RESUMEN

Approximately 12-18% of hypertensive patients are diagnosed with resistant hypertension (RH). The risk of having worse cardiovascular outcomes is twice higher in those patients. The low effectiveness of conventional antihypertensive drugs in RH emphasizes the need to evaluate complementary drug therapies to achieve blood pressure (BP) control. Previous studies have demonstrated that phosphodiesterase 5 (PDE-5) inhibitors improve hemodynamics and reduce BP on essential hypertension. So, the authors aimed to summarize current clinical trials-based evidence published concerning the use of PDE-5 inhibitors on BP, cardiovascular function, and hemodynamics of patients with RH. We searched MEDLINE, EMBASE, LILACS, ClinicalTrials.gov, and WHO International Clinical Trials Registry databases on May 15th, 2020 using pre-defined search terms. Two independent reviewers assessed and extracted data from clinical trials that evaluated the effect of PDE-5 inhibitors on BP. We have included five articles in this systematic review. Four of them developed a single-day protocol, while one has developed a 14-day study. The main findings indicate that PDE-5 inhibitors ameliorate BP, vascular hemodynamics, and diastolic function parameters. Some data demonstrated improvement of endothelial function, but it was not a consensus. The side effects seemed to be limited and well-tolerated. In brief, our systematic review highlights the potential of PDE-5 inhibitors as a therapeutic alternative in addition to the multiple-drug regime for RH. Larger studies are still needed to determine whether the beneficial effects of PDE-5 inhibitors on RH would be maintained with chronic administration.

Asunto(s)

Hipertensión/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/farmacología , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Enfermedades Cardiovasculares , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Diástole/efectos de los fármacos , Humanos , Hipertensión/fisiopatología , Inhibidores de Fosfodiesterasa 5/metabolismo

RESUMEN

INTRODUCTION: Hypertensive mediated heart disease is the consequence of anatomical and functional changes in cardiovascular system. The benefits on left ventricular (LV) diastolic impairment and remodeling of hypertension treatment are well established. AIM: To evaluate LV structure, systolic and diastolic function of treated hypertensive patients on a medium to long term follow-up. METHODS: Prospectively observational cohort study. Hypertensive patients over 18 years, ultrasound evaluation of LV structure and diastolic and systolic function, follow-up at least once a year. Diastolic function assessed following recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging. RESULTS: 285 patients, mean follow up of 1731 ± 952 days. Sample mean age 56.3 ± 12.5 years, 166 patients (58.3%) were males. Baseline blood pressure 147.8 ± 19/86.8 ± 11 mm Hg, 5 years blood pressure 134.4 ± 15.7/79 ± 9 mm Hg (p < 0.005 SBP and p < 0.01 DBP). Baseline fixed dose combinations 115 patients (40.4%), follow-up 53.1% (p < 0.05). LV remodeling was detected in 88 patients (30.9%) vs. 30.1% at 5 years (p = NS). The frequency of an E/e' ratio > 14 was reduced from 38 patients (13.3%) to 3.6% (p < 0.001), e' septal velocity < 7 cm/sec or e' lateral velocity < 10 cm/sec was reduced from 38.6% (110 patients) to 19.3% (p < 0.001). Baseline normal diastolic function was detected in 85.6% (244 patients) and 94% at the end of the follow-up (p < 0.02). CONCLUSIONS: In this observational cohort followed by a mean of 5 years, the main benefit of hypertension treatment was the prevention or regression of diastolic dysfunction.

Asunto(s)

Antihipertensivos/uso terapéutico , Cardiopatías/etiología , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Diástole/efectos de los fármacos , Femenino , Estudios de Seguimiento , Cardiopatías/fisiopatología , Cardiopatías/prevención & control , Humanos , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/prevención & control , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sístole/efectos de los fármacos , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/prevención & control

RESUMEN

Recent studies have provided evidence that triiodothyronine (T3) might play an effective role in the recovery of ischemic myocardium, through the preservation of mitochondrial function and the improvement of energy substrate metabolism. To this respect, it has been suggested that T3 could activate AMP-activated protein kinase (AMPK), the cellular 'fuel-gauge' enzyme, although its role has yet to be elucidated. The aim of the present study was to investigate the effects produced by acute treatment with T3 (60 nM) and the pharmacological inhibition of AMPK by compound C on isolated rat left atria subjected to 75 min simulated ischemia-75 min reperfusion. Results showed that T3 increased AMPK activation during simulated ischemia-reperfusion, while compound C prevented it. At the end of simulated reperfusion, acute T3 treatment increased contractile function recovery and cellular viability conservation. Mitochondrial ultrastructure was better preserved in the presence of T3 as well as mitochondrial ATP production rate and tissue ATP content. Calcium retention capacity, a parameter widely used as an indicator of the resistance of mitochondrial permeability transition pore (MPTP) to opening, and GSK-3ß phosphorylation, a master switch enzyme that limits MPTP opening, were increased by T3 administration. All these beneficial effects exerted by T3 acute treatment were prevented when compound C was co-administrated. The present study provided original evidence that T3 enhances intrinsic activation of AMPK during myocardial ischemia-reperfusion, being this enzyme involved, at least in part, in the protective effects exerted by T3, contributing to mitochondrial structure and function preservation, post-ischemic contractile recovery and conservation of cellular viability.

Asunto(s)

Proteínas Quinasas Activadas por AMP/metabolismo , Cardiotónicos/uso terapéutico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/enzimología , Miocardio/enzimología , Miocardio/patología , Triyodotironina/uso terapéutico , Adenosina Trifosfato/metabolismo , Animales , Calcio/metabolismo , Cardiotónicos/farmacología , Supervivencia Celular/efectos de los fármacos , Diástole/efectos de los fármacos , Femenino , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Atrios Cardíacos/ultraestructura , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/ultraestructura , Contracción Miocárdica/efectos de los fármacos , Daño por Reperfusión Miocárdica/fisiopatología , Fosforilación/efectos de los fármacos , Ratas Sprague-Dawley , Sístole/efectos de los fármacos , Triyodotironina/farmacología

RESUMEN

The aim of this pilot study was to evaluate the cardioprotective effects of carvedilol in dogs receiving doxorubicin chemotherapy and provide suggestions to future studies based on results and limitations of our study. Thirteen dogs were randomized into two experimental groups: 6 dogs in carvedilol group and 7 dogs in placebo group. In carvedilol group, 0.39 mg/kg ± 0.04 twice-daily oral carvedilol was started on the day of the first doxorubicin treatment and continued throughout the chemotherapy protocol until the final cardiological evaluation. Cardiological evaluations were performed before the first doxorubicin administration and then 10 to 15 days after each subsequent dose. Troponin I and oxidative stress tests were performed with serum collected from dogs at the initial and final cardiological evaluation. Carvedilol produced some echocardiographic and electrocardiographic changes (reduced E velocity and E/IVRT ratio, as well reduced heart rate and increased PR and QT interval) due to its beta-block effect. In placebo group Doppler study showed a significant increase in mitral flow deceleration time (EDT), as well increased amplitude of the S wave in the right, and R wave in the left, precordial chest leads. There were significant difference in the EDT, E/IVRT and A' velocity, as well heart rate, PR interval and R wave in V4/CV6LU precordial chest lead between groups. In conclusion, some indexes of diastolic function and in precordial chest leads were less affected by doxorubicin in carvedilol than in control group. This suggests that carvedilol may have a beneficial effect in canine cancer patients receiving doxorubicin.

Asunto(s)

Antibióticos Antineoplásicos , Cardiotónicos , Carvedilol , Enfermedades de los Perros , Doxorrubicina , Neoplasias , Animales , Perros , Femenino , Masculino , Antibióticos Antineoplásicos/uso terapéutico , Cardiotónicos/uso terapéutico , Carvedilol/uso terapéutico , Diástole/efectos de los fármacos , Enfermedades de los Perros/tratamiento farmacológico , Método Doble Ciego , Doxorrubicina/uso terapéutico , Ecocardiografía Doppler/veterinaria , Neoplasias/tratamiento farmacológico , Neoplasias/veterinaria , Proyectos Piloto , Estudios Prospectivos

RESUMEN

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.

Asunto(s)

Angiotensina II/metabolismo , Angiotensina I/metabolismo , Cardiotónicos/uso terapéutico , Miocardio/metabolismo , Fragmentos de Péptidos/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Fosfato de Sitagliptina/uso terapéutico , Angiotensina I/sangre , Angiotensina II/sangre , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Cardiotónicos/farmacología , Diástole/efectos de los fármacos , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Riñón/efectos de los fármacos , Riñón/fisiopatología , Pruebas de Función Renal , Masculino , Miocardio/patología , Fragmentos de Péptidos/sangre , Peptidil-Dipeptidasa A/metabolismo , Ratas Wistar , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/fisiopatología , Sistema Renina-Angiotensina/efectos de los fármacos , Fosfato de Sitagliptina/farmacología , Regulación hacia Arriba/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos

RESUMEN

OBJECTIVE: Treatment of subclinical hypothyroidism (ScH), especially the mild form of ScH, is controversial because thyroid hormones influence cardiac function. We investigate left ventricular systolic and diastolic function in ScH and evaluate the effect of 5-month levothyroxine treatment. SUBJECTS AND METHODS: Fifty-four patients with newly diagnosed mild ScH (4.2

Asunto(s)

Diástole/efectos de los fármacos , Hipotiroidismo/tratamiento farmacológico , Sístole/efectos de los fármacos , Tiroxina/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Adulto , Estudios de Casos y Controles , Diástole/fisiología , Ecocardiografía Doppler de Pulso , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sístole/fisiología , Tirotropina/sangre , Tiroxina/administración & dosificación , Tiroxina/sangre , Tiroxina/uso terapéutico , Triyodotironina/sangre

RESUMEN

HIV-positive adults with hypertension have increased risk of mortality but HIV clinics often do not provide hypertension care. The authors integrated hypertension management into existing HIV services at a large clinic in Haiti. Of 1729 documented HIV-positive adults presenting for care at the GHESKIO HIV clinic between March and July 2016, 551 screened positive for hypertension, with systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg. A convenience sample of 100 patients from this group received integrated hypertension and HIV care for 6 months. At time of identification, patients were screened for proteinuria and initiated on antihypertensive medication. Hypertension and HIV visits coincided; medications were free. Outcomes were retention in care and change in blood pressure over 6 months. Average blood pressure over 6 months was described using linear mixed-effects model. Of 100 HIV-positive adults with hypertension referred for integrated care, three were ineligible due to comorbidities. Among 97 participants, 82% (N = 80) remained in care at 6 months from time of positive hypertension identification. 96% (N = 93) were on antiretroviral therapy with median CD4+ count of 442 cells/µL (IQR 257-640). Estimated average blood pressure over 6 months decreased from systolic 160 mmHg (CI 156, 165) to 146 mmHg (CI 141, 150), P-value <0.0001, and diastolic 105 mmHg (CI 102, 108) to 93 mmHg (CI 89, 96), P-value <0.0001. HIV and hypertension management were successfully integrated at a HIV clinic in Haiti. Integrated management is essential to combat the growing burden of cardiovascular disease among HIV-positive adults.

Asunto(s)

Instituciones de Atención Ambulatoria/tendencias , Prestación Integrada de Atención de Salud/métodos , Infecciones por VIH/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Adulto , Antirretrovirales/uso terapéutico , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Determinación de la Presión Sanguínea/métodos , Diástole/efectos de los fármacos , Diástole/fisiología , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Haití/epidemiología , Humanos , Hipertensión/diagnóstico , Hipertensión/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sístole/efectos de los fármacos , Sístole/fisiología

RESUMEN

Diminazene aceturate (DIZE) has been reported to enhance the catalytic efficiency of ACE-2 and presumably increases angiotensin 1-7 generation, interfering with cardiac remodeling after myocardial infarction (MI). Our aim was to investigate the chronic effects of DIZE on cardiac dysfunction post-MI. Male Wistar rats underwent myocardial infarction (MI) or SHAM surgery (SO) and were divided into groups treated with DIZE 15 mg/kg/day, s.c. or vehicle (Control). After 4 weeks, the hemodynamic variables were recorded by cardiac catheterism. Hearts were then arrested to obtain the left ventricular (LV) pressure-volume curves in situ. Cardiomyocyte hypertrophy and collagen content were determined by histology. DIZE prevented LV end-diastolic pressure increases in MI rats (MI: 26 ± 3.3 vs. MI-DIZE: 15 ± 1.6 mmHg, P < 0.001) without a significant effect on LV systolic pressure (LVSP). Moreover, DIZE improved LV contractility (+dP/dt, MI: 3014 ± 161 vs. MI-DIZE: 3884 ± 104 mmHg/s, P < 0.001) and relaxation (-dP/dt, MI: -2333 ± 91 vs. MI-DIZE: -2798 ± 120 mmHg/s, P < 0.05). Right ventricular SP was increased in the MI compared to that in the SO group (40 ± 0.6 vs. 30 ± 1.2 mmHg; P < 0.01), and DIZE partially prevented this augmentation. LV stiffness was reduced in MI-DIZE compared with that in MI (0.64 ± 0.01 vs. 0.78 ± 0.02 mmHg/mL; P < 0.01). DIZE treatment reduced the interstitial collagen content by 18% in the surviving LV myocardium. Cardiomyocyte hypertrophy remained unaffected by DIZE treatment. Our findings show that chronic DIZE treatment post-MI attenuates the morphofunctional changes induced by MI in rats. The effects on LV -dP/dt, chamber stiffness and collagen content suggest this drug can be used as a therapeutic agent to reduce interstitial fibrosis and diastolic dysfunction after MI.

Asunto(s)

Diástole , Diminazeno/análogos & derivados , Activadores de Enzimas/uso terapéutico , Infarto del Miocardio/complicaciones , Peptidil-Dipeptidasa A/metabolismo , Disfunción Ventricular/tratamiento farmacológico , Disfunción Ventricular/etiología , Enzima Convertidora de Angiotensina 2 , Animales , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Colágeno/metabolismo , Diástole/efectos de los fármacos , Diminazeno/farmacología , Diminazeno/uso terapéutico , Activadores de Enzimas/farmacología , Hemodinámica/efectos de los fármacos , Masculino , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas Wistar , Disfunción Ventricular/patología , Disfunción Ventricular/fisiopatología , Función Ventricular/efectos de los fármacos

RESUMEN

ABSTRACT Objective: Treatment of subclinical hypothyroidism (ScH), especially the mild form of ScH, is controversial because thyroid hormones influence cardiac function. We investigate left ventricular systolic and diastolic function in ScH and evaluate the effect of 5-month levothyroxine treatment. Subjects and methods: Fifty-four patients with newly diagnosed mild ScH (4.2 <TSH < 10.0 mU/L) and 30 euthyroid subjects matched by age were analysed. Laboratory analyses and an echocardiography study were done at the first visit and after 5 months in euthyroid stage in patients with ScH. Results: Compared to healthy controls, patients with ScH had a lower E/A ratio (1.03 ± 0.29 vs. 1.26 ± 0.36, p < 0.01), higher E/e' sep. ratio (762 ± 2.29 vs. 6.04 ± 1.64, p < 0.01), higher myocardial performance index (MPI) (0.47 ± 0.08 vs. 0.43 ± 0.07, p < 0.05), lower global longitudinal strain (GLS) (-19.5 ± 2.3 vs. −20.9 ± 1.7%, p < 0.05), and lower S wave derived by tissue Doppler imaging (0.077 ± 0.013 vs. 0.092 ± 0.011 m/s, p < 0.01). Levothyroxine treatment in patients with ScH contributed to higher EF (62.9 ± 3.9 vs. 61.6 ± 4.4%, p < 0.05), lower E/e' sep. ratio (6.60 ± 2.06 vs. 762 ± 2.29, p < 0.01), lower MPI (0.43 ± 0.07 vs. 0.47 ± 0.08%, p < 0.01), and improved GLS (-20.07 ± 2.7 vs. −19.55 ± 2.3%, p < 0.05) compared to values in ScH patients at baseline. Furthermore, in all study populations (ScH patients before and after levothyroxine therapy and controls), TSH levels significantly negatively correlated with EF (r = −0.15, p < 0.05), E/A (r = −0.14, p < 0.05), GLS (r = −0.26, p < 0.001), and S/TDI (r = −0.22, p < 0.01) and positively correlated with E/e' sep. (r = 0.14, p < 0.05). Conclusion: Patients with subclinical hypothyroidism versus healthy individuals had subtle changes in certain parameters that indicate involvement of systolic and diastolic function of the left ventricle. Although the values of the parameters were in normal range, they were significantly different compared to ScH and the control group at baseline, as well as to the ScH groups before and after treatment.The results of our study suggest that patients with ScH must be followed up during treatment to assess improvement of the disease. Some of the echocardiography obtained parameters were reversible after levothyroxine therapy.

Asunto(s)

Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Sístole/efectos de los fármacos , Tiroxina/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Diástole/efectos de los fármacos , Hipotiroidismo/tratamiento farmacológico , Sístole/fisiología , Tiroxina/administración & dosificación , Tiroxina/sangre , Tiroxina/uso terapéutico , Triyodotironina/sangre , Tirotropina/sangre , Estudios de Casos y Controles , Estudios Prospectivos , Ecocardiografía Doppler de Pulso , Diástole/fisiología , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/diagnóstico por imagen

RESUMEN

Serotonin (5-hydroxytryptamine; 5-HT) inhibits the rat cardioaccelerator sympathetic outflow by 5-HT1B/1D/5 receptors. Because chronic blockade of sympatho-excitatory 5-HT2 receptors is beneficial in several cardiovascular pathologies, this study investigated whether sarpogrelate (a 5-HT2 receptor antagonist) alters the pharmacological profile of the above sympatho-inhibition. Rats were pretreated for 2 weeks with sarpogrelate in drinking water (30 mg/kg per day; sarpogrelate-treated group) or equivalent volumes of drinking water (control group). Animals were pithed and prepared for spinal stimulation (C7-T1) of the cardioaccelerator sympathetic outflow or for intravenous (i.v.) bolus injections of noradrenaline. Both procedures produced tachycardic responses remaining unaltered after saline. Continuous i.v. infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT receptor agonists 5-carboxamidotryptamine (5-CT; 5-HT1/5A), CP 93,129 (5-HT1B), or PNU 142633 (5-HT1D), but not by indorenate (5-HT1A) in both groups; whereas LY344864 (5-HT1F) mimicked 5-HT only in sarpogrelate-treated rats. In sarpogrelate-treated animals, i.v. GR 127935 (310 µg/kg; 5-HT1B/1D/1F receptor antagonist) attenuated 5-CT-induced sympatho-inhibition and abolished LY344864-induced sympatho-inhibition; while GR 127935 plus SB 699551 (1 mg/kg; 5-HT5A receptor antagonist) abolished 5-CT-induced inhibition. These results confirm the cardiac sympatho-inhibitory role of 5-HT1B, 5-HT1D, and 5-HT5A receptors in both groups; nevertheless, sarpogrelate treatment specifically unmasked a cardiac sympatho-inhibition mediated by 5-HT1F receptors.

Asunto(s)

Miocardio/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Sistema Nervioso Simpático/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Carbazoles/farmacología , Diástole/efectos de los fármacos , Estimulación Eléctrica , Fluorobencenos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Masculino , Norepinefrina/farmacología , Oxadiazoles/farmacología , Piperazinas/farmacología , Ratas Wistar , Serotonina/análogos & derivados , Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Agonistas de Receptores de Serotonina/uso terapéutico , Cloruro de Sodio/farmacología , Succinatos/farmacología , Succinatos/uso terapéutico , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Taquicardia/tratamiento farmacológico , Taquicardia/fisiopatología , Receptor de Serotonina 5-HT1F

RESUMEN

BACKGROUND: In individuals with a low diastolic blood pressure (DBP), the potential benefits or risks of intensive systolic blood pressure (SBP) lowering are unclear. METHODS: SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized controlled trial that compared the effects of intensive (target <120 mm Hg) and standard (target <140 mm Hg) SBP control in 9361 older adults with high blood pressure at increased risk of cardiovascular disease. The primary outcome was a composite of cardiovascular disease events. All-cause death and incident chronic kidney disease were secondary outcomes. This post hoc analysis examined whether the effects of the SBP intervention differed by baseline DBP. RESULTS: Mean baseline SBP and DBP were 139.7±15.6 and 78.1±11.9 mm Hg, respectively. Regardless of the randomized treatment, baseline DBP had a U-shaped association with the hazard of the primary cardiovascular disease outcome. However, the effects of the intensive SBP intervention on the primary outcome were not influenced by baseline DBP level (P for interaction=0.83). The primary outcome hazard ratio for intensive versus standard treatment was 0.78 (95% confidence interval, 0.57-1.07) in the lowest DBP quintile (mean baseline DBP, 61±5 mm Hg) and 0.74 (95% confidence interval, 0.61-0.90) in the upper 4 DBP quintiles (mean baseline DBP, 82±9 mm Hg), with an interaction P value of 0.78. Results were similar for all-cause death and kidney events. CONCLUSIONS: Low baseline DBP was associated with increased risk of cardiovascular disease events, but there was no evidence that the benefit of the intensive SBP lowering differed by baseline DBP. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.

Asunto(s)

Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Síndrome Coronario Agudo/epidemiología , Anciano , Anciano de 80 o más Años , Antihipertensivos/efectos adversos , Diástole/efectos de los fármacos , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/mortalidad , Hipertensión/fisiopatología , Incidencia , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Puerto Rico , Insuficiencia Renal Crónica/epidemiología , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos

RESUMEN

Myocardial remodeling includes inappropriate collagen deposition in the interstitium. Erythropoietin (EPO) may have cardioprotective effects. We aimed to assess the role of EPO on myocardial remodeling during the chronic phase. We studied 60 Wistar rats divided into the following groups: control (CT), control + EPO (CT + EPO), myocardial infarction + EPO (MI + EPO), and myocardial infarction (MI). The interstitial collagen volume fraction (ICVF) was quantified and echocardiography was performed. We quantified asymmetric dimethylarginine and glutathione by ELISA, and used real-time PCR to assess apoptosis and inflammation. Western blotting was used to evaluate inflammatory proteins and tissue inhibitors of metalloproteinases (TIMPs), and TUNEL staining was used to detect apoptosis. For matrix metalloproteinases (MMPs), we performed zymography. Parametric and nonparametric analyses were performed according to normality testing. ICVF was greater in MI groups (p < 0.001) and was attenuated by EPO (p = 0.05). The MMP-2 did not show any difference between groups. The TIMP-1 and TIMP-2 did not have difference between groups. The MI groups had worse fraction shortening (p < 0.001), without EPO protection (p = 0.666). The MI groups had increased left ventricle diastolic dimension (p < 0.001) without EPO attenuation (p = 0.79). EPO did not act on oxidative stress. Apoptosis and inflammation were not modulated by EPO. We concluded that EPO attenuated interstitial collagen accumulation, but did not protect from heart dilation or dysfunction.

Asunto(s)

Colágeno/metabolismo , Eritropoyetina/farmacología , Corazón/efectos de los fármacos , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Animales , Apoptosis/efectos de los fármacos , Arginina/análogos & derivados , Arginina/metabolismo , Diástole/efectos de los fármacos , Glutatión/metabolismo , Corazón/fisiopatología , Hematócrito , Hemoglobinas/metabolismo , Masculino , Infarto del Miocardio/patología , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Ratas

RESUMEN

Trypanosoma cruzi induces serious cardiac alterations during the chronic infection. Intense inflammatory response observed from the beginning of infection, is critical for the control of parasite proliferation and evolution of Chagas disease. Peroxisome proliferator-activated receptors (PPAR)-α, are known to modulate inflammation. In this study we investigated whether a PPAR-α agonist, Fenofibrate, improves cardiac function and inflammatory parameters in a murine model of T. cruzi infection. BALB/c mice were sequentially infected with two T. cruzi strains of different genetic background. Benznidazole, commonly used as trypanocidal drug, cleared parasites but did not preclude cardiac pathology, resembling what is found in human chronic chagasic cardiomyopathy. Fenofibrate treatment restored to normal values the ejection and shortening fractions, left ventricular end-diastolic, left ventricular end-systolic diameter, and isovolumic relaxation time. Moreover, it reduced cardiac inflammation and fibrosis, decreased the expression of pro-inflammatory (IL-6, TNF-α and NOS2) and heart remodeling mediators (MMP-9 and CTGF), and reduced serum creatine kinase activity. The fact that Fenofibrate partially inhibited NOS2 expression and NO release in the presence of a PPAR-α non-competitive inhibitor, suggested it also acted through PPAR-α-independent pathways. Since IκBα cytosolic degradation was inhibited by Fenofibrate, it can be concluded that the NFκB pathway has a role in its effects. Thus, we demonstrate that Fenofibrate acts through PPAR-α-dependent and -independent pathways. Our study shows that combined treatment with Fenofibrate plus Benznidazole is able both to reverse the cardiac dysfunction associated with the ongoing inflammatory response and fibrosis and to attain parasite clearance in an experimental model of Chagas disease.

Asunto(s)

Cardiomiopatía Chagásica/tratamiento farmacológico , Fenofibrato/uso terapéutico , Nitroimidazoles/uso terapéutico , Tripanocidas/uso terapéutico , Disfunción Ventricular/tratamiento farmacológico , Animales , Cardiomiopatía Chagásica/complicaciones , Cardiomiopatía Chagásica/parasitología , Enfermedad de Chagas/complicaciones , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Diástole/efectos de los fármacos , Fenofibrato/administración & dosificación , Fibrosis/tratamiento farmacológico , Humanos , Inflamación/tratamiento farmacológico , Inflamación/parasitología , Inflamación/fisiopatología , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos BALB C , FN-kappa B/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/efectos de los fármacos , Nitroimidazoles/administración & dosificación , Nitroimidazoles/efectos adversos , PPAR alfa/agonistas , Volumen Sistólico/efectos de los fármacos , Tripanocidas/administración & dosificación , Tripanocidas/efectos adversos , Trypanosoma cruzi/efectos de los fármacos , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Disfunción Ventricular/etiología , Función Ventricular/efectos de los fármacos

RESUMEN

The renin-angiotensin system (RAS) plays a key role in the control of vasoconstriction as well as sodium and fluid retention mediated mainly by angiotensin (Ang) II acting at the AT1 receptor (AT1R). Ang-(1-7) is another RAS peptide, identified as the endogenous ligand of the Mas receptor and known to counterbalance many of the deleterious effects of AngII. AT1R signaling triggered by ß-arrestin-biased agonists has been associated to cardioprotection. Because position 8 in AngII is important for G protein activation, we hypothesized that Ang-(1-7) could be an endogenous ß-arrestin-biased agonist of the AT1R. Here we show that Ang-(1-7) binds to the AT1R without activating Gq, but triggering ß-arrestins 1 and 2 recruitment and activation. Using an in vivo model of cardiac hypertrophy, we show that Ang-(1-7) significantly attenuates heart hypertrophy by reducing both heart weight and ventricular wall thickness and the increased end-diastolic pressure. Whereas neither the single blockade of AT1 or Mas receptors with their respective antagonists prevented the cardioprotective action of Ang1-7, combination of the two antagonists partially impaired the effect of Ang-(1-7). Taken together, these data indicate that Ang-(1-7) mediates at least part of its cardioprotective effects by acting as an endogenous ß-arrestin-biased agonist at the AT1R.

Asunto(s)

Angiotensina I/uso terapéutico , Cardiomegalia/tratamiento farmacológico , Cardiotónicos/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Receptor de Angiotensina Tipo 1/metabolismo , beta-Arrestinas/agonistas , Angiotensina I/metabolismo , Animales , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Cardiotónicos/metabolismo , Diástole/efectos de los fármacos , Células HEK293 , Corazón/efectos de los fármacos , Corazón/fisiopatología , Humanos , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fragmentos de Péptidos/metabolismo , Fosforilación , Ratas , Ratas Endogámicas WF , Transducción de Señal/efectos de los fármacos , beta-Arrestinas/metabolismo

RESUMEN

BACKGROUND: Diastolic dysfunction develops in response to hypertension and estrogen (E2) loss and is a forerunner to heart failure (HF) in women. The cardiac renin-angiotensin system (RAS) contributes to diastolic dysfunction, but its role with respect to E2 and blood pressure remain unclear. METHODS: We compared the effects of ovariectomy (OVX) or sham surgery on the cardiac RAS, left ventricular (LV) structure/function, and systemic/intracardiac pressures of spontaneously hypertensive rats (SHRs: n = 6 intact and 6 OVX) and age-matched Wistar-Kyoto (WKY: n = 5 intact and 4 OVX) controls. RESULTS: WKY rats were more sensitive to OVX than SHRs with respect to worsening of diastolic function, as reflected by increases in Doppler-derived filling pressures (E/e') and reductions in myocardial relaxation (e'). This pathobiologic response in WKY rats was directly linked to increases in cardiac gene expression and enzymatic activity of chymase and modest reductions in ACE2 activity. No overt changes in cardiac RAS genes or activities were observed in SHRs, but diastolic function was inversely related to ACE2 activity. CONCLUSION: Endogenous estrogens exert a more significant regulatory role upon biochemical components of the cardiac RAS of WKY versus SHRs, modulating the lusitropic and structural components of its normotensive phenotype.

Asunto(s)

Cardiotónicos/farmacología , Quimasas/metabolismo , Estrógenos/farmacología , Miocardio/enzimología , Peptidil-Dipeptidasa A/metabolismo , Enzima Convertidora de Angiotensina 2 , Animales , Peso Corporal/efectos de los fármacos , Calcio/metabolismo , Colágeno/metabolismo , Diástole/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Ovariectomía , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/metabolismo , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptor de Angiotensina Tipo 1/metabolismo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos

RESUMEN

Oxidative stress is involved in the development of carotid body (CB) chemosensory potentiation and systemic hypertension induced by chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea. We tested whether peroxynitrite (ONOO(-)), a highly reactive nitrogen species, is involved in the enhanced CB oxygen chemosensitivity and the hypertension during CIH. Accordingly, we studied effects of Ebselen, an ONOO(-) scavenger, on 3-nitrotyrosine immunoreactivity (3-NT-ir) in the CB, the CB chemosensory discharge, and arterial blood pressure (BP) in rats exposed to CIH. Male Sprague-Dawley rats were exposed to CIH (5% O2, 12 times/h, 8 h/day) for 7 days. Ebselen (10 mg/kg/day) was administrated using osmotic minipumps and BP measured with radiotelemetry. Compared to the sham animals, CIH-treated rats showed increased 3-NT-ir within the CB, enhanced CB chemosensory responses to hypoxia, increased BP response to acute hypoxia, and hypertension. Rats treated with Ebselen and exposed to CIH displayed a significant reduction in 3-NT-ir levels (60.8 ± 14.9 versus 22.9 ± 4.2 a.u.), reduced CB chemosensory response to 5% O2 (266.5 ± 13.4 versus 168.6 ± 16.8 Hz), and decreased mean BP (116.9 ± 13.2 versus 82.1 ± 5.1 mmHg). Our results suggest that CIH-induced CB chemosensory potentiation and hypertension are critically dependent on ONOO(-) formation.

Asunto(s)

Cuerpo Carotídeo/patología , Hipertensión/complicaciones , Hipoxia/complicaciones , Ácido Peroxinitroso/biosíntesis , Animales , Azoles/farmacología , Presión Sanguínea/efectos de los fármacos , Cuerpo Carotídeo/efectos de los fármacos , Cuerpo Carotídeo/fisiopatología , Diástole/efectos de los fármacos , Hipertensión/patología , Hipertensión/fisiopatología , Hipoxia/patología , Isoindoles , Masculino , Plasticidad Neuronal/efectos de los fármacos , Compuestos de Organoselenio/farmacología , Ratas Sprague-Dawley , Sístole/efectos de los fármacos , Tirosina/análogos & derivados , Tirosina/metabolismo

RESUMEN

Resistant hypertension (RHTN) is a multifactorial disease characterized by blood pressure (BP) levels above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Moreover, it is well known that RHTN subjects have high prevalence of left ventricular diastolic dysfunction (LVDD), which leads to increased risk of heart failure progression. This review gathers data from studies evaluating the effects of phosphodiesterase-5 (PDE-5) inhibitors (administration of acute sildenafil and short-term tadalafil) on diastolic function, biochemical and hemodynamic parameters in patients with RHTN. Acute study with sildenafil treatment found that inhibition of PDE-5 improved hemodynamic parameters and diastolic relaxation. In addition, short-term study with the use of tadalafil demonstrated improvement of LVDD, cGMP and BNP-32 levels, regardless of BP reduction. No endothelial function changes were observed in the studies. The findings of acute and short-term studies revealed potential therapeutic effects of IPDE-5 drugs on LVDD in RHTN patients.

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A Hipertensão arterial resistente (HAR) é uma doença multifatorial caracterizada por níveis pressóricos acima das metas (140/90 mmHg), a despeito de tratamento farmacológico otimizado de 3 ou mais fármacos anti-hipertensivos de diferentes classes. Pacientes diagnosticados como hipertensos resistentes apresentam alta prevalência de disfunção diastólica do ventrículo esquerdo (DDVE) que proporciona risco aumentado para insuficiência cardíaca. Esta revisão reúne dados de estudos prévios avaliando os efeitos dos inibidores de fosfodiesterase-5 (PDE-5) (administração aguda de sildenafil e de curto prazo de tadalafil) na função diastólica e nos parâmetros bioquímicos e hemodinâmicos em pacientes com HAR. O estudo agudo com sildenafil demonstrou que a inibição da PDE-5 melhorou os parâmetros hemodinâmicos e de relaxamento diastólico. Além disso, o estudo curto prazo com o uso de tadalafil revelou melhora da DDVE e dos níveis de GMPc e BNP-32, independente de redução de pressão arterial. A função endotelial não apresentou alteração com ambos os tratamentos. Os resultados dos estudos agudo e de curto prazo sugerem efeitos terapêuticos potenciais dos fármacos inibidores da PDE-5 na disfunção diastólica em pacientes com HAR.

Asunto(s)

Humanos , Insuficiencia Cardíaca Diastólica/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , /uso terapéutico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Carbolinas/uso terapéutico , Resistencia a Medicamentos , Diástole/efectos de los fármacos , Insuficiencia Cardíaca Diastólica/fisiopatología , Hipertensión/fisiopatología , Ilustración Médica , Piperazinas/uso terapéutico , Purinas/uso terapéutico , Citrato de Sildenafil , Sulfonamidas/uso terapéutico , Tadalafilo , Resultado del Tratamiento , Disfunción Ventricular Izquierda/fisiopatología

RESUMEN

Resistant hypertension (RHTN) is a multifactorial disease characterized by blood pressure (BP) levels above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Moreover, it is well known that RHTN subjects have high prevalence of left ventricular diastolic dysfunction (LVDD), which leads to increased risk of heart failure progression. This review gathers data from studies evaluating the effects of phosphodiesterase-5 (PDE-5) inhibitors (administration of acute sildenafil and short-term tadalafil) on diastolic function, biochemical and hemodynamic parameters in patients with RHTN. Acute study with sildenafil treatment found that inhibition of PDE-5 improved hemodynamic parameters and diastolic relaxation. In addition, short-term study with the use of tadalafil demonstrated improvement of LVDD, cGMP and BNP-32 levels, regardless of BP reduction. No endothelial function changes were observed in the studies. The findings of acute and short-term studies revealed potential therapeutic effects of IPDE-5 drugs on LVDD in RHTN patients.

Asunto(s)

Insuficiencia Cardíaca Diastólica/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Carbolinas/uso terapéutico , Diástole/efectos de los fármacos , Resistencia a Medicamentos , Insuficiencia Cardíaca Diastólica/fisiopatología , Humanos , Hipertensión/fisiopatología , Ilustración Médica , Piperazinas/uso terapéutico , Purinas/uso terapéutico , Citrato de Sildenafil , Sulfonamidas/uso terapéutico , Tadalafilo , Resultado del Tratamiento , Disfunción Ventricular Izquierda/fisiopatología

RESUMEN

In vitro studies have indicated that 17ß-oestradiol exerts beneficial effects on the cardiovascular system by activating the nitric oxide pathway. However, these effects have not been demonstrated in vivo in the systemic vasculature of rats made diabetic through streptozotocin induction. Therefore, the goal of this study was to determine the effect of 17ß-oestradiol on vasopressor responses induced by sympathetic stimulation or i.v. injections of noradrenaline, methoxamine and B-HT 933 in sham-operated or ovariectomised, diabetic or non-diabetic female rats. Thus, rats were ovariectomised or sham-operated for this experiment. One week later, the animals were treated with streptozotocin (60mg/kg, i.p.) or its vehicle. Two weeks later, these rats were treated daily with 17ß-oestradiol (10µg/kg, s.c.) or its vehicle for five weeks. Next, under anaesthesia, the animals were pithed and prepared for blood pressure and heart rate measurements. 17ß-oestradiol failed to modify the vasopressor responses to (i) sympathetic stimulation, noradrenaline, methoxamine or B-HT 933 in sham-operated non-diabetic rats; (ii) sympathetic stimulation or B-HT 933 in sham-operated diabetic rats; (iii) noradrenaline or methoxamine in ovariectomised non-diabetic rats. In contrast, 17ß-oestradiol significantly decreased the vasopressor responses to (i) noradrenaline and methoxamine in sham-operated diabetic rats; (ii) sympathetic stimulation or B-HT 933 in ovariectomised non-diabetic rats; and (iii) sympathetic stimulation, noradrenaline, methoxamine or B-HT 933 in ovariectomised diabetic rats. These results suggest that chronic administration of 17ß-oestradiol decreases the vasopressor responses to adrenergic system stimulation in streptozotocin-induced diabetic rats. This report describes the first in vivo study reporting this effect of 17ß-oestradiol in diabetes.

Asunto(s)

Adrenérgicos/farmacología , Diabetes Mellitus Experimental/fisiopatología , Estradiol/administración & dosificación , Estradiol/farmacología , Vasoconstrictores/farmacología , Adrenérgicos/administración & dosificación , Animales , Área Bajo la Curva , Azepinas/administración & dosificación , Azepinas/farmacología , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Diástole/efectos de los fármacos , Estradiol/sangre , Ciclo Estral/efectos de los fármacos , Femenino , Metoxamina/administración & dosificación , Metoxamina/farmacología , Norepinefrina/administración & dosificación , Norepinefrina/farmacología , Ovariectomía , Ratas , Ratas Wistar , Estreptozocina

RESUMEN

PURPOSE: Left ventricular hypertrophy and diastolic dysfunction (LVDD) remain highly frequent markers of cardiac damage and risk of progression to symptomatic heart failure, especially in resistant hypertension (RHTN). We have previously demonstrated that administration of sildenafil in hypertensive rats improves LVDD, restoring phosphodiesterase type 5 (PDE-5) inhibition in cardiac myocytes. METHODS: We hypothesized that the long-acting PDE-5 inhibitor tadalafil may be clinically useful in improving LVDD in RHTN independently of blood pressure (BP) reduction. A single blinded, placebo-controlled, crossover study enrolled 19 patients with both RHTN and LVDD. Firstly, subjects received tadalafil (20 mg) for 14 days and after a 2-week washout period, they received placebo orally for 14 days. Patients were evaluated by office BP and ambulatory BP monitoring (ABPM), endothelial function (FMD), echocardiography, plasma brain natriuretic peptide (BNP-32), cyclic guanosine monophosphate (cGMP) and nitrite levels. RESULTS: No significant differences were detected in BP measurements. Remarkably, at least four echocardiographic parameters related with diastolic function improved accompanied by decrease in BNP-32 in tadalafil use. Although increasing cGMP, tadalafil did not change endothelial function or nitrites. There were no changes in those parameters after placebo. CONCLUSION: The current findings suggest that tadalafil improves LV relaxation through direct effects PDE-5-mediated in the cardiomyocytes with potential benefit as an adjunct to treat symptomatic subjects with LVDD such as RHTN patients.

Asunto(s)

Carbolinas/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Anciano , Presión Sanguínea/efectos de los fármacos , Carbolinas/farmacología , Estudios Cruzados , GMP Cíclico/sangre , Diástole/efectos de los fármacos , Resistencia a Medicamentos , Femenino , Humanos , Hipertensión/sangre , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/sangre , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Nitritos/sangre , Inhibidores de Fosfodiesterasa 5/farmacología , Método Simple Ciego , Tadalafilo , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda/efectos de los fármacos