Influence of age and arterial blood pressure on the anti-hypertensive action of dihydro-pyridine compounds in hypertensive patients

To study the antihypertensive effect of dihydropyridines and correlated with the patient's age, the degree of hypertension and mean arterial pressure, in three groups of eight hypertensive patients with mild, moderate and severe hypertension selected from the Clinical Pharmacology Unit of Vargas Hospital in Caracas. Mean age, weight and height of the selected patients were 55.66 ¤ 3.4, years 67 ¤ 3.05 Kg and 1.63 ¤ 0.01 m, respectively. Three acute experimental designs compared with placebo were followed and each group of patients received amlodipine, nitrendipine or isradipine at different times, in single doses of 10,20 and 5 mg, respectively. The cardiovacular parameters evaluated were: mean arterial pressure, systolic blood pressure, diastolic blood pressure and cardiac frequency at regular intervals during 48,6 and 24 hours for amlodipine, nitrendipine and isradipine, respectively. Acute administration of amlodipine (10 mg) to hypertensive patients, significantly reduced blood pressure form 185 ¤ 11.21/100 ¤ 7.07 to 150.5 ¤ 10.6/88.6 ¤ 7.8 mmHg at 8 hours and to 162 ¤ 10.9/91 ¤ 5.6 mmHg at 48 hour. Cardiac frequency also increased significantly at 8 and 48 hours in 10 and 9 beats/min, respectively. There was a positive correlation between patient's age and mean arterial pressure decrease and also between pretreatment and decreased arterial pressure. Two hours after acute administration of isradipine (5 mg) to hypertensive patients, blood pressure decreased significantly from 179.50 ¤ 7.6/100.26 ¤ 3.28 mmHg to 143.75 ¤ 4.7/82 ¤ 5.18 mmHg. Cardiac frequency increased in 5 beats/min at the same time of measure. There was a positive correlation between patient's age and arterial pressure decrease and slight but not significant correlation between pretreatment and mean arterial blood pressure decrease. Acute dose of nitrendipine (20 mg) to hypertensive patients induced significant fall of arterial blood pressure from 172.25 ¤ 7.8/107.13 ¤ 3,58 to 134.5 ¤ 5.08/81 ¤ 5.84 mmHg two hours after the administration of the drug, and the cardiac frequency increased significantly in 11 beats/min during this time. There was no significant correlation between patient's age and the mean arteral pressure fall, neither between pretreatment and the decrease of arterial blood pressure

Dopaminergic drugs: pharmacological and therapeutic aspects / Drogas dopaminergicas: aspectos farmacológicos y terapéuticos

It has been widely established that dopamine and its agonists exect an import role in the regulation of the cardiovascular, renal hormonal systems, acting through adrenergic and beta-adrenergic systems. There are several DA-2 agonists such as bromocriptine pergolide, lisuride, and largotrile, which belong to the ergolin family and act both at central and peropheral levels-inhibiting norepinephrine release, which produces a decrease of arterial pressure and, in some cases, such as with bromocriptine and pergolide, a decrease in the heart rate. From a therapeutic viewpoint, the above mentioned DA-2 agonists are widely used for treating Parkinso's disease; these agonists act at the level of DA-2 receptors located in the nigrostriatal system. Bromocriptine and the other mentioned agonists DA-2 are used in the treatment of hyperprolatinemia and in pivitary tumors, since they decrease prolactin secretion and reduce the size of the tumor acting through inhibitory DA-2 receptors located in the tuberoinfuldibolar system. Similarly, there are Also DA-1 agonists such fenoldopam (selective) and piribedil non selective) which activate peripheral receptors, producing, a reduction of peripheral resistance and renal vascular resistance and an renal vascular resistance and an increase of renal blood flow. All these effects produce a decrease in arterial pressure and a reflex hearth rate increase. Fenoldopam in used in the treatment of arterial hypertensión, renal failure and heart failure. This agonist exerts its action at the level of the DA-1 receptors located in peripheral and renal resistance vessels (which leads to an increase use in renal blood flow and a decrease pressure). Among the selecttive antagonists of DA-2 receptors, we can mention metoclopramide and domperidone. Both antagonists produce a decrease in the hypotensor response of treatment of schizophrenia; it acts by activating DA-1 and DA-4 recepts located at the hypothalamus, olfactory bulb, and frontal cortex

Dopamine: pharmacologic and therapeutical aspects / Dopamina: aspectos farmacologicos y terapeuticos

Dopamine is a biogenic amine synthesized in the hypothalamus, in the arcuato and caudate nuclei and in several areas of the central peripheral nervous system. It has been widely established that dopamine and its agonists play an important role in cardiovascular, renal hormonal and central nervous system regulation through stimulation of alpha and beta adrenergic and dopaminergic receptors. There are several agonists of DA2 dopaminergic receptors such as: bromocriotine, pergolide, lisuride, quinpirole, and carmoxirole, which inhibit nerepinephrine release, and produces a decrease of arterial blood pressure and, in some cases, bromocriptine and pergolide reduce heart rate. From a therapeutical point of view, the abone mentined agonists are used for treatment od Parkinson's disease, acting on DA2 dopaminergic receptors of the nigrostriatal system. Bromocriptine and the other domaminergic agonists mentioned act on DA2 receptor of the tuberoinfundibular system inhibiting prolactin release, decreasing hyperprolactinemia and tumor size. Among DA1 receptor agonists we can mention: fenoldopan, pirebedil, ibopamine, SKF 3893, apomorphine (non specific). Activation of these receptors decreases peripheral resistance and reduces arterial blood pressure, increases heart rate and sympathetic tone and the renin aldosterone system activity. Among DA2 receptor antagonists we can mention: metoclopramide, domperidone, sulpiride and haloperidol. From a therapeutic point of view, metoclopramide and domperidone are used in gastric motility disorders and haloperidol in psychotic alterations. Antagonists of DA1 receptors are: SCH23390 and clozapine. Clozapine is used for traating schizophrenia

Metoclopramide and domperidone block the antihypertensive effect of bromocriptime in hypertensive patients / Loa bloqueadores metadopramida y domperidona en pacientes hipertensos y el efecto antihipertensivo de la bromocriptina

This study was conduced in normotensive and hypertensive patients at the Vargas Hospital of Caracas. Normotensive subjects received, in a crossover fashion, placebo, metoclopramide or domperidone, 40 mg of each drug daily for one week. The first group of patients under placebo for one(1) week received a single 2.5 mg oral dose bromocriptine (Br). The second group of patients received 30 mg of metoclopramide (MTC) daily (divided in 3 doses) for week. At the end of period a single dose of 2.5 mg of Br was given to each patient . The third group received domperidone (DOMP) during one week at 30 mg/daily dose to eight hypertesive patients and then a single dose of 2.5 mg Br. Cardiovascular and biochemical parameters including arterial pressure, heart rate, plasma renin activity, and plasma aldosterone concentration were evaluated during the 6 hour period before and after the administration of Br. Neither DOMP nor MTC modified significantly blood presure and heart rate in normotensive subjects. Br reduced both systolic and diastolic arterial pressure in hypertensive subjects. The peak of antihypertensive effect appeared 3 hours after drug administration, but reduction of arterial pressure lasted aproximately 6 hours. At the same time Br reduced plasma aldosterone levels and plasma renin activity. MTC and DOMP reversed the antihypertensive effct or Br and its effect on aldosterone levels and plasma renin activity. We conclude from these findings that Br acts as an antihypertensive agent at peripheral and central levels by stimulating DA2 receptors, which are involved in the aldosterone and renin secretion

Cardiovascular and Hormonal Effects of Domperidone, A Peripheral Dopaminergic Blocker, in Bromocriptine-Treated Hypertensive Patients.

Nine patients with mild or moderate essential hypertension were studied at the Vargas Hospital of Caracas, Venezuela. After antihypertensive treatment discontinuation, all patients were placed on placebo during a 1-week period, after which domperidone, a peripheral DA(2) dopaminergic blocker, was orally administered at the dose of 20 mg every 12 h during a period of 1 week. A final 1-week period of bromocriptine, 2.5 mg orally every 8 h, followed the domperidone period. Cold pressor test caused an increase of mean blood pressure and of heart rate, which was more accentuated after adding bromocriptine. Domperidone also caused an increase of serum aldosterone levels. Our results suggest that a dopaminergic mechanism is acting during the cold pressor test and during aldosterone secretion.

Effect of Domperidone on the Bromocriptine-Induced Antihypertensive Action in Hypertensive Patients.

Dopaminergic receptors have been involved in the cardiovascular and renin-angiotensin systems (RAS). We have recently reported that bromocriptine is an effective antihypertensive drug by stimulating DA(2) dopaminergic receptors. However, the nature of the dopaminergic receptors in RAS has not been established. Ten outpatients with essential hypertension were treated at the Vargas Hospital with bromocriptine (BR) (11.25 mg day(minus sign1)), a DA(2) dopaminergic agonist, for a 2-week period, after which an oral dose of 30 mg day(minus sign1) of domperidone (DO), a peripheric DA(2) dopaminergic antagonist, was added for 2 additional weeks. The active period was preceeded by a 2-week placebo period. Bromocriptine decreased blood pressure (BP) significantly by 19/9 mm Hg (systolic/diastolic BP). Bromocriptine did not cause heart rate (HR) changes. Bromocriptine decreased plasma aldosterone (ALD) without altering plasma renin activity (PRA). Domperidone partially blocked bromocriptine-induced antihypertensive submaximal treadmill effects and reversed ALD decrease. Exercise response was not significantly altered by BR + DO. We conclude the following: (1) BR is an effective antihypertensive agent; (2) BR seems to be acting at both the central and peripheric nervous systems, and (3) the nature of the dopaminergic receptor involved in renin secretion does not seem to be DA(2).

Central Acting Antihypertensive Drugs: Past, Present, and Future.

The central antihypertensive drugs such as methyldopa or clonidine have been agents of importance in the therapy of hypertension. Due to the side effects and the rebound hypertensive phenomenon in the case of clonidine, the use of these agents have been clearly diminished. There are several evidences that a new type of receptor, imidazoline receptor, is present in the central nervous system and in the periphery. A specific agonist for these receptors, rilmenidine, has been studied in experimental animals and in hypertensive patients. Clinical studies have shown that rilmenidine exhibits similar efficacy but a better tolerability compared to clonidine. Rilmenidine may represent a good alternative in the therapy of hypertension.

Dopaminergic Influence on the Cardiovascular and Hormonal Responses to Cold Stress in Hypertensive Patients.

Immersion of one hand into ice water (cold pressor test) in eight hypertensive subjects induces elevation of mean arterial pressure, increase in heart rate, and no significant changes of plasma renin activity and plasma aldosterone concentrations. Domperidone, a DA2 dopaminergic antagonist, attenuates heart rate increase induced by the cold pressor test, and the combination of bromocriptine, a known DA2 dopaminergic agonist, with domperidone again provoked a heart rate increase during the cold pressor test. Domperidone caused an increase of both plasma renin activity and plasma aldosterone concentrations, which were reversed by bromocriptine. These results suggest that a dopamine-receptor stimulation is taking place during the cold pressor test.

Drogas dopaminergicas: aspectos farmacológicos y terapeúticos / Drug therapy dopamine effects pharmacology and therapeutic

Está ampliamente establecido que la dopamina y sus agonistas ejercen un papel importante en la regulación del sistema cardiovascular, renal y hormonal, actuando a través de los receptores-adrenérgicos y ß adrenérgicos. Existen varios agonistas DA-2 tales como bromocriptina, el pergolide, el lisuride pertenece a la familia de las ergolinas que actúan tanto a nivel central como a nivel periférico, inhibiendo la liberación de norepinefrina lo cual produce una disminución de la presión arterial y en algunos casos tales como la bromocriptina y el pergolide, causan una disminución de la frecuencia cardíaca. Desde el punto de vista terapéutico, los agonistas DA-2 antes mencionados se utilizan ampliamente en el tratamiento de la enfermedad de Parkinson, estos agonistas actúan a nivel de receptores DA2 situados en el sistema nigroestríado. La bromocriptina y los otros agonistas DA2 mencionados, se utilizan en el tratamiento de la hiperprolactinemia y en tumores hipofisarios, estos agonistas disminuyen la secreción de prolactina y reducen el tamaño del tumor actuando a través de receptores DA2 inhibidores situados en el sistema tuberoinfundibular. De manera similar también existen agonistas DA-1 como el fenoldopam (selectivo) y el piribedil (no selectivo) estos agonistas actúan los receptores periféricos causando una reducción de la resistencia periférica, de la resistencia vascular renal y un aumento del flujo sanguíneo renal. Todos estos efectos traen como consecuencia un descenso en la presión arterial y un aumento reflejo en la frecuencia cardíaca. El fenoldopam se utiliza en el tratamiento de la hipertensión arterial, insufiencia renal e insuficiencia cardíaca este agonista ejerce su acción a nivel de la de los receptores DA-1 localizados en las arterias periféricas y renales reduciendo la resistencia periférica, y la resistencia renal, esto trae como consecuencia un aumento del flujo sanguíneo renal y una disminución de la presión arterial. Dentro de los antagonsitas de los receptores DA-2 selectivos podemos mencionar la metoclopramida y la domperidona. ambos antagonistas causan disminución de la respuesta depresora de la dopamina. Se utiliza ampliamente en el tratamiento de desórdenes gastrointestinales. El antagonista específico de los receptores DA1 es la clozapina y el SCH23390. La clozapina se utiliza ampliamente en el tratamiento de la esquizofrenia, actúa activando los receptores DA1 y DA4 situados en el hipotálamo bulbo olfatorio y corteza frontal

Respuestas cardiovasculares y hormonales durante la exposición al frío: un estudio comparativo en normotensos y pacientes hipertensos / Cardiovascular and hormonal responses during cold exposure: a comparative study in normotensive and hypertensive patients

Hemos examinado las respuestas cardiovasculares (presión arterial, frecuencia cardiaca (FC) y hormonales (actividad renina plasmática (ARP), concentración de aldosterona plasmática (CAP) en sujetos normotensos e hipertensos. Se estudiaron 21 voluntarios sanos y 25 pacientes con hipertensión arterial esencial (HAE) en el Hospital Vargas de Caracas. Todos fueron sometidos a la prueba presora al frío (PPF). Hubo en ambos grupos un incremento de presión arterial, la cual fue mayor en hipertensos que en normotensos. Según la reactividad al frío, los normotensos fueron clasificados en dos grupos: Hiperreactores e hiporreactores. En hiporreactores (n=9) hubo incremento significativo de la presión arterial (13,4mmHg) sin alteraciones significativas en la FC, ARP y CAP. En hiperreactores (n=12) hubo un incremento significativo mayor (26,6mmHg) pero similar al de los hipertensos (23,9mmHg). En los tres grupos hubo una disminución de la ARP pero ésta fue significativa sólo en hiperreactores. Nuestro estudio sugiere una probable interrelación entre los efectos cardiovasculares y las respuestas hormonales en normotensos e hipertensos

Efectos cardiovasculares, renales y hormonales del piribedil en pacientes hipertensos / Cardiovascular renal and hormonals effects of the piribedil in hypertensive patients

La dopamina y sus derivados, los agonistas dopaminérgicos, han sido estudiados en pacientes con insuficiencia cardíaca, insuficiencia renal crónica y shock cardiogénico. Su utilidad en estas patologías se ha explicado por su accion agonista sobre los receptores adrenérgicos y dopaminérgicos. Recientemente fue introducido un agonista dopaminérgico, Piribedil (Trivastal), en el tratamiento de la insuficiencia circulatoria cerebral y del Síndrome de Raynaud. En este estudio se señalan sus efectos cardiovasculares, renales y sobre el Sistema Renina-Angiotensiva en pacientes hipertensos. El piribedil se empleó en dosis de 50 a 100 mg diarios durante un período de 8 semanas, como parte de un diseño experimental placebo comparativo-cruzado en 9 pacientes con hipertensión esencial. Se midió: 1.- Presión arterial (PA) y frecuencia cardíaca (FC), antes y durante el ejercicio submáximo en una cincha sin fin. 2.- Fracción de eyección (FE) y fracción de acortamiento (FA) por ecocardiograma. 3.- Depuración de urea (UCI) y de creatinina (CrCl). 4.- Actividad de renina plasmática por radioinmunoensayo. 5.- Aldosterona por radioinmunoensayo en fase sólida. El PIRIBEDIL redujo la presión arterial con un discreto aumento de la frecuencia cardíaca, acompañado de un modesto incremento no significativo de la actividad de renina plasmática y de aldosterona, y un incremento importante de la función renal. Concluimos que la activación del RD (D-1) es una respuesta vasodilatadora y antihipertensiva, con activación refleja del sistema simpático

Efectos cardiovasculares, renales y hormonales de la bromocriptina en pacientes hipertensos / Cardiovascular, renal and hormonal effect of the bromocriptine in hypertensive patients

El objetivo de este estudio fue el de investigar el efecto de la Bromocriptina sobre los sistemas Cardiovasculares, Renal y sobre el Sistema Renina-Angiotensina-Aldosterona. Los agonistas dopaminérgicos, tales como la dopamina y sus derivados, inducen aumento de la contractibilidad cardíaca, natriuresis y aumento del flujo sanguíneo renal por activación de recptores adrenérgicos y dopaminérgicos. En el presente estudio se definen los efectos cardiovasculares, renales, y sobre el sistema Renina-Angiotensina-Aldosterona de un activador dopaminérgico-bromocriptina en un programa abierto con placebo comparativo cruzado en 9 pacientes con hipertensión leve y moderada. Se midieron los siguientes parámetros durante un período de placebo (de 4 semanas) y durante un período de bromocriptina (de 8 semanas) en dosis de 2,5 mg-5 mg/día: Presión Arterial (PA); Frecuencia Cardíaca (FC); Fracción de Eyección (FE); y Fracción de Acortamiento (FA) por ecocardiografía; respuesta cardiovascular del ejercicio submáximo en una cincha sin fin y utilizando la metodología de Bruce; depuración de Urea (cl U) (por método colorimétrico); depuración de Creatinina (Cl Cr) (por métodos cinéticos); Aldosterona (por radioinmunoensayo); Actividad de renina plasmática (PRA) (por radioinmunoensayo). La Bromocriptina redujo significativamente la presión arterial promedio de 155/105 a 136/92 mmHg. También produjo un descenso importante de la frecuencia cardíaca en posición de pie; pero no así en posición supina. Respecto a la función cardiovascular no se observaron cambios significativos en la fracción de eyección (Fa) y de acortamiento (Fa)..