El conocimiento de las propiedades farmacocinéticas-farmacodinámicas (PK/PD) de los fármacos puede optimizar la terapia antihipertensiva. El modelado PK/PD en la investigación clínica podría contribuir en el desarrollo del fármaco y en la práctica clínica en varios aspectos, entre ellos la evaluación de eficacia y seguridad de los antihipertensivos, mayor información durante el proceso del desarrollo, identificación de factores de variabilidad de la respuesta farmacológica, y permitir además una identificación rápida de malos respondedores o no respondedores y ayudar a determinar requerimientos óptimos del fármaco y dosis en cada paciente hipertenso. Hay algunas limitaciones en el modelado PK/PD de los antihipertensivos en la práctica clínica, entre las que se incluyen el uso de modelos farmacodinámicos inadecuados y la incapacidad de estudiar dosis elevadas de antihipertensivos para determinar el rango farmacodinámico completo del efecto antihipertensivo. El propósito de esta revisión es describir el conocimiento actual del modelado PK/PD de los fármacos antihipertensivos en la investigación clínica y sus usos futuros.

Con el objetivo en este estudio de evaluar los efectos cardiovasculares y la farmacocinética del nebivolol en ratas hipertensas por sobrecarga de fructosa y en ratas control, se registraron los efectos de la administración intravenosa de nebivolol, 3 mg/kg o 10 mg/kg, sobre la presión arterial, la frecuencia cardíaca y la variabilidad de la presión arterial a corto plazo y latido-a-latido, y se evaluó la farmacocinética enantioselectiva a partir del análisis de la concentración plasmática de los enantiómeros d-nebivolol y l-nebivolol. La variabilidad de la presión arterial a corto plazo y latido-a-latido se evaluó mediante la desviación estándar y el análisis espectral del registro de la presión arterial, respectivamente. El estado hipertensivo alteró la farmacocinética del nebivolol, evidenciado por una reducción en el aclaramiento del nebivolol en el grupo fructosa respecto del grupo control luego de la administración de la dosis más alta. El efecto antihipertensivo del nebivolol fue similar en ambos grupos, en tanto que el efecto bradicardizante fue mayor en las ratas del grupo control. Aunque no se observaron diferencias significativas en la variabilidad de la presión arterial latido-a-latido, la reducción de la variabilidad de la presión arterial a corto plazo inducida por el nebivolol fue significativamente superior en las ratas del grupo fructosa en comparación con los animales normotensos (-57,9% ± 11,8% vs. -19,6% ± 9,2%; p < 0,05). En conclusión, si bien el nebivolol reduce la presión arterial y la variabilidad de la presión arterial en ambos grupos, no se encontraron diferencias significativas en las ratas con sobrecarga de fructosa en cuanto a la farmacocinética y los efectos cardiovasculares, a excepción de una eficacia bradicardizante menor y una reducción mayor de la variabilidad de la presión arterial a corto plazo.

Background: Telmisartan and irbesartan, two of the main AT1 receptor antagonists available for the control of cardiovascular diseases, differ in their pharmacological properties, including time of dissociation from the AT1 receptor and the ability to activate other receptors, with potential impact on their relative clinical efficacy.Objectives: The aim of this study was to compare the acute cardiovascular response to single dose administration of irbesartan or telmisartan in spontaneously hypertensive rats.Methods: Twenty-four male spontaneously hypertensive rats, weighing 250-275 g, were used. The carotid artery and femoral vein were cannulated for direct mean arterial pressure measurement (MAP) and irbesartan 3-6 mg/kg or telmisartan 0,5-1 mg/kg administration. Changes in MAP, heart rate and short-term and beat-to-beat blood pressure variability were estimated.Results: Although both antagonists reduced MAP, telmisartan induced a longer antihypertensive response than irbesartan, evidenced by greater MAP reduction after 180 min (-33.3%±4.1% vs. -16.3%±4%; p<0.05). Telmisartan and irbesartan induced sustained reduction of short-term blood pressure variability without significant differences between both experimental groups. At the lower dose level, telmisartan produced greater decrease of heart rate and beat-to-beat blood pressure variability at the different frequency domains compared with irbesartan.Conclusions: In spontaneously hypertensive rats, telmisartan administration induces a more persistent antihypertensive response and a greater bradycardic response than irbesartan. Spectral analysis of beat-to-beat blood pressure variability suggests that low dose telmisartan produces greater attenuation of vascular sympathetic activity compared with irbesartan.

Background/Objective: World Health Organization latest statistics state that 17% of infectious diseases are transmitted by vectors, causing more than 700,000 deaths each year. Particularly, dengue (DENV), Zika (ZIKV) and yellow fever (YFV) viral infections have generated international awareness due to their epidemic proportion and risks of international spread. In this framework, the repositioning strategy of Efavirenz (EFV) represents a key clinical feature to improve different antiviral therapies. Therefore, the development of Soluplus®-based nanomicelles (NMs) loaded with EFV (10 mg/mL) for optimized oral pharmacotherapy against ZIKV, DENV and YFV infections was investigated. Methods: EFV-NMs were obtained by an acetone diffusion technique. Micellar size and in vitro micellar interaction with mucin were assessed by dynamic light scattering. In vitro cytocompatibility was investigated in A549 and Vero cells and micellar in vitro antiviral activity against ZIKV, DENV and YFV was evaluated. In vivo oral bioavailability and histological studies were assessed in Wistar rats. Results: EFV encapsulation within Soluplus® NMs increased the drug’s apparent aqueous solubility up to 4803-fold with a unimodal micellar size distribution and a micellar size of ~90 nm at 25 and 37 °C. Micellar in vitro interaction with mucin was also assessed in a pH range of 1.2–7.5 and its storage micellar physicochemical stability at 4 °C was confirmed over 2 years. In vitro cytocompatibility assays in A549 and Vero cells confirmed that EFV micellar dispersions resulted in safe nanoformulations. Interestingly, EFV-loaded NMs exhibited significantly higher in vitro antiviral activity compared with EFV solution for all the tested flaviviruses. In addition, the selectivity index (SI) values reveal that EFV-loaded NMs exhibited considerably more biological efficacy compared to EFV solution in A549 and Vero cell lines and for each viral infection (SI > 10). Further, the drug pharmacokinetics parameters were enhanced after the oral administration of EFV-loaded NMs, being biocompatible by not causing damage in the gastrointestinal segments. Conclusions: Overall, our EFV nanoformulation highlighted its potential as a novel drug delivery platform for optimized ZIKV, DENV and YFV antiviral therapy.

The present investigation was focused on the development of Soluplus (R)-based nanomicelles (NMs) (10 % w/v) loaded with Efavirenz (EFV) (5 mg/mL) and Curcumin (natural bio-enhancer) (CUR) (5, 10 and 15 mg/mL) to improve the oral bioavalability of EFV. Micellar formulations were obtained employing an acetone-diffusion technique. Apparent aqueous solubility was increased up to similar to 1250-fold and 25,000-fold for EFV and CUR, respectively. Drug-loaded nanoformulations showed an excellent colloidal stability with unimodal size distribution and PDI values < 0.30. In vitro drug release was 41.5 % (EFV) and 2.6 % (CUR) from EFV-CUR-NMs over 6 h in simulated gastrointestinal fluids. EFV-CUR-loaded NMs resulted as safe nanoformulations according to the in vitro cytocompatibility assays in Caco-2 cells. Furthermore, CUR bio-enhancer activity was demonstrated for those nanoformulations. A CUR concentration of 15 mg/mL produced a significant (p < 0.05) increment (2.64-fold) of relative EFV oral bioavailability. Finally, the active role of the lymphatic system in the absorption process of EFV, after its oral administration was assessed in a comparative pharmacokinetic study in presence and absence of cycloheximide, a lymphatic transport inhibitor. Overall our EFV-CUR-NMs denoted their potential as a novel nanotechnological platform, representing a step towards an optimized "nano-sized" therapy for AIDS patients.

INTRODUCTION:Chronic pulmonary aspergillosis is a fungal disease that, without specific treatment, generates a slow and progressive destruction of the lung parenchyma. The recommended pharmacological therapy is long-term oral antifungal administration. The efficacy of the treatment (especially with itraconazole) is around 65% and the frequency of recurrences 10-15%. One of the causes could be a deficient plasma level of itraconazole. The objective was to implement therapeutic monitoring (TM) of itraconazole using a sensitive, precise, rapid and reproducible method. Then, based to the results obtained, take a therapeutic approach. MATERIALS AND METHODS:Two venous blood samples of approximately 2 ml were obtained from each patient, which were analyzed by liquid chromatography (HPLC). RESULTS:Samples were taken from 36 patients and mycological, antibody and MT of itraconazole studies were performed. A total of 10 patients (27.8 %) showed levels outside the therapeutic range. DISCUSSION:The TM of itraconazole is a useful tool to improve the effectiveness of chronic pulmonary aspergillosis treatment, the prognosis of the pathology and reduce the percentage of recurrences. The developed method is fast, precise and reproducible, for this reason it can be very useful to be applied in the public hospital setting, where there is precisely no similar one, and thus modify therapeutic behaviors in order to optimize treatments.

β-Adrenergic blockers are no longer recommended as first-line therapy due to the reduced cardioprotection of traditional β-blockers compared with other antihypertensive drugs. It is unknown whether third-generation β-blockers share the limitations of traditional β-blockers. The aim of the present study was to compare the effects of nebivolol or atenolol on central and peripheral systolic blood pressure (SBP) and its variability and target organ damage (TOD) in N-nitro-L-arginine methyl ester (L-NAME) hypertensive rats. Male Wistar rats were treated with L-NAME for 8 weeks together with oral administration of nebivolol 30 mg/kg (n = 8), atenolol 90 mg/kg (n = 8), or vehicle (n = 8). The control group was composed of vehicle-treated Wistar rats. SBP and its variability, as well as echocardiographic parameters, were assessed during the last 2 weeks of treatment. Tissue levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor β (TGF-β), and histopathological parameters were evaluated in the left ventricle and aorta. Nebivolol had a greater ability than atenolol to decrease central SBP and mid-term and short-term blood pressure variability (BPV) in L-NAME rats. Echocardiographic analysis showed that nebivolol was more effective than atenolol on E/A wave ratio normalization. Compared with atenolol treatment, nebivolol had a greater protective effect on different TOD markers, inducing a decrease in collagen deposition and a reduction in the proinflammatory cytokines IL-6 and TNF-α in the left ventricle and aorta. Our findings suggest that the adverse hemodynamic profile and the reduced cardiovascular protection reported with traditional β-blockers must not be carried forward to third-generation β-blockers.

BACKGROUND:β-blockers are no longer considered as first-line antihypertensive drugs due to their lower cardioprotection.METHOD:Considering the differences in the pharmacological properties of β-blockers, the present work compared the effects of third-generation β-blockers - carvedilol and nebivolol - with a first-line agent - amlodipine - on hemodynamic parameters, including short-term blood pressure variability (BPV), and their ability to prevent target organ damage in spontaneously hypertensive rats (SHR). SHR rats were orally treated with carvedilol, nebivolol, atenolol, amlodipine or vehicle for 8 weeks. Wistar Kyoto rats treated with vehicle were used as normotensive group. Echocardiographic evaluation, BP, and short-term BPV measurements were performed. Left ventricle and thoracic aorta were removed for histological evaluations and to assess the expression of transforming growth factor β (TGF-β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).RESULTS:Carvedilol, nebivolol or amlodipine induced a greater reduction of carotid BP, short-term BPV and echocardiography parameters than atenolol in SHR rats. Carvedilol, nebivolol and amlodipine were more effective than atenolol in the prevention of cardiac hypertrophy, and cardiac and aortic collagen deposit. Carvedilol and nebivolol, but not atenolol, reduced the expressions of fibrotic and inflammatory biomarkers - TGF-β, TNF-α and IL-6 - in SHR rats to a similar extent to that of amlodipine.CONCLUSION:Chronic treatment with carvedilol or nebivolol attenuates carotid BP and short-term BPV, and reduces target organ damage in SHR to a greater extent than atenolol. Our findings suggest that the lower cardiovascular protection of nonvasodilating β-blockers, as atenolol, in hypertension must not be translated to third-generation β-blockers.

espanolObjetivo: El objetivo del presente estudio fue el desarrollo y la evaluacion farmacocinetica y farmacodinamica de la liberacionin vivo de implantes subcutaneos de carvedilol capaces de aportar niveles tisulares estables en modelos experimentales dehipertension arterial.La incorporacion del polimero hidrofilico SoluPlus (SP) en los implantes PCL:SP 150:150 y 50:250 favorece un incrementode la liberacion de carvedilol dado que aporta concentraciones plasmaticas en el rango de 100-200 ng/mL durante 2 semanas,lo que tiene como resultado una reduccion sostenida de la presion arterial sistolica indirecta en animales SHR.Material y metodos: Se prepararon implantes subcutaneos de poli (epsilon-caprolactona) (PCL) con diferentes proporcionesdel polimero hidrofilico SoluPlus (300:0; 250:50; 150:150 y 50:250 mg) cargados con 100 mg de carvedilol. Se evaluo el perfilplasmatico y el efecto sobre la presion arterial sistolica (PAS) luego del implante de cada formulacion en el tejido subcutaneode ratas espontaneamente hipertensas (REH) macho.Resultados: Las formulaciones PCL:SP 50:250 y 150:150 aportaron niveles en el rango de 100-200 ng/mL. Las formulacionesPCL:SP 250:50 y 300:0 aportaron concentraciones inferiores de carvedilol comprendidas en el rango de los 0-100 ng/mL duranteel transcurso del tratamiento. Los animales espontaneamente hipertensos tratados con PCL:SP 50:250 y 150:150 experimentaronun descenso significativo de la presion arterial sistolica (PCL:SP 50:250: DPAS: –36,6 ± 2,0 mmHg; PCL:SP150:150:35,7 ± 2,2 mmHg; p EnglishObjective: The aim of this study was the development and pharmacokinetic/pharmacodynamic evaluation of the in vivo releaseof subcutaneous implants of carvedilol capable of providing stable tissue levels in experimental models of hypertension.Methods: The subcutaneous implants were prepared with poly (epsilon-caprolactone) (PCL) and different proportions of theSoluPlus (SP) hydrophilic polymer (300:0; 250:50; 150:150 and 50:250 mg) loaded with 100 mg carvedilol. The plasma profileand the effect on systolic blood pressure (SBP) after subcutaneous implantation of each formulation was evaluated in malespontaneously hypertensive rats (SHR).Results: The PCL:SP 50:250 and 150:150 formulations provided levels ranging from 100 to 200 ng/mL and the PCL:SP 250:50and 300:0 formulations provided lower concentrations of carvedilol ranging from 0 to 100 ng/mL during the treatment period.Spontaneously hypertensive animals treated with the PCL:SP 50:250 y 150:150 implants presented a significant decrease inSBP (PCL:SP 50:250: DPAS: –36.6 ± 2.0 mm Hg; PCL:SP150:150: -35.7 ± 2.2 mmHg; p

Introduction: Although main antihypertensive drugs are able to efficiently reduce blood pressure, only a third of treated hypertensive patients achieve optimal blood pressure control. Extensive interpatient variability on drug metabolism and oral disposition of blood pressure lowering drugs can contribute to this failure in hypertension management. Areas covered: The aim of the present review is to update the knowledge on the features of hepatic metabolism of the main antihypertensive agents, including beta-blockers, calcium channel blockers, angiotensin receptor blockers, and angiotensin converting enzyme inhibitors. The factors that contribute to the large interindividual variability of main antihypertensive drugs are also covered. Expert opinion: The variability of plasma concentration of antihypertensive drugs due to the involvement of hepatic metabolism can contribute to the inadequate control of blood pressure in the daily clinical practice. Genotype screening of specific hepatic drug-metabolizing enzymes may contribute to optimize dose selection and to increase the rate of blood pressure control in patients treated with specific beta-blockers, calcium channel blockers, and angiotensin receptor blockers.

Introduction: Actually, similar to 17.8 million women and 1.8 million children (<15years) are currently infected with the Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS). Particularly, the majority of pediatric infections (>90%) resulted from HIV mother-to-child transmission' (MTCT), both in pregnancy, labour, delivery and later by breastfeeding. Due to its high pediatric incidence, MTCT represents a public health concern.Areas covered: In this review, we focus on available treatments and antiretroviral drugs recommended by the World Health Organization, and the main clinical investigations in antiretroviral pharmacotherapy to prevent the MTCT.Expert opinion: The MTCT has been improved dramatically in the last few years mainly due to prophylactic perinatal antiretroviral therapy for pregnant women living with HIV. However, there is still a milestone to reach since HIV MTCT remains as a public health challenge associated with MTCT though breastfeeding (post-natal transmission). In this context, different strategies could be employed as an attempt to reduce pediatric HIV infections. One of them involves the improvement of patient adherence to the HIV therapy. One possible solution is the development of novel long-acting formulations for prophylaxis of mothers and children, and a second possible solution is increase the inclusion of mothers and infants in care programs to more effectively prevent the vertical transmission.

OBJECTIVE:This review covers the pharmacokinetics and pharmacodynamic of β-blockers, the rationale for their use, some recent controversies in its use for managing hypertension, as well as, the beneficial properties of the third-generation β-blockers beyond hypertension.BACKGROUND:The efficacy and safety of β-blockers in the treatment of hypertension and other cardiovascular diseases have been established during more than 50 years of clinical experience. Recent updates of clinical guidelines have downgraded the use of β-blockers for the treatment of uncomplicated hypertension to second and third line therapy. It is a well-known fact that β-blockers exhibit heterogeneous pharmacokinetic and pharmacodynamic properties that clearly influence their clinical efficacy and tolerability in the management of essential hypertension. Conventional nonvasodilating β-blockers (atenolol and metoprolol) are inferior to first-line antihypertensive agents in terms of cardioprotection due to lower ability to reduce central blood pressure and its variability and the adverse effects on glycemic and lipid metabolism.CONCLUSION:New vasodilating β-blockers, mainly carvedilol and nebivolol, show enhanced hemodynamic and metabolic properties, which probably result in a higher prevention of major cardiovascular events in hypertensive patients. Despite head-to-head clinical trials comparing the effects of vasodilating vs nonvasodilating β-blockers on hard clinical endpoints are lacking, the current evidence suggests that third-generation β-blockers are superior to conventional β-blockers for the prevention of cardiovascular events in patients with essential hypertension. Moreover, beyond their antihypertensive properties, third-generation β-blockers also have pleiotropic, antioxidant and antiinflammatory effects that warrant a "promissory new era" of this newly group.

The aim of the study was to compare the effects of chronic oral treatment with carvedilol or amlodipine on blood pressure, blood pressure variability and target organ damage in N-nitro-l-arginine methyl ester (L-NAME) hypertensive rats. Wistar rats were treated with L-NAME administered in the drinking water for 8 weeks together with oral administration of carvedilol 30 mg/kg (n = 6), amlodipine 10 mg/kg (n = 6), or vehicle (n = 6). At the end of the treatment, echocardiographic evaluation, blood pressure, and short-term variability measurements were performed. Left ventricular and thoracic aortas were removed to assess activity of metalloproteinase 2 and 9 and expression levels of transforming growth factor β, tumor necrosis factor α, and interleukin 6. Histological samples were prepared from both tissues. Carvedilol and amlodipine induced a comparable reduction of systolic and mean arterial pressure and its short-term variability in L-NAME rats. The expression of transforming growth factor β, tumor necrosis factor α, and interleukin 6 decreased in both organs after carvedilol or amlodipine treatment and the activity of metalloproteinase was reduced in aortic tissue. Treatment with carvedilol or amlodipine completely prevented left ventricular collagen deposition and morphometric alterations in aorta. Oral chronic treatment with carvedilol or amlodipine significantly attenuates blood pressure variability and reduces target organ damage and biomarkers of tissue fibrosis and inflammation in L-NAME hypertensive rats.

Fil: Bertera, Facundo Martin. Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Departamento de Farmacologia. Catedra de Farmacologia; Argentina

Objectives Carvedilol (CAR) is a poorly water-soluble beta-blocker. Its encapsulation within nanomicelles (NMs) could improve drug solubility and its oral bioavailability, allowing the development of a paediatric liquid CAR formulation with commercially available copolymers: D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) and poly(vinyl caprolactam)-poly(vinyl acetate)-poly (ethylene glycol) (Soluplus (R)).Methods Drug-loaded NMs were prepared by copolymer and CAR dispersion in distilled water. Micellar size and morphology were characterized by dynamic light scattering and transmission electron microscopy, respectively. In-vitro drug permeation studies were evaluated by conventional gut sac method. In-vivo CAR oral bioavailability from NMs dispersions and drug control solution was evaluated in Wistar rats.Key findings Carvedilol apparent aqueous solubility was increased (up to 60.4folds) after its encapsulation within NMs. The micellar size was ranged between 10.9 and 81.9 nm with a monomodal size distribution. There was a significant enhancement of CAR relative oral bioavailability for both copolymers vs a micelle-free drug solution (P < 0.05). This improvement was higher for TPGSbased micelles (4.95-fold) in accordance with the in-vitro CAR permeation results.Conclusions The present investigation demonstrates the development of highly concentrated CAR liquid micellar formulation. The improvement on drug oral bioavailability contributes to the potential of this NMs formulation to enhance CAR paediatric treatment.

Introduccion: El telmisartan y el irbesartan, dos de los principales antagonistas del receptor AT1 disponibles para el control de enfermedades cardiovasculares, difieren en sus propiedades farmacologicas, incluyendo el tiempo de disociacion desde el receptor AT1 y la capacidad de activar otros receptores, con potencial impacto en su eficacia clinica relativa.Objetivo: Comparar la respuesta cardiovascular aguda de la administracion de una dosis unica de irbesartan o de telmisartan en ratas espontaneamente hipertensas.Material y metodos: Se utilizaron 24 ratas espontaneamente hipertensas macho de 250-275 g, a las que se les canulo la arteria carotida y la vena femoral para la medicion directa de la presion arterial media (PAM) y la administracion de irbesartan 3-6 mg/kg o de telmisartan 0,5-1 mg/kg. Se estimo el cambio en la PAM, la frecuencia cardiaca y la variabilidad de la presion arterial a corto plazo y latido-a-latido.Resultados: Aunque ambos antagonistas redujeron la PAM, el telmisartan indujo una respuesta antihipertensiva mas prolongada que el irbesartan, evidenciada por mayor reduccion de la PAM luego de 180 minutos (-33,3% ± 4,1% vs. -16,3% ± 4%; p < 0,05). El telmisartan y el irbesartan atenuaron de manera prolongada la variabilidad de la presion arterial a corto plazo, sin diferencias entre ambos grupos experimentales. En el nivel de dosis mas bajo, el telmisartan disminuyo en mayor medida la frecuencia cardiaca y la variabilidad latido-a-latido en los diferentes dominios de frecuencia en comparacion con el irbesartan.Conclusiones: En ratas espontaneamente hipertensas, la administracion de telmisartan induce un efecto antihipertensivo mas prolongado y una respuesta bradicardizante mayor que el irbesartan. El analisis espectral de la variabilidad latido-a-latido sugiere que el telmisartan, en la dosis mas baja, atenua en mayor medida la actividad simpatica vascular en comparacion con el irbesartan.

Fil: Lucero, Matias. Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Departamento de Farmacologia; Argentina

Background: Increased blood pressure variability is a novel risk factor for the development of target organ injury both inhypertensive and normotensive subjects, so its reduction should be considered as a new therapeutic goal.Objective: The aim of this study was to evaluate the effect of long-term oral carvedilol treatment on blood pressure, bloodpressure variability and target organ injury in the left ventricle and thoracic aorta in a model of blood pressure liability.Methods: Twelve male Wistar rats submitted to sinoaortic denervation were treated during 8 weeks with a single dose ofcarvedilol 30 mg/kg or vehicle. At the end of treatment, echocardiographic evaluation and blood pressure and short-term variabilitymeasurements were performed. Left ventricular and thoracic aortic weights were determined and histological sampleswere prepared from both tissues. Metalloproteinase MMP-2 and transforming growth factor b (TGF-b) were quantified in theleft ventricle and thoracic aorta.Results: Carvedilol reduced systolic blood pressure and its variability in sinoaortic-denervated rats compared with the controlgroup (126±5 vs. 142±11 mmHg, p<0.05; SD: 2.9±0.5 vs. 6.0±0.5 mmHg; p<0.05). A lower amount of connective tissue wasfound in carvedilol-treated animals. The expression of TGF-b decreased in both organs after carvedilol treatment.Conclusions: Chronic carvedilol treatment significantly reduces systolic blood pressure and its short-term variability insinoaortic-denervated rats, decreasing the degree of left ventricular fibrosis.

The cardiovascular and pharmacokinetic effects of nebivolol were evaluated in hypertensive fructose-fed and control rats,analyzing the effect of intravenously administered nebivolol 3 or 10 mg/kg on blood pressure, heart rate, and short-term andbeat-to-beat blood pressure variability. The enantioselective pharmacokinetic profile of d- and l-nebivolol enantiomers wasevaluated. Short-term and beat-to-beat blood pressure variability was assessed using standard deviation and blood pressurespectral analysis, respectively. The hypertensive state altered the pharmacokinetics of nebivolol, evidenced by reduction ofnebivolol clearance in the fructose group compared to the control group after administration of the highest dose. The antihypertensiveeffect of nebivolol was similar in both groups, while the bradycardic effect was greater in control rats. Althoughno significant differences were found in beat-to-beat blood pressure variability, short-term blood pressure variability showedgreater reduction after nebivolol administration in fructose-fed rats compared to control normotensive animals (-57.9%±11.8%vs.-19.6%±9.2%; p<0.05). In conclusion, although nebivolol reduces blood pressure and blood pressure variability in bothgroups, no significant differences were found in the pharmacokinetics and cardiovascular effects of fructose-fed rats, exceptfor lower bradycardic efficacy and greater reduction in short-term blood pressure variability.

Background: Increased blood pressure variability is a novel risk factor for the development of target organ injury both in hypertensive and normotensive su...