac catheterization. Blood gas results were obtained from the pulmonary artery, right ventricle, right atrium, superior and inferior vena cava, and femoral artery. Pulmonary vascular resistance (PVR) and systemic arterial resistance (SVR) were calculated. RESULTS: The changes in systolic pulmonary artery pressure (sPAP) (-13.1% vs -9.3%, P < .05), diastolic PAP (dPAP) (-17.6% vs -14.5%, P < .05), mean PAP (mPAP) (-12.4% vs -8.5%, P < .05), and PVR (-35.8% vs -22.2%, P < .05) were more pronounced in the 60-mg group than in the 30-mg group. All patients had no obvious adverse reactions related to peripheral blood pressure. CONCLUSIONS: Fasudil could improve the hemodynamics of patients with CHD-PAH, especially with the 60-mg dose. There were no serious adverse reactions.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Pressão Sanguínea/fisiologia , Cardiopatias Congênitas/tratamento farmacológico , Hipertensão Pulmonar/tratamento farmacológico , Resistência Vascular/efeitos dos fármacos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/administração & dosagem , Adolescente , Adulto , Pressão Sanguínea/efeitos dos fármacos , Cateterismo Cardíaco , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/fisiopatologia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores de Proteínas Quinases/administração & dosagem , Resultado do Tratamento , Resistência Vascular/fisiologia , Adulto Jovem
8.
Nat Rev Cardiol ; 16(9): 555-574, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31123340

RESUMO

Testosterone is the main male sex hormone and is essential for the maintenance of male secondary sexual characteristics and fertility. Androgen deficiency in young men owing to organic disease of the hypothalamus, pituitary gland or testes has been treated with testosterone replacement for decades without reports of increased cardiovascular events. In the past decade, the number of testosterone prescriptions issued for middle-aged or older men with either age-related or obesity-related decline in serum testosterone levels has increased exponentially even though these conditions are not approved indications for testosterone therapy. Some retrospective studies and randomized trials have suggested that testosterone replacement therapy increases the risk of cardiovascular disease, which has led the FDA to release a warning statement about the potential cardiovascular risks of testosterone replacement therapy. However, no trials of testosterone replacement therapy published to date were designed or adequately powered to assess cardiovascular events; therefore, the cardiovascular safety of this therapy remains unclear. In this Review, we provide an overview of epidemiological data on the association between serum levels of endogenous testosterone and cardiovascular disease, prescription database studies on the risk of cardiovascular disease in men receiving testosterone therapy, randomized trials and meta-analyses evaluating testosterone replacement therapy and its association with cardiovascular events and mechanistic studies on the effects of testosterone on the cardiovascular system. Our aim is to help clinicians to make informed decisions when considering testosterone replacement therapy in their patients.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Terapia de Reposição Hormonal , Testosterona/sangue , Testosterona/uso terapêutico , Animais , Aterosclerose/diagnóstico por imagem , Plaquetas/fisiologia , Débito Cardíaco/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/mortalidade , Vasos Coronários , Progressão da Doença , Prescrições de Medicamentos/estatística & dados numéricos , Endotélio/fisiopatologia , Tolerância ao Exercício/efeitos dos fármacos , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos , Lipoproteínas/sangue , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Testosterona/farmacologia , Resistência Vascular/efeitos dos fármacos
9.
Am J Vet Res ; 80(5): 455-460, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31034277

RESUMO

OBJECTIVE: To evaluate the cardiovascular effects of atipamezole administered at half the volume or the same volume as dexmedetomidine to isoflurane-anesthetized cats. ANIMALS: 6 adult (1 to 2 years old) domestic shorthair cats (body weight, 3 to 6 kg). PROCEDURES: Each cat was anesthetized with isoflurane and rocuronium 3 times; there was a 1-week washout period between successive anesthetic procedures. For each anesthetic procedure, dexmedetomidine (5 µg/kg) was administered IV. Five minutes after dexmedetomidine was administered, atipamezole (25 or 50 µg/kg) or saline (0.9% NaCl) solution was administered IM. Pulse rate, mean arterial blood pressure (MAP), cardiac output (CO), and systemic vascular resistance (SVR) were measured during anesthesia before dexmedetomidine administration (baseline), after dexmedetomidine administration, and 15, 30, 60, and 120 minutes after administration of atipamezole or saline solution. Pulse rate and MAP were also recorded when MAP was at its lowest value. Hemodynamic variables were compared among treatments at baseline, after dexmedetomidine administration, and after administration of atipamezole or saline solution. Effects of treatment and time on all variables were assessed with mixed-effects models. RESULTS: Both doses of atipamezole resulted in a significantly lower MAP than did saline solution. Pulse rate, CO, and SVR were not significantly different among treatments after atipamezole or saline solution were administered. CONCLUSIONS AND CLINICAL RELEVANCE: Atipamezole administered IM at half the volume or the same volume as dexmedetomidine was ineffective at increasing pulse rate or CO in anesthetized cats that received dexmedetomidine. However, atipamezole caused short-lasting but severe arterial hypotension.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Anestesia/veterinária , Gatos , Dexmedetomidina/antagonistas & inibidores , Imidazóis/uso terapêutico , Animais , Débito Cardíaco/efeitos dos fármacos , Estudos Cross-Over , Dexmedetomidina/administração & dosagem , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Isoflurano/administração & dosagem , Masculino , Distribuição Aleatória , Resistência Vascular/efeitos dos fármacos
10.
Intern Med ; 58(14): 2045-2049, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30996179

RESUMO

A 72-year-old woman with primary biliary cholangitis was admitted to our hospital with heart failure with a preserved ejection fraction. An accidental right ventricular perforation that occurred during an endomyocardial biopsy precipitated cardiogenic shock. Despite successful surgical treatment, she demonstrated progressive hemodynamic deterioration, which was resistant to the administration of high-dose catecholamines. She was diagnosed with acute adrenal insufficiency, which was attributed to the discontinuation of Celestamine® (betamethasone/dextrochlorpheniramine combination) just after the perforation. Prompt intravenous administration of hydrocortisone (150 mg/day) led to hemodynamic stabilization. The serial noninvasive assessment of systemic vascular resistance using transthoracic echocardiography was instrumental in detecting acute adrenal insufficiency in this case.


Assuntos
Insuficiência Adrenal/tratamento farmacológico , Betametasona/uso terapêutico , Clorfeniramina/uso terapêutico , Insuficiência Cardíaca/fisiopatologia , Hidrocortisona/uso terapêutico , Adesão à Medicação , Resistência Vascular/efeitos dos fármacos , Insuficiência Adrenal/diagnóstico , Idoso , Ecocardiografia , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Choque Cardiogênico/diagnóstico , Choque Cardiogênico/tratamento farmacológico , Resultado do Tratamento
11.
Pregnancy Hypertens ; 15: 141-145, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30825911

RESUMO

OBJECTIVE: The objective of this study was to understand the effect of acetylsalicylic acid (aspirin) on resistance arteries from mesentery and uterus. During pregnancy, the uterine vasculature undergoes consistent growth to provide sufficient uteroplacental blood flow, a process whose failure is associated with pregnancy complications characterized by high uterine vascular resistance. METHODS: Uterine arcuate (UA) and mesenteric arteries (MA; diameter <300 µm) isolated from non-gravid, mid-gravid (day 14), and late-gravid rats (day 20) were exposed to aspirin (10-12 to 10-5 M). Further, in UA from late-gravid rats, aspirin was evaluated in presence of inhibitors of nitric oxide synthases, cyclooxygenase, cyclic nucleotides (cAMP, cGMP) and BK channels, and also on endothelium-denuded vessels. RESULTS: Aspirin dilated both UA and MA in a dose dependent manner. Pregnancy increased aspirin vasodilation in MA and UA from mid-gravid rats, an effect that was reduced in vessels from late gravid animals at concentrations >10-7 M. Further, uterine vasodilation was significantly reduced when the endothelium was removed (p < 0.001), and by inhibitors of nitric oxide synthase (p < 0.001), cyclooxygenase synthase (p < 0.05), cyclic nucleotides cGMP/cAMP and BK channels. CONCLUSION: This is the first study to show a direct vasodilatory effect of aspirin on rat uterine artery that is mediated by a combination of cellular - primarily endothelial - mechanisms. Our results in UA suggest that the use of aspirin may be effective in enhancing uteroplacental blood flow, while its vasodilation effect on MA may lower peripheral resistance.


Assuntos
Aspirina/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Artéria Uterina/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Vasodilatação , Vasodilatadores/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Placenta/irrigação sanguínea , Pré-Eclâmpsia/prevenção & controle , Gravidez , Ratos , Ratos Sprague-Dawley
12.
Am J Cardiol ; 123(10): 1559-1564, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30851939

RESUMO

Diabetes mellitus (DM) increases cardiovascular morbidity and mortality. A statin is routinely prescribed to patients with DM. However, whether a statin therapy is equally effective in plaque stabilization in DM patients compared with non-DM patients is unknown. A total of 117 lipid-rich plaques were imaged in 90 patients (54 plaques in 41 DM patients and 63 plaques in 49 non-DM patients) with coronary artery disease, those who were treated with a statin and underwent serial optical coherence tomography imaging were included in this study (mean follow-up period, 362 ± 38 days). The changes in minimum fibrous cap thickness (FCT) and lipid index between baseline and 1-year follow-up were compared between the 2 groups. Minimum FCT increased and lipid index decreased with statin therapy in both groups. No significant differences were observed in percent changes of minimum FCT (p = 0.796) and lipid index (p = 0.336) between DM and non-DM patients. Statin therapy induced a significant increase in FCT and a significant decrease in lipid index in both groups. Vascular response to statin therapy was similar between the 2 groups irrespective of DM status.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Vasos Coronários/diagnóstico por imagem , Diabetes Mellitus/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Lipídeos/sangue , Resistência Vascular/efeitos dos fármacos , Biomarcadores/sangue , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Imagem Tridimensional , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tomografia de Coerência Óptica/métodos , Resultado do Tratamento , Ultrassonografia de Intervenção/métodos
13.
PLoS One ; 14(3): e0214336, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30893362

RESUMO

Evidence suggests that ethanol-induced hypertension is associated with increased cardiovascular responsiveness to vasopressors in vivo and enhanced reactivity of isolated arteries to vasopressors ex vivo. The underlying mechanisms are not well understood and the contribution of ethanol metabolites to vascular effects induced by ethanol consumption are unclear. Mesenteric resistance arteries were harvested from Sprague-Dawley rats. Pressure myography was utilized to test effects of ethanol, acetaldehyde and phosphatidylethanol on myogenic tone and on vasoconstriction induced by phenylephrine, arginine vasopressin (aVP), endothelin-1 and KCl. Ethanol, acetaldehyde and phosphatidylethanol concentrations were monitored during the experiments. Ethanol concentrations in the vessel bath decreased with a half-life of 25min; acetaldehyde and phosphatidylethanol concentrations remained constant. Pretreatment with ethanol dose-dependently increased the potency of phenylephrine to induce vasoconstriction 4-fold (p<0.01). These effects were comparable when arteries were pre-treated with a single dose of ethanol for 30min and when ethanol concentrations were kept constant during 30min and 60min of pretreatment. While ethanol also dose-dependently increased the potency of aVP to induce vasoconstriction 1.7-fold (p<0.05), it did not affect vasoconstriction induced by endothelin-1 or KCl. Acetaldehyde pre-treatment (30 min) dose-dependently increased the potency of phenylephrine to induce vasoconstriction 2.7-fold (p<0.01) but did not affect other vasoconstrictor responses. Phosphatidylethanol did not affect any vasoconstrictor responses. Ethanol and its metabolites did not affect myogenic tone. These data suggest that ethanol and acetaldehyde selectively sensitize intrinsic constrictor responses upon activation of vascular α1-adrenergic and/or vasopressin receptors at clinically relevant concentrations. Our findings support the concept that enhanced vasoreactivity to vasoactive hormones contributes to the development of hypertension induced by ethanol consumption. Ex vivo exposure of resistance arteries to ethanol and acetaldehyde resembles effects of chronic ethanol consumption on intrinsic vascular function, and thus could serve as test platform to evaluate interventions aimed to mitigate vascular effects associated with ethanol consumption.


Assuntos
Etanol/farmacologia , Artérias Mesentéricas/fisiologia , Resistência Vascular/efeitos dos fármacos , Vasoconstritores/farmacologia , Acetaldeído/farmacologia , Animais , Arginina Vasopressina/farmacologia , Endotelina-1/farmacologia , Etanol/química , Glicerofosfolipídeos/farmacologia , Masculino , Artérias Mesentéricas/química , Artérias Mesentéricas/efeitos dos fármacos , Miografia , Fenilefrina/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Vasoconstrição
14.
Equine Vet J ; 51(5): 646-652, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30793362

RESUMO

BACKGROUND: Medetomidine suppresses cardiovascular function and reduces gastrointestinal motility in horses mainly through peripheral α2 -adrenoceptors. Vatinoxan, a peripheral α2 -antagonist, has been shown experimentally to alleviate the adverse effects of some α2 -agonists in horses. However, vatinoxan has not been investigated during constant-rate infusion (CRI) of medetomidine in standing horses. OBJECTIVES: To evaluate effects of vatinoxan on cardiovascular function, gastrointestinal motility and on sedation level during CRI of medetomidine. STUDY DESIGN: Experimental, randomised, blinded, cross-over study. METHODS: Six healthy horses were given medetomidine hydrochloride, 7 µg/kg i.v., without (MED) and with (MED+V) vatinoxan hydrochloride, 140 µg/kg i.v., followed by CRI of medetomidine at 3.5 µg/kg/h for 60 min. Cardiorespiratory variables were recorded and borborygmi and sedation levels were scored for 120 min. Plasma drug concentrations were measured. The data were analysed using repeated measures ANCOVA and paired t-tests as appropriate. RESULTS: Initially heart rate (HR) was significantly lower and mean arterial blood pressure (MAP) significantly higher with MED compared with MED+V. For example at 10 min HR (mean ± s.d.) was 26 ± 2 and 31 ± 5 beats/minute (P = 0.04) and MAP 129 ± 15 and 103 ± 13 mmHg (P<0.001) respectively. At 10 min, cardiac index was lower (P = 0.02) and systemic vascular resistance higher (P = 0.001) with MED than with MED+V. Borborygmi were reduced after MED; this effect was attenuated by vatinoxan (P<0.001). All horses were sedated with medetomidine, but the mean sedation scores were reduced with MED+V until 20 min (6.8 ± 0.8 and 4.5 ± 1.5 with MED and MED+V, respectively, at 10 min, P = 0.001). Plasma concentration of dexmedetomidine was significantly lower in the presence of vatinoxan (P = 0.01). MAIN LIMITATIONS: Experimental study with healthy, unstimulated animals. CONCLUSIONS: Vatinoxan administered i.v. with a loading dose of medetomidine improved cardiovascular function and gastrointestinal motility during medetomidine CRI in healthy horses. Sedation was slightly yet significantly reduced during the first 20 min.. The Summary is available in Portuguese - see Supporting Information.


Assuntos
Motilidade Gastrointestinal/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Cavalos , Medetomidina/farmacologia , Quinolizinas/farmacologia , Respiração/efeitos dos fármacos , Animais , Área Sob a Curva , Estudos Cross-Over , Feminino , Meia-Vida , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Masculino , Medetomidina/metabolismo , Medetomidina/farmacocinética , Quinolizinas/administração & dosagem , Resistência Vascular/efeitos dos fármacos
15.
Hypertension ; 73(4): 900-909, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30798663

RESUMO

Despite optimal current therapies, cardiovascular disease remains the leading cause for death worldwide. Importantly, advances in peptide engineering have accelerated the development of innovative therapeutics for diverse human disease states. Additionally, the advancement of bispecific therapeutics targeting >1 signaling pathway represents a highly innovative strategy for the treatment of cardiovascular disease. We, therefore, engineered a novel, designer peptide, which simultaneously targets the pGC-A (particulate guanylyl cyclase A) receptor and the MasR (Mas receptor), potentially representing an attractive cardiorenoprotective therapeutic for cardiovascular disease. We engineered a novel, bispecific receptor activator, NPA7, that represents the fusion of a 22-amino acid sequence of BNP (B-type natriuretic peptide; an endogenous ligand of pGC-A) with Ang 1-7 (angiotensin 1-7)-the 7-amino acid endogenous activator of MasR. We assessed NPA7's dual receptor activating actions in vitro (second messenger production and receptor interaction). Further, we performed an intravenous peptide infusion comparison study in normal canines to study its biological actions in vivo, including in the presence of an MasR antagonist. Our in vivo and in vitro studies demonstrate the successful synthesis of NPA7 as a bispecific receptor activator targeting pGC-A and MasR. In normal canines, NPA7 possesses enhanced natriuretic, diuretic, systemic, and renal vasorelaxing and cardiac unloading properties. Importantly, NPA7's actions are superior to that of the individual native pGC-A or MasR ligands. These studies advance NPA7 as a novel, bispecific designer peptide with potential cardiorenal therapeutic benefit for the treatment of cardiovascular disease, such as hypertension and heart failure.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Desenho de Drogas , Hipertensão/tratamento farmacológico , Oligopeptídeos/farmacologia , Resistência Vascular/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Cães , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino
16.
Pharmacol Res Perspect ; 7(1): e00462, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30693089

RESUMO

Acute pulmonary embolism may cause right heart failure due to increased pulmonary vascular resistance and arterial hypoxemia. Effective vasodilator therapy of the pulmonary hypertension is highly needed. Therefore, we investigated the effects of a newly developed effective pulmonary vasodilator, the organic mononitrites of 1,2-propanediol (PDNO), in a rabbit model of acute pulmonary embolism. In anesthetized and ventilated rabbits, systemic and pulmonary hemodynamics, exhaled nitric oxide (NO), plasma nitrite concentration, and blood gases were monitored. First, dose-response experiments with intravenous and left heart ventricle infusions of PDNO and inorganic nitrite were done in naive animals and in pulmonary hypertension induced by a thromboxane A2 analogue. Second, acute pulmonary embolism was induced and either PDNO or placebo were administered intravenously within 20 minutes and evaluated within 1 hour after pulmonary embolization. PDNO intravenously, in contrast to inorganic nitrite intravenously, increased exhaled NO and counteracted pulmonary hypertension and vasodilated the systemic circulation, dose-dependently, thereby showing efficient NO donation. Pulmonary embolization induced pulmonary hypertension and gas exchange disturbances. PDNO significantly decreased and normalized pulmonary vascular resistance and the right ventricle rate-pressure product, without causing tolerance, with no significant side effects on the systemic circulation, nor on blood-gas values or on methemoglobin formation. In conclusion, PDNO is a NO donor and an efficient vasodilator in the pulmonary circulation. Treatment with this or similar organic nitrites intravenously may be a future option to avoid right heart failure in life-threatening acute pulmonary embolism.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Doadores de Óxido Nítrico/uso terapêutico , Propilenoglicol/uso terapêutico , Embolia Pulmonar/tratamento farmacológico , Vasodilatadores/uso terapêutico , Animais , Hipertensão Pulmonar/metabolismo , Masculino , Óxido Nítrico/metabolismo , Nitritos/uso terapêutico , Embolia Pulmonar/metabolismo , Coelhos , Resistência Vascular/efeitos dos fármacos
17.
Phytomedicine ; 56: 74-82, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668356

RESUMO

BACKGROUND: Luehea divaricata Mart. (Malvaceae) is an important medicinal species widely used by indigenous and riverside populations of the Brazilian Pantanal region. It has been shown that the several extracts obtained from leaves of this species have important cardioprotective effects. Nevertheless, the secondary metabolites responsible for this activity, as well as the molecular mechanisms responsible for their pharmacological effects remain unknown. PURPOSE: To carry out a biomonitoring study to identify possible active metabolites present in different ESLD fractions and evaluate the mechanisms responsible for the vasodilatory effects on isolated perfused mesenteric beds. METHODS: First, ESLD was obtained from L. divaricata leaves and a liquid-liquid fractionation was performed. The resulting fractions were analyzed by liquid chromatography-mass spectrometry. Then, the possible vasodilatory effects of ESLD, chloroform, ethyl acetate, n-butanolic and aqueous fractions on perfused arterial mesenteric vascular beds were evaluated. Finally, the molecular mechanisms involved in vasodilator responses of the aqueous fraction and its chemical component, isovitexin, on the mesenteric arteriolar tone were also investigated. RESULTS: In preparations with functional endothelium ESLD, n-butanolic, aqueous fraction and isovitexin dose-dependently reduced the perfusion pressure in mesenteric vascular beds. Endothelium removal or inhibition of nitric oxide synthase enzymes by L-NAME reduced the vasodilatory effects induced by aqueous fraction and isovitexin. Perfusion with nutritive solution containing 40 mM KCl abolished the vasodilatory effect of all aqueous fractions and Isovitexin doses. Treatment with glibenclamide, a Kir6.1 (ATP-sensitive) potassium channels blocker, tetraethylammonium, a non-selective KCa (calcium-activated) potassium channels blocker, or apamin, a potent blocker of small conductance Ca2+-activated (SK KCa) potassium channels reduced by around 70% vasodilation induced by all aqueous fractions and isovitexin doses. In addition, association of tetraethylammonium and glibenclamide, or L-NAME and glibenclamide, fully inhibited aqueous fraction and Isovitexin -induced vasodilation. CONCLUSION: This study showed that AqueFr obtained from Luehea divaricata and its metabolite - isovitexin - has important vasodilatory effects on MVBs. Apparently, these effects are dependent on endothelium-NO release and both SK KCa K+ channels and Kir6.1 ATP-sensitive K+ channels activation in the vascular smooth muscle.


Assuntos
Apigenina/farmacologia , Malvaceae/química , Extratos Vegetais/farmacologia , Resistência Vascular/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Brasil , Feminino , Glibureto/farmacologia , Canais KATP/antagonistas & inibidores , Canais KATP/metabolismo , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Técnicas de Cultura de Órgãos , Plantas Medicinais/química , Ratos Wistar , Vasodilatação/efeitos dos fármacos
18.
Bull Exp Biol Med ; 166(3): 313-316, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30680492

RESUMO

Changes in the pulmonary microcirculation in isolated perfused rabbit lungs during modeling of pulmonary thromboembolism were studied in control animals and against the background of α-adrenoceptors blockade with phentolamine. Intravenous injection of emboli to control animals was followed by an increase in pressure in the pulmonary artery, mean capillary hydrostatic pressure, capillary filtration coefficient, pulmonary vascular resistance, as well as precapillary and postcapillary resistances. Against the background of α-adrenoceptor blockade, the increase in most parameters was less pronounced than in control animals, while capillary filtration coefficient increased more drastically. Thus, adrenergic mechanisms are involved in the constrictor reactions of both arterial and venous pulmonary vessels under conditions of pulmonary thromboembolism.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Pulmão/efeitos dos fármacos , Microcirculação/efeitos dos fármacos , Fentolamina/farmacologia , Embolia Pulmonar/tratamento farmacológico , Receptores Adrenérgicos alfa/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Pulmão/fisiopatologia , Técnicas de Cultura de Órgãos , Perfusão , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Embolia Pulmonar/metabolismo , Embolia Pulmonar/fisiopatologia , Veias Pulmonares/efeitos dos fármacos , Veias Pulmonares/metabolismo , Veias Pulmonares/fisiopatologia , Coelhos , Resistência Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos
19.
Eur J Nutr ; 58(2): 515-527, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29748816

RESUMO

PURPOSE: Cardiovascular disease is the leading cause of mortality globally. Epicatechin has previously been shown to improve vascular responses and possess cardioprotective properties. However, the mechanisms underpinning these cardiotropic outcomes remain unknown. The aim of this study was to further identify epicatechin's mechanism of action in the cardiovasculature. METHODS: The effects of epicatechin on isolated rat conduit arteries, resistance vessels and cardiac electrophysiology were investigated on resting tension and precontracted vessels and cardiac action potential parameters, both in the presence and in the absence of various antagonists. RESULTS: At resting tension, epicatechin alone did not affect the vasoreactivity of either conduit or resistance vessels. In noradrenaline pre-contracted thoracic aortic arteries and potassium chloride pre-contracted mesenteric vessels, epicatechin (10-9-10-4 M) induced significant vasorelaxation. The addition of naloxone (10-5 M), NG-nitro-L-arginine methyl ester (10-5M), 4-aminopyridine (5 mM) and verapamil (10-5 M) attenuated epicatechin-mediated vasorelaxation. No change in epicatechin-mediated vasorelaxation was observed with the addition of atropine (10-5 M). Epicatechin significantly improved cardiac electrophysiology by reducing the resting membrane potential, action potential amplitude and force of contraction that was mitigated following the addition of naloxone (10-5 M). Epicatechin significantly decreased the action potential duration at 20, 50 and 90% duration and time to 90% relaxation of force that was unchanged following the addition of naloxone (10-5 M). CONCLUSIONS: These findings suggest epicatechin's vascular responses and cardioprotective effects are mediated through opioid receptors, nitric oxide, potassium channel and calcium channel activation and highlight the importance of the endothelium/nitric oxide in epicatechin mediated vasorelaxation.


Assuntos
Cardiotônicos/farmacologia , Catequina/farmacologia , Coração/efeitos dos fármacos , Óxido Nítrico/metabolismo , Receptores Opioides/efeitos dos fármacos , Animais , Endotélio Vascular/efeitos dos fármacos , Feminino , Masculino , Modelos Animais , Ratos , Ratos Wistar , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
20.
A A Pract ; 12(6): 205-207, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30247162

RESUMO

Pulmonary vein stenosis (PVS) is a progressive disease with pulmonary hypertension (PH) as a major cause of morbidity and mortality. Traditional management of PH with inhaled nitric oxide (iNO) is typically avoided in PVS patients because, while iNO may reduce pulmonary vascular resistance, PH persists as pulmonary blood flow increases in the presence of a downstream resistive lesion. We report 3 cases with primary PVS and PH in which iNO was used to successfully decrease mean pulmonary artery pressures with clinical improvement. Based on this experience, we suggest that iNO can be used to treat PH in select patients with PVS.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Óxido Nítrico/administração & dosagem , Estenose de Veia Pulmonar/tratamento farmacológico , Administração por Inalação , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Lactente , Masculino , Circulação Pulmonar/efeitos dos fármacos , Estenose de Veia Pulmonar/fisiopatologia , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos
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