RESUMEN
We studied changes of pulmonary microhemodynamics when modeling pulmonary artery thromboembolism on perfused isolated rabbit lungs after pretreatment with ranolazine and ivabradine. The increase in pulmonary artery pressure, pulmonary vascular resistance, and pre- and postcapillary resistance was less pronounced than in control animals, but was close to that in case of pulmonary thromboembolism after pretreatment with voltage-gated Na+ channel blockers lidocaine and ropivacaine. The increase of capillary filtration coefficient inversely correlated with values of capillary hydrostatic pressure. Thus, ranolazine and ivabradine exhibit the properties of voltage-gated Na+ channel blockers mainly in smooth muscles of pulmonary arterial vessels and promote the decrease in endothelial permeability.
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Ivabradina , Arteria Pulmonar , Embolia Pulmonar , Ranolazina , Resistencia Vascular , Animales , Conejos , Ivabradina/farmacología , Ivabradina/uso terapéutico , Embolia Pulmonar/tratamiento farmacológico , Embolia Pulmonar/fisiopatología , Ranolazina/farmacología , Resistencia Vascular/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Pulmón/efectos de los fármacos , Pulmón/irrigación sanguínea , Modelos Animales de Enfermedad , Masculino , Lidocaína/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacologíaRESUMEN
BACKGROUND: Heart failure (HF) is a chronic-progressive disease. Once established, it is almost impossible to obtain a restitutio ad integrum of the cardiac function, but current strategies aim at slowing down the progression towards the terminal stages of the disease, which inevitably lead to the exitus. On the basis of these considerations, it appears clear that pharmacological interventions applied in this clinical condition should prevent first the development of the disease, by controlling the risk factors for HF thus reducing the onset of the disease, second slowing the disease evolution towards the terminal phases thus containing clinical symptoms and reducing the number of hospitalizations. In this scenario, the add-on therapy with vericiguat seems promising as reported in the VICTORIA study without affecting renal function. Several evidence indicates that renal arterial resistance index (RRI) seems to better reflect cardiovascular damage also in HF patients, thus affecting patients prognosis METHODS: In the present study we have analyzed the effect of vericiguat administration in 27 HF patients specifically evaluating RRI. RESULTS: Vericiguat signicantly reduces RRI. CONCLUSIONS: The findings of the present study seems to indicate that vericiguat, beyond its primary mechanism of action, might offer an additional advantage in HF patients.
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Insuficiencia Cardíaca , Resistencia Vascular , Humanos , Masculino , Femenino , Anciano , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Persona de Mediana Edad , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiología , Arteria Renal/efectos de los fármacos , Pirimidinas/administración & dosificación , Compuestos Heterocíclicos con 2 AnillosRESUMEN
Angiotensin II (ANG II) is known to play an important role in regulating renal hemodynamics. We sought to quantify this effect in an in vivo rat model with high-resolution renal arterial (RA) impedance. This study examines the effects of ANG II and its type 1 receptor blocker telmisartan (TELM) on RA impedance. In baroreflex-deactivated rats, we measured RA pressure (Pr) and blood flow (Fr) during random ventricular pacing to induce pressure fluctuation at three different mean Pr (60, 80, and 100 mmHg). We then estimated RA impedance as the transfer function from Fr to Pr. The RA impedance was found to align with a three-element Windkessel model consisting of proximal (Rp) and distal (Rd) resistance and compliance (C). Our study showed Rd reflected the composite characteristics of afferent and efferent arterioles. Rd increased with increasing Pr under the baseline condition with a slope of 1.03 ± 0.21 (× 10-1) min·mL-1. ANG II significantly increased the slope by 0.72 ± 0.29 (× 10-1) min·mL-1 (P < 0.05) without affecting the intercept. TELM significantly reduced the intercept by 34.49 ± 4.86 (× 10-1) mmHg·min·mL-1 (P < 0.001) from the baseline value of 37.93 ± 13.36 (× 10-1) mmHg·min·mL-1, whereas it did not affect the slope. In contrast, Rp was less sensitive than Rd to ANG II or TELM, suggesting Rp may represent the characteristics of elastic large arteries. Our findings provide valuable insights into the influence of ANG II on the dynamics of the renal vasculature.NEW & NOTEWORTHY This present method of quantifying high-resolution renal arterial impedance could contribute to elucidating the characteristics of renal vasculature influenced by physiological mechanisms, renal diseases, or pharmacological effects. The present findings help construct a lumped-parameter renal hemodynamic model that reflects the influence of angiotensin II.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II , Angiotensina II , Ratas Sprague-Dawley , Arteria Renal , Circulación Renal , Telmisartán , Resistencia Vascular , Animales , Telmisartán/farmacología , Angiotensina II/farmacología , Masculino , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Arteria Renal/efectos de los fármacos , Circulación Renal/efectos de los fármacos , Resistencia Vascular/efectos de los fármacos , Bencimidazoles/farmacología , Ratas , Benzoatos/farmacología , Modelos CardiovascularesRESUMEN
As individuals age, there is a gradual decline in cardiopulmonary function, often accompanied by cardiac pump dysfunction leading to increased pulmonary vascular resistance (PVR). Our study aims to investigate the changes in cardiac and pulmonary vascular function associated with aging. Additionally, we aim to explore the impact of phosphodiesterase 9A (PDE9A) inhibition, which has shown promise in treating cardiometabolic diseases, on addressing left ventricle (LV) dysfunction and elevated PVR in aging individuals. Young (3 months old) and aged (32 months old) male C57BL/6 mice were used. Aged mice were treated with the selective PDE9A inhibitor PF04447943 (1 mg/kg/day) through intraperitoneal injections for 10 days. LV function was evaluated using cardiac ultrasound, and PVR was assessed in isolated, ventilated lungs perfused under a constant flow condition. Additionally, changes in PVR were measured in response to perfusion of the endothelium-dependent agonist bradykinin or to nitric oxide (NO) donor sodium nitroprusside (SNP). PDE9A protein expression was measured by Western blots. Our results demonstrate the development of LV diastolic dysfunction and increased PVR in aged mice. The aged mice exhibited diminished decreases in PVR in response to both bradykinin and SNP compared to the young mice. Moreover, the lungs of aged mice showed an increase in PDE9A protein expression. Treatment of aged mice with PF04447943 had no significant effect on LV systolic or diastolic function. However, PF04447943 treatment normalized PVR and SNP-induced responses, though it did not affect the bradykinin response. These data demonstrate a development of LV diastolic dysfunction and increase in PVR in aged mice. We propose that inhibitors of PDE9A could represent a novel therapeutic approach to specifically prevent aging-related pulmonary dysfunction.
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Envejecimiento , Ratones Endogámicos C57BL , Resistencia Vascular , Animales , Masculino , Envejecimiento/fisiología , Resistencia Vascular/efectos de los fármacos , Ratones , 3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Disfunción Ventricular Izquierda/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/farmacología , Western BlottingRESUMEN
Dexamethasone is frequently prescribed for preterm infants to wean from respiratory support and/or to facilitate extubation. This pre-/postintervention prospective study ascertained the impact on clinical (respiratory support) and echocardiographic parameters after dexamethasone therapy in preterm fetal growth restriction (FGR) infants compared with appropriate for gestational age (AGA) infants. Echocardiography was performed within 24 h before the start and after completion of 10-day therapy. Parameters assessed included those reflecting pulmonary vascular resistance and right ventricular output. Seventeen FGR infants (birth gestation and birth weight, 25.2 ± 1.1 wk and 497 ± 92 g, respectively) were compared with 22 AGA infants (gestation and birth weight, 24.5 ± 0.8 and 663 ± 100 g, respectively). Baseline respiratory severity score (mean airway pressure × fractional inspired oxygen) was comparable between the groups, (median [interquartile range] FGR, 10 [6, 13] vs. AGA, 8 ± 2.8, P = 0.08). Pre-dexamethasone parameters of pulmonary vascular resistance (FGR, 0.19 ± 0.03 vs. AGA, 0.2 ± 0.03, P = 0.16) and right ventricular output (FGR, 171 ± 20 vs. 174 ± 17 mL/kg/min, P = 0.6) were statistically comparable. At post-dexamethasone assessments, the decrease in the respiratory severity score was significantly greater in AGA infants (median [interquartile range] FGR, 10 [6, 13] to 9 [2.6, 13.5], P = 0.009 vs. AGA, 8 ± 2.8 to 3 ± 1, P < 0.0001). Improvement in measures of pulmonary vascular resistance (ratio of time to peak velocity to right ventricular ejection time) was greater in AGA infants (FGR, 0.19 ± 0.03 to 0.2 ± 0.03, P = 0.13 vs. AGA 0.2 ± 0.03 to 0.25 ± 0.03, P < 0.0001). The improvement in right ventricular output was significantly greater in AGA infants (171 ± 20 to 190 ± 21, P = 0.014 vs. 174 ± 17 to 203 ± 22, P < 0.0001). This highlights differential cardiorespiratory responsiveness to dexamethasone in extremely preterm FGR infants, which may reflect the in utero maladaptive state.NEW & NOTEWORTHY Dexamethasone (DEX) is frequently used in preterm infants dependent on ventilator support. Differences in vascular structure and function that may have developed prenatally arising from the chronic intrauterine hypoxemia in FGR infants may adversely affect responsiveness. The clinical efficacy of DEX was significantly less in FGR (birth weight < 10th centile) infants, compared with appropriate for gestational age (AGA) infants. Echocardiography showed significantly less improvement in pulmonary vascular resistance in FGR, compared with AGA infants.
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Dexametasona , Retardo del Crecimiento Fetal , Recien Nacido Extremadamente Prematuro , Resistencia Vascular , Humanos , Dexametasona/administración & dosificación , Retardo del Crecimiento Fetal/fisiopatología , Retardo del Crecimiento Fetal/tratamiento farmacológico , Recién Nacido , Femenino , Masculino , Estudios Prospectivos , Resistencia Vascular/efectos de los fármacos , Edad Gestacional , Función Ventricular Derecha/efectos de los fármacos , Glucocorticoides/administración & dosificación , Resultado del Tratamiento , Peso al NacerRESUMEN
Background: Living donor kidney transplantation (LDKT) is a crucial treatment for end-stage renal disease, with pre-emptive LDKT (transplantation before dialysis initiation) offering significant benefits in graft function and patient survival. The selection of a vasopressor during LDKT, particularly between norepinephrine and dopamine, and its impact on renal arterial hemodynamics measured using the renal arterial resistive index (RARI) is poorly understood. Methods: This retrospective observational cohort study enrolled 347 eligible pre-emptive LDKT recipients from the Seoul St. Mary's Hospital between January 2019 and June 2023. Utilizing propensity score matching (PSM), the patients were categorized into dopamine and norepinephrine groups to compare the effects of these vasopressors on the intraoperative RARI, postoperative estimated glomerular filtration rate (eGFR), and hourly urine output. The RARI was measured via the Doppler ultrasonography of the renal hilum and parenchyma post-graft vascular and ureteral anastomoses. Results: The preoperative differences in the recipients' and donors' characteristics were mitigated following PSM. The dopamine group exhibited higher intraoperative RARI values at the renal hilum (0.77 ± 0.11 vs. 0.66 ± 0.13, p < 0.001) and parenchyma (0.71 ± 0.1 vs. 0.6 ± 0.1, p < 0.001) compared to those of the norepinephrine group. However, these differences were not statistically significant on postoperative day 7. The norepinephrine infusion adjusted for the propensity scores was associated with significantly lower odds of an RARI > 0.8 (hilum: OR = 0.214, 95% CI = 0.12-0.382, p < 0.001; parenchyma: OR = 0.1, 95% CI = 0.029-0.348, p < 0.001). The early postoperative outcomes showed a higher eGFR (day 1: 30.0 ± 13.3 vs. 25.1 ± 17.4 mL/min/1.73 m2, p = 0.004) and hourly urine output (day 1: 41.8 ± 16.9 vs. 36.5 ± 14.4 mL/kg/h, p = 0.002) in the norepinephrine group. Furthermore, the long-term outcomes were comparable between the groups. Conclusions: Norepinephrine infusion during pre-emptive LDKT is associated with more favorable intraoperative renal arterial hemodynamics, as evidenced by a lower RARI and improved early postoperative renal function compared to those of dopamine. These findings suggest a potential preferential role for norepinephrine in optimizing perioperative management and early graft functions in LDKT recipients. Given the retrospective nature of this study, further prospective studies are needed to confirm these observations. Additionally, the study limitations include the potential for unmeasured confounding factors and the inability to determine causality due to its observational design.
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Dopamina , Trasplante de Riñón , Donadores Vivos , Norepinefrina , Puntaje de Propensión , Arteria Renal , Humanos , Trasplante de Riñón/métodos , Masculino , Femenino , Dopamina/uso terapéutico , Dopamina/administración & dosificación , Estudios Retrospectivos , Persona de Mediana Edad , Norepinefrina/uso terapéutico , Norepinefrina/administración & dosificación , Adulto , Arteria Renal/efectos de los fármacos , Vasoconstrictores/uso terapéutico , Vasoconstrictores/administración & dosificación , Estudios de Cohortes , Resistencia Vascular/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiologíaRESUMEN
Changes in renal hemodynamics impact renal function during physiological and pathological conditions. In this context, renal vascular resistance (RVR) is regulated by components of the Renin-Angiotensin System (RAS) and the Kallikrein-Kinin System (KKS). However, the interaction between these vasoactive peptides on RVR is still poorly understood. Here, we studied the crosstalk between angiotensin-(1-7) and kinins on RVR. The right kidneys of Wistar rats were isolated and perfused in a closed-circuit system. The perfusion pressure and renal perfusate flow were continuously monitored. Ang-(1-7) (1.0-25.0â¯nM) caused a sustained, dose-dependent reduction of relative RVR (rRVR). This phenomenon was sensitive to 10â¯nM A-779, a specific Mas receptor (MasR) antagonist. Bradykinin (BK) promoted a sustained and transient reduction in rRVR at 1.25â¯nM and 125â¯nM, respectively. The transient effect was abolished by 4⯵M des-Arg9-Leu8-bradykinin (DALBK), a specific kinin B1 receptor (B1R) antagonist. Accordingly, des-Arg9-bradykinin (DABK) 1⯵M (a B1R agonist) increased rRVR. Interestingly, pre-perfusion of Ang-(1-7) changed the sustained reduction of rRVR triggered by 1.25â¯nM BK into a transient effect. On the other hand, pre-perfusion of Ang-(1-7) primed and potentiated the DABK response, this mechanism being sensitive to A-779 and DALBK. Binding studies performed with CHO cells stably transfected with MasR, B1R, and kinin B2 receptor (B2R) showed no direct interaction between Ang-(1-7) with B1R or B2R. In conclusion, our findings suggest that Ang-(1-7) differentially modulates kinin's effect on RVR in isolated rat kidneys. These results help to expand the current knowledge regarding the crosstalk between the RAS and KKS complex network in RVR.
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Angiotensina I , Bradiquinina , Fragmentos de Péptidos , Receptor de Bradiquinina B1 , Resistencia Vascular , Animales , Cricetinae , Masculino , Ratas , Angiotensina I/farmacología , Angiotensina I/metabolismo , Angiotensina II/análogos & derivados , Bradiquinina/farmacología , Bradiquinina/análogos & derivados , Células CHO , Cricetulus , Sistema Calicreína-Quinina/fisiología , Sistema Calicreína-Quinina/efectos de los fármacos , Riñón/metabolismo , Riñón/efectos de los fármacos , Cininas/metabolismo , Fragmentos de Péptidos/farmacología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/metabolismo , Ratas Wistar , Receptor de Bradiquinina B1/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Circulación Renal/efectos de los fármacos , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Resistencia Vascular/efectos de los fármacosRESUMEN
Nitric oxide (NO) inhalation improves pulmonary hemodynamics in participants with pulmonary arterial hypertension (PAH). Although it can reduce pulmonary vascular resistance (PVR) in PAH, its impact on the dynamic mechanics of pulmonary arteries and its potential difference between control and participants with PAH remain unclear. PA impedance provides a comprehensive description of PA mechanics. With an arterial model, PA impedance can be parameterized into peripheral pulmonary resistance (Rp), arterial compliance (Cp), characteristic impedance of the proximal arteries (Zc), and transmission time from the main PA to the reflection site. This study investigated the effects of inhaled NO on PA impedance and its associated parameters in control and monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) male rats (6/group). Measurements were obtained at baseline and during NO inhalation at 40 and 80 ppm. In both groups, NO inhalation decreased PVR and increased the left atrial pressure. Notably, its impact on PA impedance was frequency dependent, as revealed by reduced PA impedance modulus in the low-frequency range below 10 Hz, with little effect on the high-frequency range. Furthermore, NO inhalation attenuated Rp, increased Cp, and prolonged transmission time without affecting Zc. It reduced Rp more pronouncedly in MCT-PAH rats, whereas it increased Cp and delayed transmission time more effectively in control rats. In conclusion, the therapeutic effects of inhaled NO on PA impedance were frequency dependent and may differ between the control and MCT-PAH groups, suggesting that the effect on the mechanics differs depending on the pathological state.NEW & NOTEWORTHY Nitric oxide inhalation decreased pulmonary arterial impedance in the low-frequency range (<10 Hz) with little impact on the high-frequency range. It reduced peripheral pulmonary resistance more pronouncedly in pulmonary hypertension rats, whereas it increased arterial compliance and transmission time in control rats. Its effect on the mechanics of the pulmonary arteries may differ depending on the pathological status.
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Óxido Nítrico , Arteria Pulmonar , Resistencia Vascular , Animales , Masculino , Óxido Nítrico/metabolismo , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/efectos de los fármacos , Administración por Inhalación , Resistencia Vascular/efectos de los fármacos , Monocrotalina , Ratas , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/inducido químicamente , Presión Arterial/efectos de los fármacosRESUMEN
BACKGROUND: Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy. METHODS: The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed. FINDINGS: From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group. INTERPRETATION: Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH. FUNDING: Gossamer Bio.
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Hipertensión Arterial Pulmonar , Humanos , Masculino , Método Doble Ciego , Femenino , Persona de Mediana Edad , Adulto , Resultado del Tratamiento , Anciano , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Resistencia Vascular/efectos de los fármacos , Administración por Inhalación , Hipertensión Pulmonar/tratamiento farmacológicoRESUMEN
The principle of proportionality of the systolic area of the central aortic pressure to stroke volume (SV) has been long known. The aim of the present work was to evaluate an in silico solution derived from this principle for modelling SV (iSV model) in cardiovascular safety pharmacology studies by telemetry. Blood pressure was measured in the abdominal aorta in accordance with standard practice. Central aortic pressure was modelled from the abdominal aortic pressure waveform using the N-point moving average (NPMA) method for beat-to-beat estimation of SV. First, the iSV was compared to the SV measured by ultrasonic flowmetry in the ascending aorta (uSV) after various pharmacological challenges in beagle dogs anaesthetised with etomidate/fentanyl. The iSV showed minimal bias (0.2 mL i.e. 2%) and excellent agreement with uSV. Then, previous telemetry studies including reference vasoactive and inotropic compounds were retrospectively reanalysed to model drug effects on stroke volume (iSV), cardiac output (iCO) and systemic vascular resistance (iSVR). Among them, the examples of nicardipine and isoprenaline highlight risks of erroneous or biased estimation of drug effects from the abdominal aortic pressure due to pulse pressure amplification. Furthermore, the examples of verapamil, quinidine and moxifloxacin show that iSV, iCO and iSVR are earlier biomarkers than blood pressure itself for predicting drug effect on blood pressure. This in silico modelling approach included in vivo telemetry safety pharmacology studies can be considered as a New Approach Methodology (NAM) that provides valuable additional information and contribute to improving non-clinical translational research to the clinic.
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Gasto Cardíaco , Simulación por Computador , Volumen Sistólico , Telemetría , Resistencia Vascular , Animales , Perros , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Resistencia Vascular/efectos de los fármacos , Telemetría/métodos , Gasto Cardíaco/efectos de los fármacos , Gasto Cardíaco/fisiología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , MasculinoRESUMEN
BACKGROUND: Despite major advances in the pharmacologic treatment of hypertension in the nonpregnant population, treatments for hypertension in pregnancy have remained largely unchanged over the years. There is recent evidence that a more adequate control of maternal blood pressure is achieved when the first given antihypertensive drug is able to correct the underlying hemodynamic disorder of the mother besides normalizing the blood pressure values. OBJECTIVE: This study aimed to compare the blood pressure control in women receiving an appropriate or inappropriate antihypertensive therapy following the baseline hemodynamic findings. STUDY DESIGN: This was a prospective multicenter study that included a population of women with de novo diagnosis of hypertensive disorders of pregnancy. A noninvasive assessment of the following maternal parameters was performed on hospital admission via Ultrasound Cardiac Output Monitor before any antihypertensive therapy was given: cardiac output, heart rate, systemic vascular resistance, and stroke volume. The clinician who prescribed the antihypertensive therapy was blinded to the hemodynamic evaluation and used as first-line treatment a vasodilator (nifedipine or alpha methyldopa) or a beta-blocker (labetalol) based on his preferences or on the local protocols. The first-line pharmacologic treatment was retrospectively considered hemodynamically appropriate in either of the following circumstances: (1) women with a hypodynamic profile (defined as low cardiac output [≤5 L/min] and/or high systemic vascular resistance [≥1300 dynes/second/cm2]) who were administered oral nifedipine or alpha methyldopa and (2) women with a hyperdynamic profile (defined as normal or high cardiac output [>5 L/min] and/or low systemic vascular resistances [<1300 dynes/second/cm2]) who were administered oral labetalol. The primary outcome of the study was to compare the occurrence of severe hypertension between women treated with a hemodynamically appropriate therapy and women treated with an inappropriate therapy. RESULTS: A total of 152 women with hypertensive disorders of pregnancy were included in the final analysis. Most women displayed a hypodynamic profile (114 [75.0%]) and received a hemodynamically appropriate treatment (116 [76.3%]). The occurrence of severe hypertension before delivery was significantly lower in the group receiving an appropriate therapy than in the group receiving an inappropriately treated (6.0% vs 19.4%, respectively; P=.02). Moreover, the number of women who achieved target values of blood pressure within 48 to 72 hours from the treatment start was higher in the group who received an appropriate treatment than in the group who received an inappropriate treatment (70.7% vs 50.0%, respectively; P=.02). CONCLUSION: In pregnant individuals with de novo hypertensive disorders of pregnancy, a lower occurrence of severe hypertension was observed when the first-line antihypertensive agent was tailored to the correct maternal hemodynamic profile.
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Antihipertensivos , Hemodinámica , Labetalol , Preeclampsia , Humanos , Femenino , Embarazo , Antihipertensivos/uso terapéutico , Antihipertensivos/farmacología , Antihipertensivos/administración & dosificación , Estudios Prospectivos , Adulto , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Preeclampsia/fisiopatología , Preeclampsia/tratamiento farmacológico , Preeclampsia/diagnóstico , Labetalol/administración & dosificación , Labetalol/farmacología , Gasto Cardíaco/efectos de los fármacos , Gasto Cardíaco/fisiología , Nifedipino/farmacología , Nifedipino/administración & dosificación , Nifedipino/uso terapéutico , Resistencia Vascular/efectos de los fármacos , Metildopa/administración & dosificación , Metildopa/farmacología , Metildopa/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Hipertensión Inducida en el Embarazo/tratamiento farmacológico , Hipertensión Inducida en el Embarazo/fisiopatología , Hipertensión Inducida en el Embarazo/diagnóstico , Resultado del Tratamiento , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacología , Vasodilatadores/uso terapéuticoRESUMEN
OBJECTIVES: To determine the utility of using total peripheral systemic vascular resistance assessed using non-invasive cardiac monitor for individualizing the duration of postpartum magnesium sulfate in individuals with preeclampsia with severe features. STUDY DESIGN: Single center pilot randomized controlled trial in which singleton pregnant individuals with preeclampsia with severe features were randomized to 24 h of postpartum magnesium sulfate per standard of care (control group) or individualized duration of postpartum magnesium sulfate based on reduction in post-delivery systemic vascular resistance (intervention group). Systemic vascular resistance was assessed with non-invasive cardiac monitoring using the Cheetah® system. A 30 % reduction (maintained for 1 h) from baseline post-delivery systemic vascular resistance was used as a cutoff for discontinuation of postpartum magnesium sulfate. Our primary outcome was duration of postpartum magnesium sulfate use in hours. Secondary outcomes included a composite of maternal morbidities associated with preeclampsia. RESULTS: Of 53 individuals enrolled, we excluded 6 from this analysis due to insufficient data to assess primary outcome. Baseline characteristics of the control (n = 26) and intervention (n = 21) groups were similar. Six (28.6 %) individuals in intervention group met the systemic vascular resistance criteria and had their postpartum magnesium sulfate discontinued before 24 h. The duration of postpartum magnesium sulfate infusion was shorter in the intervention group (21.6 ± 4.7 h; range: 7-24 h) compared with control group (24 h, p = 0.02). There was no difference in secondary outcomes between the two groups. There was no difference in adverse outcomes in individuals that had magnesium discontinued earlier than 24 h. CONCLUSION: Non-invasive monitoring of systemic vascular resistance can be a valuable tool to individualize the duration of postpartum magnesium sulfate for preeclampsia with severe features. These findings should be conformed in a larger trial.
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Sulfato de Magnesio , Periodo Posparto , Preeclampsia , Resistencia Vascular , Humanos , Femenino , Sulfato de Magnesio/administración & dosificación , Preeclampsia/tratamiento farmacológico , Embarazo , Adulto , Resistencia Vascular/efectos de los fármacos , Proyectos Piloto , Monitoreo Fisiológico/métodosRESUMEN
One of the reasons of the development of pathologies causing death is hypoxia. The purposes of this study were (1) to study some physiological and biochemical mechanisms of α2-adrenoblockers, which ensure the tissue resistance increase to hypoxia; (2) to offer new drugs contributing to the increase of tissues' stability towards the hypoxic affection; and (3) to submit new medications to surpass by their anti-hypoxic activity of those already used in modern medicine and have some advantages. The reactivity of postsynaptic vascular α2-adrenoceptors was determined on the damaged spinal cord expressed by the blood pressure increase in response to intravenous administration of azepexole that selectively binds to α2-adrenoceptors. Determination of the systemic hemodynamic values and the vascular resistance to the blood flow was performed by the method with plastic microspheres of marked isotopes. pO2 in the blood and the oxygen-transporting function were determined in a sample of 0.1 ml of blood in 30, 90, and 180 min after the α2-adrenoblockers' injections. It has been found that one of the major hemodynamic effects of mesedin and beditin was an improvement in cardiac output, as well as a prolonged increase in coronary blood flow and vasodilation of the heart vessels. Some anti-hypoxic mechanisms of the studied α2-adrenoblockers are an improvement of blood oxygen-transporting function followed by tissue oxygenation and the increased level of corticosterone and resistance to hypoxia. Revealing the mechanisms of action of the postsynaptic α2-adrenoceptors suggests that mesedin and beditin are potentially effective therapeutic means for many hypoxic conditions.
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Antagonistas de Receptores Adrenérgicos alfa 2 , Sistema Cardiovascular , Hipoxia , Animales , Masculino , Ratas , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Presión Sanguínea/efectos de los fármacos , Sistema Cardiovascular/efectos de los fármacos , Corticosterona/sangre , Hemodinámica/efectos de los fármacos , Hipoxia/tratamiento farmacológico , Hipoxia/fisiopatología , Oxígeno/metabolismo , Ratas Wistar , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Resistencia Vascular/efectos de los fármacosRESUMEN
BACKGROUND: An increasing number of hypertensive persons travel to high altitude (HA) while using antihypertensive medications such as beta-blockers. Nevertheless, while hypoxic exposure initiates an increase in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), the contribution of the autonomic nervous system is unclear. In animals, beta-adrenergic blockade has induced pulmonary vasoconstriction in normoxia and exaggerated hypoxic pulmonary vasoconstriction (HPV) and both effects were abolished by muscarinic blockade. We thus hypothesized that in humans, propranolol (PROP) increases Ppa and PVR in normoxia and exaggerates HPV, and that these effects of PROP are abolished by glycopyrrolate (GLYC). METHODS: In seven healthy male lowlanders, Ppa was invasively measured without medication, with PROP and PROP + GLYC, both at sea level (SL, 488 m) and after a 3-week sojourn at 3454 m altitude (HA). Bilateral thigh-cuff release manoeuvres were performed to derive pulmonary pressure-flow relationships and pulmonary vessel distensibility. RESULTS: At SL, PROP increased Ppa and PVR from (mean ± SEM) 14 ± 1 to 17 ± 1 mmHg and from 69 ± 8 to 108 ± 11 dyn s cm-5 (21% and 57% increase, P = 0.01 and P < 0.0001). The PVR response to PROP was amplified at HA to 76% (P < 0.0001, P[interaction] = 0.05). At both altitudes, PROP + GLYC abolished the effect of PROP on Ppa and PVR. Pulmonary vessel distensibility decreased from 2.9 ± 0.5 to 1.7 ± 0.2 at HA (P < 0.0001) and to 1.2 ± 0.2 with PROP, and further decreased to 0.9 ± 0.2% mmHg-1 with PROP + GLYC (P = 0.01). CONCLUSIONS: Our data show that beta-adrenergic blockade increases, and muscarinic blockade decreases PVR, whereas both increase pulmonary artery elastance. Future studies may confirm potential implications from the finding that beta-adrenergic blockade exaggerates HPV for the management of mountaineers using beta-blockers for prevention or treatment of cardiovascular conditions.
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Antagonistas Adrenérgicos beta , Altitud , Hipoxia , Propranolol , Arteria Pulmonar , Resistencia Vascular , Vasoconstricción , Masculino , Humanos , Resistencia Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Adulto , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Antagonistas Adrenérgicos beta/farmacología , Hipoxia/fisiopatología , Propranolol/farmacología , Glicopirrolato/farmacologíaRESUMEN
BACKGROUND: Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. METHODS: We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. RESULTS: A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. CONCLUSIONS: In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).
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Hipertensión Arterial Pulmonar , Proteínas Recombinantes de Fusión , Adulto , Humanos , Método Doble Ciego , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/diagnóstico , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico , Resultado del Tratamiento , Resistencia Vascular/efectos de los fármacos , Inyecciones Subcutáneas , Prueba de Paso , Tolerancia al Ejercicio/efectos de los fármacos , Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/efectos adversos , Fármacos Cardiovasculares/farmacología , Fármacos Cardiovasculares/uso terapéutico , Fármacos del Sistema Respiratorio/administración & dosificación , Fármacos del Sistema Respiratorio/efectos adversos , Fármacos del Sistema Respiratorio/farmacología , Fármacos del Sistema Respiratorio/uso terapéuticoRESUMEN
PURPOSE: Previous work suggests that endurance-trained athletes have superior pulmonary vasculature function as compared to untrained individuals, which may contribute to their greater maximal oxygen uptake ([Formula: see text]O2max). Inhaled nitric oxide (iNO) reduces pulmonary vascular resistance in healthy individuals, which could translate into greater cardiac output and improved [Formula: see text]O2max, particularly in untrained individuals. The purpose of the study was to examine whether iNO improved [Formula: see text]O2max in endurance trained and untrained individuals. METHODS: Sixteen endurance-trained and sixteen untrained individuals with normal lung function completed this randomized double-blind cross-over study over four sessions. Experimental cardiopulmonary exercise tests were completed while breathing either normoxia (placebo) or 40 ppm of iNO, on separate days (order randomized). On an additional day, echocardiography was used to determine pulmonary artery systolic pressure at rest and during sub-maximal exercise (60 Watts) while participants breathed normoxia or iNO. RESULTS: Right ventricular systolic pressure was significantly reduced by iNO during exercise (Placebo: 34 ± 7 vs. iNO: 32 ± 7; p = 0.04). [Formula: see text]O2max was greater in the endurance trained group (Untrained: 3.1 ± 0.7 vs. Endurance: 4.3 ± 0.9 L min-1; p < 0.01), however, there was no effect of condition (p = 0.79) and no group by condition interaction (p = 0.68). Peak cardiac output was also unchanged by iNO in either group. CONCLUSION: Despite a reduction in right ventricular systolic pressure, the lack of change in [Formula: see text]O2max with iNO suggests that the pulmonary vasculature does not limit [Formula: see text]O2max in young healthy individuals, regardless of fitness level.
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Entrenamiento Aeróbico , Óxido Nítrico/administración & dosificación , Óxido Nítrico/farmacología , Consumo de Oxígeno/fisiología , Resistencia Vascular/efectos de los fármacos , Administración por Inhalación , Adulto , Ecocardiografía , Prueba de Esfuerzo , Femenino , Voluntarios Sanos , Humanos , Masculino , Pruebas de Función RespiratoriaAsunto(s)
Procedimientos Quirúrgicos Cardíacos , Hipertensión Pulmonar , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Puente Cardiopulmonar/efectos adversos , Cardiotónicos , Niño , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Simendán/efectos adversos , Resistencia Vascular/efectos de los fármacosRESUMEN
Levosimendan exerts positive inotropic and vasodilatory effects. Currently, its effects on right heart function remain uncertain. This systematic review and meta-analysis is intended to illustrate the impacts of levosimendan on systolic function of the right heart in patients with heart dysfunction. We systematically searched electronic databases (PubMed, the Cochrane Library, Embase and Web of Science) up to November 30, 2020, and filtered eligible studies that reported the impacts of levosimendan on right heart function. Of these, only studies whose patients suffered from heart dysfunction or pulmonary hypertension were included. Additionally, patients were divided into two groups (given levosimendan or not) in the initial research. Then, RevMan5.3 was used to conduct further analysis. A total of 8 studies comprising 390 patients were included. The results showed that after 24 h of levosimendan, patients' right ventricular fractional area change [3.17, 95% CI (2.03, 4.32), P < 0.00001], tricuspid annular plane systolic excursion [1.26, 95% CI (0.35, 2.16), P = 0.007] and tricuspid annular peak systolic velocity [0.86, 95% CI (0.41, 1.32), P = 0.0002] were significantly increased compared to the control group. And there is an increasing trend of cardiac output in levosimendan group [1.06, 95% CI (- 0.16, 2.29), P = 0.09 ] .Furthermore, patients' systolic pulmonary arterial pressure [- 5.57, 95% CI (- 7.60, - 3.54), P < 0.00001] and mean pulmonary arterial pressure [- 1.01, 95% CI (- 1.64, - 0.37), P = 0.002] were both significantly decreased, whereas changes in pulmonary vascular resistance [- 55.88, 95% CI (- 206.57, 94.82), P = 0.47] were not significant. Our study shows that in patients with heart dysfunction, levosimendan improves systolic function of the right heart and decreases the pressure of the pulmonary artery.
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Cardiotónicos , Simendán/administración & dosificación , Simendán/farmacología , Vasodilatadores , Disfunción Ventricular Derecha/tratamiento farmacológico , Anciano , Gasto Cardíaco/efectos de los fármacos , Femenino , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Masculino , Persona de Mediana Edad , Sístole/efectos de los fármacos , Resistencia Vascular/efectos de los fármacos , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Derecha/efectos de los fármacosRESUMEN
Endotoxemia-activated tumor necrosis factor (TNFα)/nuclear factor kappa B (NFκB) signals result in acute on chronic inflammation-driven renal dysfunction in advanced cirrhosis. Systemic activation of peroxisome proliferator-activated receptor gamma (PPARγ) with pioglitazone can suppress inflammation-related splanchnic and pulmonary dysfunction in cirrhosis. This study explored the mechanism and effects of pioglitazone treatment on the abovementioned renal dysfunction in cirrhotic rats. Cirrhotic ascitic rats were induced with renal dysfunction by bile duct ligation (BDL). Then, 2 weeks of pioglitazone treatment (Pio, PPAR gamma agonist, 12 mg/kg/day, using the azert osmotic pump) was administered from the 6th week after BDL. Additionally, acute lipopolysaccharide (LPS, Escherichia coli 0111:B4; Sigma, 0.1 mg/kg b.w, i.p. dissolved in NaCl 0.9%) was used to induce acute renal dysfunction. Subsequently, various circulating, renal arterial and renal tissue pathogenic markers were measured. Cirrhotic BDL rats are characterized by decreased mean arterial pressure, increased cardiac output and portal venous pressure, reduced renal arterial blood flow (RABF), increased renal vascular resistance (RVR), increased relative renal weight/hydroxyproline, downregulated renal PPARγ expression, upregulated renal inflammatory markers (TNFα, NFκB, IL-6, MCP-1), increased adhesion molecules (VCAM-1 and ICAM-1), increased renal macrophages (M1, CD68), and progressive renal dysfunction (increasing serum and urinary levels of renal injury markers (lipocalin-2 and IL-18)). In particular, acute LPS administration induces acute on chronic renal dysfunction (increasing serum BUN/creatinine, increasing RVR and decreasing RABF) by increased TNFα-NFκB-mediated renal inflammatory markers as well as renal M1 macrophage infiltration. In comparison with the BDL+LPS group, chronic pioglitazone pre-treatment prevented LPS-induced renal pathogenic changes in the BDL-Pio+LPS group. Activation of systemic, renal vessel and renal tissue levels of PPARγ by chronic pioglitazone treatment has beneficial effects on the endotoxemia-related TNFα/NFκB-mediated acute and chronic renal inflammation in cirrhosis. This study revealed that normalization of renal and renal arterial levels of PPARγ effectively prevented LPS-induced acute and chronic renal dysfunction in cirrhotic ascitic rats.
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Ascitis/complicaciones , Endotoxemia/complicaciones , Riñón/fisiopatología , Cirrosis Hepática/complicaciones , Pioglitazona/farmacología , Enfermedad Aguda , Alanina Transaminasa/sangre , Animales , Ascitis/sangre , Conductos Biliares/patología , Bilirrubina/sangre , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/patología , Enfermedad Crónica , Regulación hacia Abajo/efectos de los fármacos , Endotoxemia/sangre , Endotoxinas/sangre , Inflamación/sangre , Inflamación/complicaciones , Inflamación/patología , Interleucina-6/sangre , Riñón/efectos de los fármacos , Ligadura , Lipopolisacáridos/administración & dosificación , Cirrosis Hepática/sangre , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , FN-kappa B/metabolismo , PPAR gamma/agonistas , PPAR gamma/metabolismo , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/sangre , Resistencia Vascular/efectos de los fármacosRESUMEN
The balance between endothelial nitric oxide (NO) synthase (eNOS) activation and production of reactive oxygen species (ROS) is very important for NO homeostasis in liver sinusoidal endothelial cells (LSECs). Overexpression of cyclooxygenase-2 (COX-2), a major intravascular source of ROS production, has been observed in LSECs of cirrhotic liver. However, the links between low NO bioavailability and COX-2 overexpression in LSECs are unknown. This study has confirmed the link between low NO bioavailability and COX-2 overexpression by COX-2-dependent PGE2-EP2-ERK1/2-NOX1/NOX4 signalling pathway in LSECs in vivo and in vitro. In addition, the regulation of COX-2-independent LKB1-AMPK-NRF2-HO-1 signalling pathway on NO homeostasis in LSECs was also elucidated. The combinative effects of celecoxib on diminishment of ROS via COX-2-dependent and COX-2-independent signalling pathways greatly decreased NO scavenging. As a result, LSECs capillarisation was reduced, and endothelial dysfunction was corrected. Furthermore, portal hypertension of cirrhotic liver was ameliorated with substantial decreasing hepatic vascular resistance and great increase of portal blood flow. With the advance understanding of the mechanisms of LSECs protection, celecoxib may serve as a potential therapeutic candidate for patients with cirrhotic portal hypertension.