RESUMO
We describe here and validate an in vivo technique to measure the regional proportionate removal of norepinephrine (NE) by neuronal uptake (Uptake1) in man. The measurement is based on the steady-state arterial and venous concentrations of tritiated NE and tritiated isoproterenol (ISO) during simultaneous infusion of both. The validity of this technique depends on the removal of circulating NE, but not of ISO, by sympathetic nerve endings and on there being no other factor contributing to the net difference in the plasma disappearance of these catecholamines. To test these hypotheses, we compared the removal of NE in the arm with that of ISO in 14 people and the effects of pretreatment with the specific inhibitor of Uptake1, desipramine, in 8 people. In all the subjects a greater percent of NE than of ISO was removed during passage of blood through the forearm (54 vs. 46%, P less than 0.0001). Pretreatment with desipramine decreased significantly the removal of NE to virtually exactly that of ISO. The difference in NE and ISO clearances by arm tissues was therefore completely accounted for by Uptake1. About 15% of infused NE which is removed in the arm is removed by Uptake1. The ability to measure regional Uptake1 should contribute to better understanding of the relationship between circulating levels of plasma NE and sympathetic neural activity and may allow detection of abnormalities of neuronal norepinephrine removal in clinical disease states.
Assuntos
Neurônios/metabolismo , Norepinefrina/metabolismo , Braço , Transporte Biológico/efeitos dos fármacos , Desipramina/farmacologia , Humanos , Hipertensão/metabolismo , Isoproterenol/metabolismo , Cinética , Taxa de Depuração Metabólica/efeitos dos fármacosRESUMO
BACKGROUND: C-reactive protein (CRP) elevated in inflammation is associated with atherosclerotic disease. We describe the distribution of CRP and its association with coronary heart disease (CHD) risk factors in a large CHD patient group. METHODS: This analysis comprises 2,723 male and 256 female CHD patients, included in the Bezafibrate Infarction Prevention (BIP) study. High sensitive CRP levels were determined in frozen plasma samples. RESULTS: CRP distribution, was normalized upon log transformation. Levels among women were higher than in men in the entire group (4.4 vs. 3.5 mg/l) and in each age group. Co-morbidities, smoking, lower education level, and use of cardiovascular drugs, were associated with elevated CRP levels in both sexes. The correlation between CRP and body mass index (BMI), insulin and glucose was stronger among women. The explained variability in CRP level was larger in women (20%) compared to men (13%). Among women, BMI explained 10% of CRP variability, whereas the contribution of each variable among men was significantly smaller. CONCLUSIONS: Among men and women with CHD, CRP level was correlated with traditional risk factors and to a lesser degree to manifestation of CHD. BMI is the main contributor to CRP variability, explained by these factors among women.
Assuntos
Proteína C-Reativa/análise , Doença das Coronárias/sangue , Idoso , Biomarcadores/sangue , Doença Crônica , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores SexuaisRESUMO
BACKGROUND: Exogenous subclinical hyperthyroidism, caused by long-term thyrotropin (TSH)-suppressive treatment with levothyroxine (LT(4)), is associated with several cardiovascular abnormalities. In order to assess the effect of long-term thyroid hormone-suppressive therapy on the blood vessels and myocardium, we determined the arterial elasticity, using the pulse wave contour analysis. METHODS AND RESULTS: Twenty-six athyreotic patients receiving TSH-suppressive LT(4) therapy for periods ranging from 3 to 21 years at a mean daily dose of 2.25 +/- 0.5 microg/kg per day were included in the study. Twenty six age- and gender-matched healthy subjects served as controls. Arterial elasticity of large and small arteries was evaluated using pulse wave contour analysis method (HDI CR 200, Eagen, MN). Cardiac structure was assessed by two-dimensional echocardiography. We found decreased large artery elasticity in subclinical hyperthyroidism (sHT) patients compared to controls (14.14 +/- 3.38 versus 10.53 +/- 2.43 L/mm Hg x 100, p < 0.000). Small artery elasticity was also lower in patients than in controls (5.42 +/- 1.82 versus 4.30 +/- 1.75 mL/mm Hg x 100, p < 0.056). The echocardiographic data showed significantly increased left ventricular (LV) mass index (101.90 +/- 18.61 versus 88.03 +/- 22.01 g/m(2), p < 0.049) and interventricular septum thickness (10.61 +/- 1.46 versus 9.11 +/- 1.13 mm, p < 0.002) in LT(4)-treated patients compared to controls. CONCLUSIONS: We found impaired vascular elasticity of large and small arteries and increased LV mass in patients receiving long-term TSH-suppressive therapy with LT(4).
Assuntos
Elasticidade/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Hipertireoidismo/tratamento farmacológico , Neoplasias da Glândula Tireoide/terapia , Tireotropina/antagonistas & inibidores , Tiroxina/uso terapêutico , Artérias/fisiologia , Ecocardiografia , Feminino , Ventrículos do Coração/patologia , Humanos , Assistência de Longa Duração , Masculino , Pessoa de Meia-IdadeRESUMO
The rate of ouabain-resistant Li+-efflux was studied in erythrocytes of normal controls and of patients with essential hypertension. Despite variability in rate, erythrocytes from normotensive persons revealed a uniform pattern of temperature dependence of the efflux, with two slopes (K = 9.4 and 19.1 kcal/mol, respectively) and a transition at about 25 degrees C. Erythrocytes from the patients showed both a higher rate of Li+ efflux and significant changes in the temperature response, with essentially a single slope (Ka = 14 kcal/mol). The data indicate localized changes in the membrane organization of hypertensive erythrocytes, involving lipid-protein interaction.
Assuntos
Membrana Eritrocítica/metabolismo , Eritrócitos/metabolismo , Hipertensão/sangue , Lítio/sangue , Acetilcolinesterase/sangue , Transporte Biológico , Calorimetria , Humanos , Cinética , Valores de Referência , TemperaturaRESUMO
OBJECTIVES: The purpose of this study was to evaluate the ability of impedance cardiography to determine the change in cardiac output caused by modifications in the atrioventricular (AV) delay in DDD (dual-chamber) pacing mode while pacing the atrium and ventricle at different programmed rates. BACKGROUND: Impedance cardiography permits continuous noninvasive monitoring of hemodynamic variables on a beat to beat basis. METHODS: Eleven patients with a DDD pacemaker were evaluated by impedance cardiography. Stroke volume, cardiac output and total peripheral resistance were assessed in the supine rest position during both DDD and ventricular (VVI) pacing. Hemodynamic variables were measured during DDD pacing at rates ranging from 60 to 110 beats/min in 10-beats/min increments with programmed AV delay varying from 50 to 250 ms in 50-ms increments. When the pacemaker was reprogrammed to the VVI pacing mode, these measurements were repeated at the same pacing rates. RESULTS: Cardiac output measurements during programmed conditions were found to be highly reproducible. The mean coefficient of variation was 3% during DDD pacing; it was 6% in the VVI pacing mode. A large decrease in cardiac output (approximately 30%) was found when a pacemaker was reprogrammed from the DDD to the VVI pacing mode. At DDD pacing rates between 70 to 110 beats/min, the highest cardiac output occurred at an average AV delay of < 120 ms from atrial stimulus to ventricular stimulus. At an average AV delay of > or = 200 ms, the cardiac output in the DDD and VVI pacing modes was similar. CONCLUSIONS: 1) Impedance cardiography allows highly reproducible noninvasive assessments of cardiac output in pacemaker patients; 2) inappropriate programming of the AV interval in patients with atrial and ventricular pacing can decrease cardiac output significantly, and the extent of the decrease is similar to or less than that observed in ventricular pacing; 3) hemodynamic measurements obtained with impedance cardiography can facilitate optimal programming of pacemaker variables.
Assuntos
Débito Cardíaco/fisiologia , Estimulação Cardíaca Artificial/métodos , Cardiografia de Impedância , Hemodinâmica/fisiologia , Marca-Passo Artificial , Estudos de Avaliação como Assunto , Feminino , Bloqueio Cardíaco/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Descanso , Síndrome do Nó Sinusal/terapia , Volume Sistólico/fisiologiaRESUMO
1,25-Dihydroxyvitamin D3 (1,25[OH]2D3) caused a rise in the concentration of intracellular free calcium ions ([Ca2+]i) in HL-60 cells. This effect of 1,25(OH)2D3 parallels its suppression of cell proliferation and its induction of cell differentiation into monocyte-like cells. The changes in [Ca2+]i are dose and time dependent. The concentration of 1,25(OH)2D3 (10(-7) M) that induced maximal differentiation also caused the maximal increase in intracellular Ca2+. The rise in cytoplasmic free Ca2+ concentration was not immediate and reached statistical significance only after 24 h. The [Ca2+]i reached its peak at 48 h (134 +/- 4 nM vs 101 +/- 3 nM in controls) and remained stable at this level. The increase in intracellular Ca2+ was found to be related to new protein synthesis, because it was inhibited in the presence of specific RNA and protein synthesis inhibitors. The rise in [Ca2+]i was not observed during incubation of HL-60 cells with 24,25-dihydroxyvitamin D3 (24,25[OH]2D3), a vitamin D metabolite that does not induce the differentiation of HL-60 cells. In contrast, 25-hydroxyvitamin D3 (25-OH-D3) and phorbol 12-myristate 13-acetate (TPA), both of which induce differentiation in this cell line, also increase [Ca2+]i. In conclusion, the present study emphasizes that a significant increase in intracellular free Ca2+ occurs in the effect of 1,25(OH)2D3 on HL-60 cells.
Assuntos
Calcitriol/farmacologia , Cálcio/metabolismo , Citosol/metabolismo , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Imunofluorescência , Humanos , Cinética , Leucemia Promielocítica Aguda , Espectrometria de Fluorescência , Acetato de Tetradecanoilforbol/farmacologia , Células Tumorais Cultivadas , Vitamina D/farmacologiaRESUMO
ACT-280778 is an oral, non-dihydropyridine, dual L-/T-type calcium channel blocker. This phase 2a, double-blind, randomized, placebo- and active-controlled study investigated the efficacy and safety of 10 mg ACT-280778. Patients with mild-to-moderate essential hypertension received once-daily placebo (n=53), ACT-280778 10 mg (n=52) or amlodipine 10 mg (n=54) for 4 weeks. The primary end point was the change from baseline to week 4 in placebo-adjusted mean trough sitting diastolic blood pressure (SiDBP) with ACT-280778. Tolerability was assessed by recording treatment-emergent adverse events (TEAEs). Baseline clinical characteristics were similar across groups. No significant difference was observed at week 4 in mean trough SiDBP between placebo (-9.9 (95% confidence limit (CL) -12.7, -7.0) mm Hg) and ACT-280778 (-9.5 (-12.4, -6.5) mm Hg; P=0.86); amlodipine reduced mean trough SiDBP by -16.8 (-19.0, -14.5) mm Hg, confirming assay validity. Change in mean PR interval at week 4 (pre-dose) differed between placebo (-1.0 (95% CL -4.4, 2.3) ms) and ACT-280778 (6.5 (3.5, 9.6) ms); amlodipine did not increase PR interval (1.1 (-1.6, 3.9) ms).Treatment-emergent adverse events (TEAE) frequency was 32.1% (placebo), 32.7% (ACT-280778) and 33.3% (amlodipine). The most common TEAEs were headache, peripheral edema, hypertension and second-degree atrioventricular block. ACT-280778 (10 mg) did not lower blood pressure in mild-to-moderate hypertension.
Assuntos
Anti-Hipertensivos/uso terapêutico , Benzimidazóis/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Compostos Bicíclicos com Pontes/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo T/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Administração Oral , Adulto , Idoso , Anlodipino/uso terapêutico , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/efeitos adversos , Compostos Bicíclicos com Pontes/farmacocinética , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacocinética , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo T/metabolismo , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Israel , Masculino , Pessoa de Meia-Idade , Sérvia , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
In bovine adrenomedullary cells in primary culture, angiotensin II (AII) elicited virtually immediate, dose-related increments in cytosolic calcium [( Ca++]i) measured by the Quin 2 technique and stimulated approximately proportional secretion of norepinephrine, epinephrine, and dopamine measured by liquid chromatography with electrochemical detection. Peak responses of [Ca++]i to AII were similar to peak responses to nicotine or KCl. Pre-treatment with verapamil or washing the cells in calcium-free medium attenuated the stimulatory effect of AII on [Ca++]i. Pre-treatment with nicotine, which temporarily inactivates cholinergic receptor-activated calcium channels, did not affect [Ca++]i responses to AII. The results indicate functional effects of AII on cultured chromaffin cells. The mechanism of cellular activation by AII appears to include increases in [Ca++]i due to opening of membrane calcium channels which may be unrelated to cholinergic receptor-operated calcium channels.
Assuntos
Medula Suprarrenal/metabolismo , Angiotensina II/farmacologia , Cálcio/metabolismo , Catecolaminas/metabolismo , Medula Suprarrenal/efeitos dos fármacos , Aminoquinolinas , Animais , Bovinos , Células Cultivadas , Citosol/metabolismo , Dopamina/metabolismo , Epinefrina/metabolismo , Corantes Fluorescentes , Canais Iônicos/fisiologia , Nicotina/farmacologia , Norepinefrina/metabolismo , Cloreto de Potássio/farmacologia , Espectrometria de Fluorescência , Verapamil/farmacologiaRESUMO
Clinical observations have long suggested that skin perfusion (SP), among other factors, depends on thyroid status. However, quantitative data concerning this relationship are rather sparse. This study characterizes SP by means of laser Doppler flowmetry (LDF) in various thyroid dysfunctional states. The data reveal that mean capillary flow velocity, capillary pulse wave amplitude, and capillary flow oscillation amplitude, but not capillary flow oscillation frequency, are increased in hyperthyroid patients and decreased in hypothyroid patients. Regaining the euthyroid state is accompanied by normalization of LDF parameters only in hyperthyroid patients. It is concluded that LDF is useful in monitoring the thyroid effect on SP. However, it may not be used as a biological marker for the thyroid status of a given individual.
Assuntos
Hipertireoidismo/fisiopatologia , Hipotireoidismo/fisiopatologia , Fluxometria por Laser-Doppler , Pele/irrigação sanguínea , Hormônios Tireóideos/farmacologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Fluxo Sanguíneo Regional/efeitos dos fármacos , TemperaturaRESUMO
Levels of synaptic cleft norepinephrine associated with pressor responses were estimated in humans by measuring blood pressure and arterial plasma norepinephrine during norepinephrine infusion and during yohimbine-induced release of endogenous norepinephrine. Linear pressor response-log norepinephrine concentration relationships were observed during the infusions. At a pressor response of 20 mm Hg, arterial norepinephrine averaged 3647 pg/ml. The pressor-log norepinephrine relationship was shifted more than fivefold to the left during combined ganglionic, alpha 2-adrenergic receptor, and Uptake1 (neuronal norepinephrine uptake) blockade: arterial norepinephrine averaged 684 pg/ml at a 20 mm Hg pressor response. During yohimbine-induced release of endogenous norepinephrine in desipramine-pretreated subjects, arterial norepinephrine averaged 467 pg/ml at a 20 mm Hg pressor response. Since the norepinephrine concentration in the synaptic clefts must have been between the values for plasma norepinephrine during its infusion and during its endogenous release, we estimated that in healthy people, a 20 mm Hg sympathetically mediated pressor response is associated with about a 560 pg/ml (3.3 nM) concentration of norepinephrine in the average neuroeffector junction.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Junção Neuroefetora/metabolismo , Norepinefrina/metabolismo , Sinapses/metabolismo , Adulto , Desipramina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Junção Neuroefetora/efeitos dos fármacos , Norepinefrina/sangue , Norepinefrina/farmacologia , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Adrenérgicos/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Sinapses/efeitos dos fármacos , Trimetafano/farmacologia , Ioimbina/farmacologiaRESUMO
We infused isoproterenol (ISO) intravenously into 23 subjects (3.5, 7, 14, and 35 ng/kg/min for 20 minutes at each dose) and measured venous plasma concentrations of ISO and the circulatory and plasma norepinephrine (NE) and epinephrine (E) responses. At the lowest dose, venous plasma ISO averaged 48 pg/ml and was associated with increased heart rate (9%; P less than 0.001), cardiac index (20%; P less than 0.001), and stroke volume (9%; P less than 0.02) and decreased total peripheral resistance index (-21%; P less than 0.001). Linear concentration-response relationships were observed between plasma ISO and cardiac index and between plasma ISO and heart rate. Plasma NE increased as a function of plasma ISO (mean increase 81% at 35 ng/kg/min), whereas plasma E was unchanged or decreased. The results indicate that circulatory effects of ISO are detectable in humans at plasma concentrations in the range of physiologic levels of E. Since ISO increases plasma NE, ISO may act presynaptically to enhance NE release from sympathetic nerve terminals and thereby stimulate alpha-adrenoceptors indirectly. ISO does not appear to stimulate secretion from the adrenal medulla or corelease of E with NE from sympathetic nerve endings.
Assuntos
Epinefrina/sangue , Hemodinâmica/efeitos dos fármacos , Isoproterenol/farmacologia , Norepinefrina/sangue , Adulto , Humanos , Infusões Parenterais , MasculinoRESUMO
It has been suggested that a circulating inhibitor of Na/K ATPase can stimulate natriuresis and cause vasoconstriction in essential hypertension by stimulating transmembrane Na/Ca exchange to produce increased cytosolic concentrations of ionized calcium ([Ca++]i) in renal tubular and arteriolar smooth muscle cells. If this inhibitor affected [Ca++]i in all cell types, then clinical assays for its presence could be applied to easily accessible cells such as blood cells or platelets, and the inhibitor could exert a hormonal action on Ca++-dependent adrenomedullary secretion of catecholamines. We used the Quin 2 technique for measuring [Ca++]i in lymphocytes, platelets and adrenomedullary cells in response to ouabain. Inhibition of Na/K ATPase by ouabain (10(-7) to 10(-3) mol/l enhanced transient [Ca++]i responses during Ca repletion but had no effect on steady-state [Ca++]i in any of the cell lines. Although it is possible that a Na/Ca exchange mechanism may exaggerate transient increases in [Ca++]i during Na/K ATPase inhibition, other mechanisms appear to buffer these acute perturbations of [Ca++]i in lymphocytes, platelets and adrenomedullary cells.
Assuntos
Medula Suprarrenal/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Cálcio/análise , Citosol/análise , Linfócitos/efeitos dos fármacos , Ouabaína/farmacologia , Medula Suprarrenal/citologia , Animais , Bovinos , Células Cultivadas , Citosol/efeitos dos fármacos , HumanosRESUMO
To test the hypothesis that an abnormality of the intracellular concentration of ionized calcium, [Ca2+]i, is associated with high blood pressure, we measured [Ca2+]i in the platelets of spontaneously hypertensive (SHR) and Wistar-Kyoto control (WKY) rats using the Quin 2 technique after separation of the platelets in calcium-free medium, during calcium repletion, and upon exposure to agonists which increase platelet [Ca2+]i (thrombin, adenosine diphosphate, serotonin and ionomycin). Despite clear-cut changes in [Ca2+]i during these manipulations, there were no differences between the SHR and WKY rats in baseline levels of [Ca2+]i or in the kinetics of changes in [Ca2+]i. These results do not support the hypothesis that high levels of [Ca2+]i at rest or abnormal kinetics of changes in [Ca2+]i play a pathophysiological role in the hypertension of SHR.
Assuntos
Plaquetas/análise , Cálcio/sangue , Citosol/análise , Hipertensão/metabolismo , Difosfato de Adenosina/farmacologia , Animais , Plaquetas/efeitos dos fármacos , Pressão Sanguínea , Citosol/efeitos dos fármacos , Éteres/farmacologia , Ionomicina , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Serotonina/farmacologia , Trombina/farmacologiaRESUMO
BACKGROUND: There is controversy in the literature concerning the effect of short-term insulin administration on blood pressure in different experimental situations, because in some experiments this association is clear, whereas in others it is nonexistent. OBJECTIVE: To investigate whether there is a difference in the effect of exogenous insulin administration on the blood pressure of normotensive Wistar-Kyoto (WKY) rats and hypertensive spontaneously hypertensive rats (SHR). METHODS: Hyperinsulinaemia was induced in normotensive WKY rats and in hypertensive SHR by the administration of long-acting insulin (insulin retard 0.4 U/kg body weight per day in one group and 0.8 U/kg body weight per day in another group) once a day, intraperitoneally, for 3 weeks. All of the rats drank a 10% sucrose solution, to prevent hypoglycaemia in those receiving insulin. RESULTS. Baseline serum levels were significantly higher in the SHR groups than in the WKY rat groups. At the end of the experiment, after 3 weeks' insulin therapy, systolic blood pressure measured by the tail-cuff method showed a significant increase in the SHR, but not in the WKY rats, possibly because of the genetic predisposition of the SHR to increase their blood pressure. The increase was similar in the SHR given 0.4 U/kg body weight per day insulin retard to that in those given 0.8 U/kg per day. CONCLUSIONS: Exogenous insulin increased systolic blood pressure in the SHR but not in the WKY rats. The rise was similar in rats receiving either 0.4 or 0.8 U/kg body weight per day insulin retard.
Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/fisiopatologia , Hipoglicemiantes/efeitos adversos , Insulina/sangue , Animais , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/metabolismo , Insulina/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptor de Insulina/metabolismoRESUMO
The expression of the H23 gene, previously shown to be overexpressed in breast cancer tissue, was examined in various thyroid pathologies. Thyroid papillary carcinomas demonstrate significant H23 mRNA levels, whereas benign thyroid pathologies have very low levels of expression. H23 gene expression in thyroid cancer inversely correlated with that of thyroperoxidase and thyroglobulin genes. Immunoblot assays of thyroid cancer tissues revealed overexpression of H23 gene at the protein level as well The data presented indicate that dedifferentiation of thyroid tissue to the malignant state is associated with increased H23 gene expression and suppression of some thyroidal differentiation marker genes.
Assuntos
Antígenos de Neoplasias/genética , Carcinoma Papilar/genética , Expressão Gênica , Neoplasias da Glândula Tireoide/genética , Neoplasias da Mama/genética , Immunoblotting , Iodeto Peroxidase/genética , Mucina-1 , Mucinas , RNA Mensageiro/análise , Tireoglobulina/genética , Glândula Tireoide/químicaRESUMO
The efficacy of cilazapril monotherapy was evaluated in 2 multicentre double-blind dose-response trials. After 4 weeks of a single-blind placebo run-in period, patients with uncomplicated mild to moderate essential hypertension and a sitting diastolic blood pressure of 100 to 115 mm Hg, 24 hours after the last placebo dose (trough), were randomised to take either placebo or cilazapril 2.5 mg or 5 mg for 4 weeks (study 1, 86 patients) or 8 weeks (study 2, 78 patients). Sitting diastolic blood pressure was checked every 2 weeks at trough in both studies and at peak in study 2. The reductions in sitting diastolic blood pressure from baseline at trough, and the difference from placebo, were clinically and statistically significant for both cilazapril groups in the 2 studies. The reduction in blood pressure in both active treatment groups was similar, but the response rate with cilazapril 5 mg was greater than that with 2.5 mg. More than 50% of the peak effect was still present at trough for both cilazapril groups. It is concluded that both dosages of cilazapril are effective and reduce blood pressure compared with placebo over a 24-hour period.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Hipertensão/tratamento farmacológico , Piridazinas/uso terapêutico , Adulto , Idoso , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Cilazapril , Diástole/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Postura/fisiologia , Piridazinas/efeitos adversos , Fatores de TempoRESUMO
In an open study, 16 patients with moderate essential hypertension were treated with 5 or 10 mg felodipine daily for 3 months. Hemodynamic (HD) indices were assessed at rest and during isometric effort (IE) at days 0, 3 to 7, 30, 60, and 90. Treatment efficacy was evaluated by ambulatory blood pressure monitoring for (ABPM) 24 h and divided between awake and sleep periods. Left ventricular mass (LVM) was determined before and at the end of treatment. Treatment normalized blood pressure (BP) in all patients (5 mg in 7 and 10 mg in 9). Systolic diastolic and mean arterial pressure (MAP) decreased significantly during the study (P < .01). The decrease in BP was significant on day 3 to 7 (P < .01) and tended to decrease further with treatment. Resting heart rate (HR) did not change. After 3 months systolic and diastolic pressure and MAP decreased significantly. Mean HR during ABPM differed between awake and sleep hours but did not change with treatment. When ABPM was divided into daytime and nighttime the awake BP decreased after 3 months (P < .01), but sleep measurements showed only a borderline decrease (P = .05). MAP after 3 months decreased in both awake and sleep periods. LV maximal and minimal dimensions did not change during treatment. Interventricular septum, posterior wall thickness, LVM, LVM/body surface area, and LVM/height tended to decrease, however this change was not significant. Hemodynamic measurements were measured at rest, at peak IE and posteffort. During treatment rest systemic vascular resistance (SVR) and MAP decreased, and there was no difference in ventricular ejection time, HR, and cardiac index. The increase in BP at IE was not prevented by treatment. After effort MAP decreased significantly and SVR tended to decrease in treated patients. Felodipine normalized resting BP in all patients. The main antihypertensive effect came at daytime and was less during sleep. No reflex tachycardia was seen during treatment. Echocardiographic measurements showed preservation of systolic and diastolic function and a tendency of decrease in LVM. Probably longer period of treatment is needed for clear-cut regression of LVM. Felodipine did not prevent the increase in BP and SVR during isometric effort, implying that normal cardiovascular reflexes are preserved during treatment.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Felodipino/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Monitorização Ambulatorial da Pressão Arterial , Bloqueadores dos Canais de Cálcio/efeitos adversos , Ecocardiografia , Felodipino/efeitos adversos , Feminino , Humanos , Hipertensão/diagnóstico por imagem , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Contração Isométrica , Masculino , Pessoa de Meia-IdadeRESUMO
Angiotensin II (Ang-II) and endothelin 1 (ET-1) are important peptides that induce a prolonged vasoconstriction and enhance proliferation of vascular smooth muscle cells (VSMC). These substances may have an important role in the development of hypertension and atherosclerosis. Our objectives were to determine whether there are inborn differences in the proliferation patterns of VSMC obtained from spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY) by studying the effects of Ang-II and ET-1 on VSMC from those strains before the onset of hypertension, and to evaluate the roles of protein kinase C (PKC) and intracellular Ca2+ in the mechanism of action of ET-1 and Ang-II. VSMC from aortas of young (1- to 2-week-old) SHR and WKY rats were grown as primary cultures in plates for 48 h. The cells were incubated with Ang-II (0.1 to 1000 nmol/L) or ET-1 (0.1 to 100 nmol/L). VSMC were also incubated in the presence of various concentrations of a PKC inhibitor, chelerythrine (0.1-10 nmol/L). Thymidine incorporation into DNA was measured as an indicator of DNA synthesis. Intracellular free Ca2+ was determined by using FURA-2AM. ET-1 and Ang-II caused a marked dose-dependent enhancement of thymidine incorporation into DNA. The responses of VSMC from WKY and SHR to Ang-II and ET-1 were similar. In both strains, chelerythrine caused a dose-dependent suppression in the activity of ET-1 and Ang-II. However, VSMC from SHR incubated in the presence of ET-1 were more susceptible to the inhibitory effect of chelerythrine. Both Ang-II and ET-1 induced an increase of intracellular free Ca2+. ET-1 induced a larger increase than Ang-II (190% and 100% greater than baseline free Ca2+ levels, respectively), in spite of a lower concentration of ET-1 (ET-1 = 30 nmol/L; Ang-II = 100 nmol/L). Ang-II and ET-1 exerted a similar mitogenic effect on primary cultures of VSMC obtained from young SHR before the development of hypertension, compared with WKY. The mitogenic activity of Ang-II and ET-1 was accompanied by an increase of intracellular free Ca2+. The effect of ET-1 upon intracellular Ca2+ was stronger than that of Ang-II. VSMC cultures of SHR stimulated with ET-1 were more susceptible to PKC inhibition than those of WKY. The similarity of the effects of Ang- II and ET-1 on SHR and WKY does not exclude their role in the pathogenesis of hypertension and atherosclerosis, and further studies should be carried out to determine their role.
Assuntos
Angiotensina II/farmacologia , Cálcio/metabolismo , DNA/biossíntese , Endotelina-1/farmacologia , Hipertensão/metabolismo , Líquido Intracelular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Alcaloides , Animais , Benzofenantridinas , Células Cultivadas , DNA/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Corantes Fluorescentes , Fura-2/análogos & derivados , Hipertensão/patologia , Hipertensão/fisiopatologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Fenantridinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Espectrometria de Fluorescência , Timidina , Vasoconstrição/efeitos dos fármacosRESUMO
BACKGROUND: We studied the effect of atorvastatin on arterial compliance in patients with severe hypercholesterolemia. METHODS: Seventeen patients with low-density lipoprotein cholesterol levels above 170 mg/dL, were included in the study, none of whomever received hypolipidemic medication or had other risk factors. Patients were followed for five visits, every 4 weeks. RESULTS: After 20 weeks of treatment, lipid profile improved significantly. Large artery elasticity index did not change significantly, but small artery elasticity index increased by 21% (4.6+/-0.5 to 5.6+/-0.9, P < .01). Although none of our patients suffered from hypertension, both systolic and diastolic blood pressure (BP) decreased significantly (6 mm Hg and 3 mm Hg, respectively). CONCLUSIONS: We conclude that atorvastatin improves the elasticity of small arteries and reduces systolic and diastolic BP in patients with severe hypercholesterolemia.
Assuntos
Anticolesterolemiantes/uso terapêutico , Artérias/efeitos dos fármacos , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/fisiopatologia , Pirróis/uso terapêutico , Adulto , Idoso , Atorvastatina , Complacência (Medida de Distensibilidade)/efeitos dos fármacos , Feminino , Seguimentos , Humanos , Hipercolesterolemia/sangue , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Ketanserin, a serotonin-2-receptor antagonist, was administered to 12 subjects with mild to moderate hypertension in a randomized, double-blind, placebo-controlled crossover trial. After 6 weeks of ketanserin (40 mg every 12 hours), blood pressures measured 12 hours after dosing were not significantly different from those obtained after placebo. However, 2 hours after ketanserin administration, supine systolic and diastolic blood pressures declined 11 +/- 10 mm Hg (P less than 0.01) and 6 +/- 5 mm Hg (P less than 0.005) from predose values, whereas placebo caused no change in either systolic or diastolic blood pressure. Except for a slight decline in serum prolactin levels 12 hours after dosing with ketanserin, no changes were observed in pituitary hormone levels, serum testosterone, plasma catecholamines, plasma renin activity, aldosterone, or lipoproteins. Stroke volume, measured 2 hours after dosing, increased with ketanserin therapy, but cardiac output, systemic resistance, and heart rate were unchanged. Ketanserin has a moderate antihypertensive effect and neutral metabolic-hormonal profile when used as monotherapy for the treatment of hypertension. However, further studies are needed to define the frequency of dosing that will provide 24 hours of antihypertensive activity.