Nebivolol is more effective than atenolol for blood pressure variability attenuation and target organ damage prevention in L-NAME hypertensive rats.

ß-Adrenergic blockers are no longer recommended as first-line therapy due to the reduced cardioprotection of traditional ß-blockers compared with other antihypertensive drugs. It is unknown whether third-generation ß-blockers share the limitations of traditional ß-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 ß (TGF-ß), 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 ß-blockers must not be carried forward to third-generation ß-blockers.

Effects of third-generation ß-blockers, atenolol or amlodipine on blood pressure variability and target organ damage in spontaneously hypertensive rats.

BACKGROUND: ß-blockers are no longer considered as first-line antihypertensive drugs due to their lower cardioprotection. METHOD: Considering the differences in the pharmacological properties of ß-blockers, the present work compared the effects of third-generation ß-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 ß (TGF-ß), 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-ß, 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 ß-blockers, as atenolol, in hypertension must not be translated to third-generation ß-blockers.

Factors influencing hepatic metabolism of antihypertensive drugs: impact on clinical response.

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 ß-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 ß-blockers, calcium channel blockers, and angiotensin receptor blockers.

What is the Real Efficacy of Beta-Blockers for the Treatment of Essential Hypertension?

OBJECTIVE: This review covers the pharmacokinetics and pharmacodynamic of ß-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 ß-blockers beyond hypertension. BACKGROUND: The efficacy and safety of ß-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 ß-blockers for the treatment of uncomplicated hypertension to second and third line therapy. It is a well-known fact that ß-blockers exhibit heterogeneous pharmacokinetic and pharmacodynamic properties that clearly influence their clinical efficacy and tolerability in the management of essential hypertension. Conventional nonvasodilating ß-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 ß-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 ß-blockers on hard clinical endpoints are lacking, the current evidence suggests that third-generation ß-blockers are superior to conventional ß-blockers for the prevention of cardiovascular events in patients with essential hypertension. Moreover, beyond their antihypertensive properties, third-generation ß-blockers also have pleiotropic, antioxidant and antiinflammatory effects that warrant a "promissory new era" of this newly group.

Effects of carvedilol or amlodipine on target organ damage in L-NAME hypertensive rats: their relationship with blood pressure variability.

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 ß, 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 ß, 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.

Novel carvedilol paediatric nanomicelle formulation: in-vitro characterization and in-vivo evaluation.

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-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and poly(vinyl caprolactam)-poly(vinyl acetate)-poly(ethylene glycol) (Soluplus® ). 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 60.4-folds) 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 TPGS-based 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.

Comparación de la respuesta antihipertensiva aguda al telmisartán y al irbesartán en ratas espontáneamente hipertensas / Comparison of the Acute Antihypertensive Response to Telmisartán and Irbesartán in Spontaneously Hypertensive Rats

Introducción: El telmisartán y el irbesartán, dos de los principales antagonistas del receptor AT1 disponibles para el control de enfermedades cardiovasculares, difieren en sus propiedades farmacológicas, incluyendo el tiempo de disociación desde el receptor AT1 y la capacidad de activar otros receptores, con potencial impacto en su eficacia clínica relativa. Objetivo: Comparar la respuesta cardiovascular aguda de la administración de una dosis única de irbesartán o de telmisartán en ratas espontáneamente hipertensas. Material y métodos: Se utilizaron 24 ratas espontáneamente hipertensas macho de 250-275 g, a las que se les canuló la arteria carótida y la vena femoral para la medición directa de la presión arterial media (PAM) y la administración de irbesartán 3-6 mg/kg o de telmisartán 0,5-1 mg/kg. Se estimó el cambio en la PAM, la frecuencia cardíaca y la variabilidad de la presión arterial a corto plazo y latido-a-latido. Resultados: Aunque ambos antagonistas redujeron la PAM, el telmisartán indujo una respuesta antihipertensiva más prolongada que el irbesartán, evidenciada por mayor reducción de la PAM luego de 180 minutos (-33,3% ± 4,1% vs. -16,3% ± 4%; p < 0,05). El telmisartán y el irbesartán atenuaron de manera prolongada la variabilidad de la presión arterial a corto plazo, sin diferencias entre ambos grupos experimentales. En el nivel de dosis más bajo, el telmisartán disminuyó en mayor medida la frecuencia cardíaca y la variabilidad latido-a-latido en los diferentes dominios de frecuencia en comparación con el irbesartán. Conclusiones: En ratas espontáneamente hipertensas, la administración de telmisartán induce un efecto antihipertensivo más prolongado y una respuesta bradicardizante mayor que el irbesartán. El análisis espectral de la variabilidad latido-a-latido sugiere que el telmisartán, en la dosis más baja, atenúa en mayor medida la actividad simpática vascular en comparación con el irbesartán.

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 AT 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, weighting 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.

Effects of Chronic Carvedilol administration on blood Pressure Variability and target Organ injury in rats with sinoaortic Denervation / Efectos de la administración crónica de carvedilol sobre la variabilidad de la presión arterial y el daño de órgano blanco en ratas con desnervación sinoaórtica

background: Increased blood pressure variability is a novel risk factor for the development of target organ injury both in hyperten-sive 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, blood pressure 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 of carvedilol 30 mg/kg or vehicle. At the end of treatment, echocardiographic evaluation and blood pressure and short-term variability measure-ments were performed. Left ventricular and thoracic aortic weights were determined and histological samples were prepared from both tissues. Metalloproteinase MMP-2 and transforming growth factor β (TGF-β) were quantified in the left ventricle and thoracic aorta. results: Carvedilol reduced systolic blood pressure and its variability in sinoaortic-denervated rats compared with the control group (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 was found in carvedilol-treated animals. The expression of TGF-β decreased in both organs after carvedilol treatment. Conclusions: Chronic carvedilol treatment significantly reduces systolic blood pressure and its short-term variability in sinoaortic-denervated rats, decreasing the degree of left ventricular fibrosis.

introducción: El incremento en la variabilidad de la presión arterial resulta un nuevo factor de riesgo para el desarrollo de daño de órgano blanco en individuos tanto hipertensos como normotensos, por lo que se postula que su reducción debe considerarse una posible nueva meta terapéutica. Objetivos: Evaluar el efecto del tratamiento a largo plazo con carvedilol sobre la presión arterial, su variabilidad y el daño de órgano blanco en el ventrículo izquierdo y la aorta torácica en el modelo de la labilidad de presión. Material y métodos: Se incluyeron 12 ratas Wistar macho sometidas a desnervación sinoaórtica, las cuales fueron tratadas durante 8 semanas con una única administración diaria de carvedilol 30 mg/kg o vehículo. Finalizado el tratamiento se realizó la medición de la presión arterial y de la variabilidad a corto plazo y la evaluación ecocardiográfica. Se determinó el peso del ventrículo y de la aorta torácica y se realizaron preparados histológicos sobre ambos tejidos. Se cuantificó la expresión de metaloproteinasa 2 (MMP-2) y factor de crecimiento transformante β (TGF-β) en el ventrículo izquierdo y la aorta torácica. resultados: El carvedilol redujo la presión arterial sistólica y su variabilidad en las ratas con desnervación sinoaórtica en comparación con el grupo control (126 ± 5 vs. 142 ± 11 mm Hg, p < 0,05; DE: 2,9 ± 0,5 vs. 6,0 ± 0,5 mm Hg; p < 0,05). Se evidenció menor cantidad de tejido conectivo en los animales tratados con carvedilol. La expresión de TGF-β se encuentra disminuida en ambos órganos luego del tratamiento con carvedilol. Conclusiones: El tratamiento crónico con carvedilol reduce significativamente la presión arterial y su variabilidad a corto plazo en ratas con desnervación sinoaórtica, disminuyendo el grado de fibrosis del ventrículo izquierdo.

Perfil farmacocinético y farmacodinámico del nebivolol en un modelo experimental de síndrome metabólico / Pharmacokinetic and Pharmacodynamic Profile of Nebivolol in an Animal Model of Metabolic Syndrome

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.

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 and beat-to-beat blood pressure variability. The enantioselective pharmacokinetic profile of d- and l-nebivolol enantiomers was evaluated. Short-term and beat-to-beat blood pressure variability was assessed using standard deviation and blood pressure spectral analysis, respectively. The hypertensive state altered the pharmacokinetics of nebivolol, evidenced by reduction of nebivolol clearance in the fructose group compared to the control group after administration of the highest dose. The antihypertensive effect of nebivolol was similar in both groups, while the bradycardic effect was greater in control rats. Although no significant differences were found in beat-to-beat blood pressure variability, short-term blood pressure variability showed greater 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 both groups, no significant differences were found in the pharmacokinetics and cardiovascular effects of fructose-fed rats, except for lower bradycardic efficacy and greater reduction in short-term blood pressure variability.

Heme oxygenase-1 overexpression fails to attenuate hypertension when the nitric oxide synthase system is not fully operative.

Heme oxygenase (HO) is an enzyme that is involved in numerous secondary actions. One of its products, CO, seems to have an important but unclear role in blood pressure regulation. CO exhibits a vasodilator action through the activation of soluble guanylate cyclase and the subsequent production of cyclic guanosine monophosphate (cGMP). The aim of the present study was to determine whether pathological and pharmacological HO-1 overexpression has any regulatory role on blood pressure in a renovascular model of hypertension. We examined the effect of zinc protoporyphyrin IX (ZnPP-IX) administration, an inhibitor of HO activity, on mean arterial pressure (MAP) and heart rate in sham-operated and aorta-coarcted (AC) rats and its interaction with the nitric oxide synthase (NOS) pathway. Inhibition of HO increased MAP in normotensive rats with and without hemin pretreatment but not in hypertensive rats. Pretreatment with NG-nitro-L-arginine methyl ester blocked the pressor response to ZnPP-IX, suggesting a key role of NOS in the cardiovascular action of HO inhibition. In the same way, AC rats, an experimental model of hypertension with impaired function and low expression of endothelial NOS (eNOS), did not show any cardiovascular response to inhibition or induction of HO. This finding suggests that eNOS was necessary for modulating the CO response in the hypertensive group. In conclusion, the present study suggests that HO regulates blood pressure through CO only when the NOS pathway is fully operative. In addition, chronic HO induction fails to attenuate the hypertensive stage induced by coarctation as a consequence of the impairment of the NOS pathway.

Increased sensitivity to diltiazem hypotensive effect in an experimental model of high-renin hypertension.

OBJECTIVES: The aim of this work was to evaluate the pharmacokinetic-pharmacodynamic properties of diltiazem in an experimental model of high-renin hypertension, such as the aortic coarctated (ACo) rat, to further characterize the responsiveness of this model to calcium channel blockers. METHODS: A 'shunt' microdialysis probe was inserted in a carotid artery of anaesthetized ACo and control sham-operated (SO) rats for simultaneous determination of diltiazem plasma concentrations and their effects on mean arterial pressure and heart rate after the intravenous application of 3 and 6 mg/kg of the drug. Correlation between plasma levels and cardiovascular effects was established by fitting the data to a modified Emax model. KEY FINDINGS: Volume of distribution was greater in ACo than in SO rats. Diltiazem plasma clearance (Cl) was significantly greater in ACo rats than in normotensive SO rats after administration of diltiazem (6 mg/kg). Moreover, Cl increased with dose in ACo but not in SO rats. No differences were observed in the maximal bradycardic effect comparing both experimental groups, and sensitivity (S0) to diltiazem chronotropic effect was similar comparing SO and ACo rats. Differences were not found in the maximal response of the hypotensive effect comparing SO and ACo rats, but the S0 to diltiazem hypotensive effect was greater in ACo rats than in SO rats. CONCLUSIONS: ACo induced profound changes in diltiazem pharmacokinetic behaviour. In addition, our results suggested an increased sensitivity to diltiazem blood pressure lowering effect in experimental renovascular hypertension with high-renin levels.

Modelado farmacocinético-farmacodinámico de fármacos antihipertensivos: su aplicación en la práctica clínica / Pharmacokinetic-Pharmacodynamic Modelling of Antihypertensive Drugs: Its Application to Clinical Practice

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.

Knowing the pharmacokinetic-pharmacodynamic properties (PK/PD) of drugs might optimize antihypertensive therapy. PK/PD modelling might not only contribute to develop the drug but might also help in clinical practice assessing the efficacy and safety of antihypertensive drugs, bringing more information during the developing process, identifying factors responsible for the variability in pharmacologic response, bad responders or non-responders, and determining the optimal requisites of the drug and doses in each patient with hypertension. There are some limitations in PK/ PD modelling of antihypertensive drugs in clinical practice, such as inadequate pharmacodynamic models and the inability to study high doses of antihypertensive drugs to determine the whole pharmacodynamic range of the antihypertensive effect. The aim of this review is to describe the current knowledge on PK/PD modelling of antihypertensive drugs in clinical research, and its further uses.

Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension.

INTRODUCTION: The aim of this work was to compare the suitability of different pharmacodynamic models for PK-PD modeling of verapamil cardiovascular effects in aortic coarctated rats (ACo), a model of renovascular hypertension. METHODS: A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized sham-operated (SO) and ACo rats for determination of verapamil plasma concentrations and their effects on blood pressure and heart rate after intravenous application (1 and 3 mg kg(-1)). Correlation between verapamil plasma levels and their cardiovascular effects was established by fitting data to a linear, and a conventional and modified E(max) model. RESULTS: No differences in verapamil volume of distribution were observed between experimental groups. Whilst clearance increased with dose in SO rats, no differences were found in verapamil clearance in ACo comparing both dose levels. A good correlation between verapamil plasma unbound concentrations and their hypotensive and chronotropic effects was found in both experimental groups using the tested PK-PD models. Although all pharmacodynamic models allowed a precise estimation of verapamil PK-PD parameters, linear and E(max) model did not permit an accurate PK-PD parameter estimation for the hypotensive and chronotropic effect, respectively. Conversely, the modified E(max) model allows both a precise and accurate estimation of PK-PD parameters for verapamil effects. Although, absolute verapamil blood pressure lowering effect was greater in ACo rats compared with SO rats, no differences were found in verapamil PK-PD parameters estimated for the hypotensive response. DISCUSSION: Side-by-side comparison of the tested pharmacodynamic models showed that accuracy of PK-PD parameters estimation by using the linear and classical E(max) model depends on the magnitude of concentration-effect curve covered in the study. Conversely, the modified E(max) model allowed both a precise and accurate estimation of PK-PD parameters, suggesting that the modified E(max) pharmacodynamic model is the most suitable for verapamil PK-PD modeling.

Involvement of angiotensin-(1-7) in the hypothalamic hypotensive effect of captopril in sinoaortic denervated rats.

The role of anterior hypothalamic angiotensin-(1-7) (Ang-(1-7)) on blood pressure regulation was studied in sinoaortic denervated (SAD) rats. Since angiotensin-converting enzyme inhibitors increase endogenous levels of Ang-(1-7), we addressed the involvement of Ang-(1-7) in the hypotensive effect induced by captopril in SAD rats. Wistar rats 7 days after SAD or sham operation (SO) were anaesthetized and the carotid artery was cannulated for monitoring mean arterial pressure (MAP). A needle was inserted into the anterior hypothalamus for drug administration. Intrahypothalamic administration of Ang-(1-7) (5 pmol) was without effect in SO rats but reduced MAP in SAD rats by 15.5+/-3.2 mm Hg and this effect was blocked by 250 pmol [D-Ala(7)]-Ang-(1-7), a Mas receptor antagonist. Angiotensin II (Ang II) induced an increase in MAP in both groups being the effect greater in SAD rats (DeltaMAP=15.8+/-1.4 mm Hg) than in SO rats (DeltaMAP=9.6+/-1.0 mm Hg). Ang-(1-7) partially abolished the pressor response caused by Ang II in SAD rats. Whilst the captopril intrahypothalamic injection did not affect MAP in SO animals, it significantly reduced MAP in SAD rats (DeltaMAP=-13.3+/-1.9 mm Hg). Either [D-Ala(7)]-Ang-(1-7) or an anti-Ang-(1-7) polyclonal antibody partially blocked the MAP reduction caused by captopril. In conclusion, whilst Ang-(1-7) does not contribute to hypothalamic blood pressure regulation in SO normotensive animals, in SAD rats the heptapeptide induces a reduction of blood pressure mediated by Mas receptor activation. Although Ang-(1-7) is not formed in enough amount in the AHA of SAD animals to exert cardiovascular effects in normal conditions, our results suggest that enhancement of hypothalamic Ang-(1-7) levels by administration of captopril is partially involved in the hypotensive effect of the ACE inhibitor.

Pharmacokinetic-pharmacodynamic modeling of diltiazem in spontaneously hypertensive rats: a microdialysis study.

INTRODUCTION: The aim of the present work was to study the applicability of a modified E(max) pharmacodynamic model for the pharmacokinetic-pharmacodynamic (PK-PD) modeling of diltiazem in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats. METHODS: A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized SHR and WKY rats for simultaneous determination of unbound plasma concentrations of diltiazem and their effects on mean arterial pressure (MAP) and heart rate (HR) after the intravenous application of 1 and 3 mg kg(-1) of the drug. Correlation between diltiazem plasma levels and their cardiovascular effects was established by fitting the data to a conventional and modified E(max) model. RESULTS: Volume of distribution and clearance of diltiazem was greater in SHR than in WKY animals. A proportional increase of area under curve with dose increment was observed in WKY animals but not in SHR. A good correlation between plasma unbound concentrations of diltiazem and their hypotensive and chronotropic effects was found in both experimental groups using both PK-PD models. The application of the modified E(max) model for PK-PD modeling of diltiazem allowed a more accurate and precise estimation of PK-PD parameters than the E(max) equation do. Chronotropic effect of 3 mg kg(-1) diltiazem was lower in SHR compared to WKY animals. Initial sensitivity (S(0)) to diltiazem chronotropic effect was greater in SHR with regards to WKY animals after administration of 1 mg kg(-1). S(0) to diltiazem hypotensive effect was greater in SHR with regards to WKY animals after administration of both doses of diltiazem. DISCUSSION: Microdialysis sampling is a useful technique for the pharmacokinetic study and pharmacokinetic-pharmacodynamic (PK-PD) modeling of diltiazem. The modified E(max) model allows an accurate estimation of drug sensitivity in conditions when maximal pharmacological response can not be attained. Genetic hypertension induced changes in the pharmacokinetic and PK-PD behavior of diltiazem suggesting that SHR is an interesting animal model for pre-clinical evaluation of calcium channel blockers.