RESUMEN
A large number of astronauts returning from spaceflight experience orthostatic hypotension. This hypotension may be due to overproduction of vasodilatory mediators, such as nitric oxide (NO) and prostaglandins. To evaluate the role of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) as a countermeasure against the post-suspension reduction in mean arterial pressure (MAP), we assessed the cardiovascular responses and vascular reactivity to 7-day 30 degrees tail-suspension and a subsequent 6 hr post-suspension period in conscious rats. After a pre-suspension reading, direct MAP and heart rate (HR) were measured daily and every 2 hrs post-suspension. The NO synthase inhibitor L-NAME (20 mg/kg, i.v.), or saline, were administered after the 7th day reading prior to release from suspension and at 2 and 4 hrs post-suspension. At 6 hrs post-suspension, vascular reactivity was assessed. While MAP did not change during the suspension period, it was reduced post-suspension. Heart rate was not significantly altered. L-NAME administration reversed the post-suspension reduction in MAP. In addition, the baroreflex sensitivity for heart rate was modified by L-NAME. Thus, the post-suspension reduction in MAP may be due to overproduction of NO and altered baroreflex activity.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hipotensión Ortostática/tratamiento farmacológico , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/farmacología , Animales , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Suspensión Trasera/efectos adversos , Suspensión Trasera/fisiología , Humanos , Hipotensión Ortostática/etiología , Hipotensión Ortostática/fisiopatología , Masculino , Óxido Nítrico/biosíntesis , Ratas , Ratas Sprague-Dawley , Vuelo EspacialRESUMEN
Chronic infusion of angiotensin (1-7) [Ang-(1-7)] lowers blood pressure in spontaneously hypertensive rats (SHR). To assess the role of Ang-(1-7) in salt-induced hypertension, Ang-(1-7) (24 microg/kg/hr) or saline was administered chronically via osmotic minipump into the jugular vein of 5-6 wk-old male (M) and female (F) Dahl salt-sensitive rats placed on a high-salt (8% NaCl) diet for 2 weeks. Blood pressure (BP) and heart rate were measured prior to the start of the diet and weekly thereafter. Ang-(1-7) significantly attenuated the BP increase after 1 wk on the diet in both M and F rats, but after 2 weeks only in F rats. Enhanced release of prostacyclin, (6-keto PGF1 alpha), following Ang-(1-7) treatment was observed in both M and F rats. In addition, significant increases in aortic blood flow and plasma levels of nitric oxide were observed in the F rats following Ang-(1-7) treatment. These findings demonstrate that the reduction in BP is due to both prostacyclin and NO and that there is a gender difference in the attenuation of salt-induced hypertension by Ang-(1-7).
Asunto(s)
Angiotensinas/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , 6-Cetoprostaglandina F1 alfa/sangre , Angiotensinas/farmacología , Animales , Aorta/metabolismo , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Dinoprostona/sangre , Epoprostenol/sangre , Epoprostenol/farmacología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Riñón/metabolismo , Masculino , Óxido Nítrico/sangre , Ratas , Ratas Endogámicas Dahl , Sales (Química)/metabolismo , Factores Sexuales , Factores de TiempoRESUMEN
To evaluate gender differences in salt-induced hypertension, female and male Dahl salt-sensitive rats were fed high (8.0% NaCl, HS) and low (0.3% NaCl, LS) salt diets. During a 3-week treatment period, blood pressure was significantly elevated in both female and male HS groups compared to their respective LS groups. The blood pressure and 4 week mortality rate of the female HS group, however, were significantly lower than those of the male HS group. Renal and aortic blood flows were reduced in male rats on HS diet compared to the LS group, while, in females, renal blood flow was elevated and aortic flow was maintained while on HS diet. Plasma prostaglandin E2 and prostacyclin levels were higher in females than males and unaffected by diet. In contrast, plasma nitric oxide levels were reduced by HS, regardless of gender. In isolated aortic rings, HS diet caused a smaller elevation in the stimulated norepinephrine release ratio in female rats than in males. Thus, salt-induced hypertension is associated with a reduction in levels of nitric oxide regardless of gender. Plasma prostaglandin E2 and prostacyclin levels were higher in females. Taken together, the higher plasma prostaglandin levels and reduced sympathetic activity in females may be contributing factors in their lower blood pressure and reduced mortality.
Asunto(s)
Hipertensión/inducido químicamente , Caracteres Sexuales , Cloruro de Sodio , Animales , Circulación Sanguínea , Presión Sanguínea , Peso Corporal , Estimulación Eléctrica , Femenino , Frecuencia Cardíaca , Hipertensión/mortalidad , Hipertensión/patología , Hipertensión/fisiopatología , Masculino , Óxido Nítrico/sangre , Norepinefrina/metabolismo , Prostaglandinas/sangre , Prostaglandinas/fisiología , Ratas , Ratas Endogámicas Dahl , Resistencia Vascular , Vasodilatación/fisiologíaRESUMEN
BACKGROUND: There are conflicting reports regarding the effect of salt sensitivity on the calciuric response to salt, perhaps because of gender differences and different modes of salt administration. We tested the hypothesis that the calciuric response to dietary salt would not differ for male Dahl salt-sensitive (S) and salt-resistant (R) rats. METHOD: S and R rats were fed high- (80 g/kg) or low- (3 g/kg) salt diets for 3 weeks and urine (24 hour) was collected weekly. RESULTS: Urinary calcium excretion was up to 20-fold greater for S and R rats fed a high-salt diet (P < 0.001) than for S and R rats fed a low-salt diet and did not differ significantly between S and R rats. S rats, however, excreted calcium in significantly higher urine volumes (P< 0.001) during high salt intake and developed hypertension. Plasma parathyroid hormone concentrations of S and R rats did not differ during low salt intake and increased significantly to the same concentration after 3 weeks of high salt intake. CONCLUSIONS: We have previously reported that plasma 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D concentrations of male S rats, but not male R rats, were drastically reduced by 3 weeks of high salt intake. These data suggest that salt-induced hypertension and salt-induced alterations in the vitamin D endocrine system of male S rats do not affect the calciuric response to dietary salt.
Asunto(s)
Calcio/orina , Ratas Endogámicas Dahl , Sodio en la Dieta/farmacología , Animales , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Masculino , Hormona Paratiroidea/sangre , Ratas , Sodio/orinaRESUMEN
BACKGROUND: We have shown previously that the calciuric response to salt does not differ in Dahl salt-sensitive (S) and salt-resistant (R) male rats. Clinical studies with women, however, suggest an effect of salt sensitivity on the calciuric response to salt. The objective of this study was to determine whether there is an effect of salt sensitivity on the calciuric response to salt of female S and R rats. METHOD: Dahl S and R female rats were fed high- (8%) or low- (0.3%) salt diets for 3 weeks. The rats were placed in metabolic cages for 24-hour urine collection at baseline and weekly (for sodium and calcium determination). RESULTS: Blood pressure of female S rats was 177+/-3.0 mm Hg at week 3 of high salt intake compared with 96+/-1 mm Hg for female R rats. Female S rats excreted significantly more calcium than female R rats at baseline (P < 0.001), when fed a nonpurified diet, and during high salt intake (P = 0.004). Salt sensitivity significantly increased calcium excretion, water intake, and urine output when rats were fed a high-salt diet. Calcium excretion, water intake, and urine output of female S rats were time-dependent during high salt intake. Plasma 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D concentrations were markedly lower in female S rats fed a high-salt diet, but not in female R rats. Plasma parathyroid hormone and 1,25-dihydroxyvitamin D concentrations did not significantly differ between female S and R rats, but plasma concentrations of these two hormones at week 3 were significantly higher in S rats fed a high-salt diet compared with S rats fed a low-salt diet. CONCLUSIONS: Our data indicate that the calciuric response to salt is greater in female S compared with female R rats, thus supporting findings on the effect of salt sensitivity reported in several clinical studies with women. The greater calciuric response to salt of female S rats compared with female R rats, which was not seen in a previous study when male S rats were compared to male R rats, suggest a gender difference in the calciuric response to salt.
Asunto(s)
Calcio/orina , Hipertensión/orina , Cloruro de Sodio Dietético/farmacología , Sodio/orina , Animales , Determinación de la Presión Sanguínea , Peso Corporal , Ingestión de Líquidos , Femenino , Hormona Paratiroidea/sangre , Ratas , Ratas Endogámicas Dahl , Vitamina D/sangreRESUMEN
Orthostatic hypotension is a serious condition that is sometimes manifested in astronauts during standing postflight. These observations may be related to impairment of autonomic function and/or excessive production of endothelium-dependent relaxing factors. To evaluate the role of the cyclooxygenase inhibitor indomethacin as a countermeasure against the post-suspension reduction in mean arterial pressure (MAP), we examined the cardiovascular responses to 7-day 30 degrees tail-suspension and a subsequent 6-hr post-suspension period in conscious male Sprague-Dawley rats. Indomethacin (2 mg/kg) or saline were administered intravenously prior to release from suspension and at 2 and 4 hrs post-suspension. Direct MAP and heart rate were determined prior to suspension, daily and every 2 hrs post-suspension. During suspension, MAP did not change, in contrast, during post-suspension; it decreased compared to parallel non-suspended, untreated animals. There were no significant changes in heart rate. The reduction in MAP post-suspension was associated with significant increases in plasma prostacyclin. Indomethacin attenuated the observed post-suspension reduction in MAP and reduced plasma prostacyclin levels. Also, the baroreflex sensitivity for heart rate was modified by indomethacin--the MAP threshold for baroreflex activation was raised and the effective MAP range expanded. Thus, the post suspension reduction in mean arterial pressure may be due to overproduction of vasodilatory prostaglandins and/or other endothelium-dependent relaxing factors and alteration in baroreflex activity.
Asunto(s)
Inhibidores de la Ciclooxigenasa/uso terapéutico , Epoprostenol/metabolismo , Hipotensión Ortostática/prevención & control , Indometacina/uso terapéutico , Medidas contra la Ingravidez , Simulación de Ingravidez/efectos adversos , Animales , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Epoprostenol/sangre , Inclinación de Cabeza , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Suspensión Trasera , Hipotensión Ortostática/tratamiento farmacológico , Hipotensión Ortostática/etiología , Masculino , Nitroprusiato/farmacología , Fenilefrina/farmacología , Ratas , Ratas Sprague-Dawley , Vasoconstrictores/farmacología , Vasodilatadores/farmacologíaRESUMEN
Microgravity is known to induce orthostatic intolerance and baroreflex impairment in astronauts. Cardiovascular responses observed in 30 degrees head-down tilt rat models, whether 24 hr whole body suspension (WBS) or 7 day tail-suspension (TS), mimic observations made during exposure to microgravity. We evaluated the cardiovascular effects of simulated microgravity and the subsequent post-suspension in rats using the above models. Mean arterial pressure (MAP) of both WBS and TS rats did not change during suspension. In both models, MAP decreased post-suspension and this response lasted for 6 hrs. Salt-loaded animals did not show a post-suspension reduction in MAP. Plasma ionized calcium was decreased at 2 hr of WBS, with no change in sodium, potassium, magnesium, glucose, or hematocrit. Body weight changes were similar for all animals whether under suspension or control conditions. Both rat models demonstrate post-suspension hypotension and these results support the notion that salt-loading may have some beneficial effects in ameliorating this hypotension.
Asunto(s)
Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Simulación de Ingravidez , Animales , Peso Corporal/fisiología , Calcio/sangre , Catecolaminas/sangre , Modelos Animales de Enfermedad , Suspensión Trasera/fisiología , Hipotensión Ortostática/sangre , Hipotensión Ortostática/etiología , Hipotensión Ortostática/fisiopatología , Masculino , Ratas , Ratas Sprague-Dawley , Sistema Nervioso Simpático/fisiologíaRESUMEN
The purpose of this study was to evaluate potential countermeasures for bone loss during long-term space missions in the hindquarter suspended rat, including partial weight bearing (surrogate for artificial gravity) episodic full weight bearing (2 hour/day full weight bearing) and treatment with the third generation bisphosphonate ibandronate (Roche). Graded mechanical loading was studied by housing the animals on a novel servo controlled force plate system which permitted the titration of mechanical force at varying frequency and amplitude and different levels of weight bearing. The force plate, which forms the cage floor, is a glass platform supported by an 18" diameter speaker cone filled with expanding polyurethane foam. An infrared optical sensor attached to the speaker cone yields a voltage linearly related to vertical displacement of the glass platform. The dynamic force on the paw was computed as a product of the apparent mass of the animal on the platform at rest and the acceleration of the platform determined from the second derivative of the optical sensor output. The mass of the animal on the platform was varied by adjusting tension on the tether suspending the animal. Mechanical impact loading was titrated with the force plate resonating at different frequencies, including 3 Hz and 16 Hz.
Asunto(s)
Resorción Ósea/prevención & control , Difosfonatos/farmacología , Condicionamiento Físico Animal , Medidas contra la Ingravidez , Simulación de Ingravidez , Animales , Colágeno/análisis , Femenino , Suspensión Trasera , Vivienda para Animales , Húmero/efectos de los fármacos , Ácido Ibandrónico , Ratas , Ratas Sprague-Dawley , Estrés Mecánico , Soporte de PesoRESUMEN
Cardiovascular adaptations observed during exposure to microgravity results in impairment of baroreflex activity partially as a result of fluid and electrolyte shifts. The head-down tilt rat model mimics some of the physiological observations that have been made in astronauts. We examined the effects of salt-loading on baroreflex activity after 7 day simulated microgravity (30 degrees tail-suspension) and the subsequent 6 hr post-suspension in Sprague-Dawley (SD) rats, using low salt (0.3% NaCl) and high salt (8% NaCl) diets. In suspended animals on a low salt diet, the baroreflex response curve was shifted to the left, while the heart rate (HR) range and MAP50 values were reduced compared to their parallel tethered, non-suspended controls. For non-suspended animals, salt-loading shifted the curve to the right with a reduced HR range. In salt-loaded, suspended animals, the curve and its parameters resemble those of non-suspended animals on a low salt diet. In summary, these data have demonstrated that a short-term (seven days) simulated weightlessness may elicit cardiovascular deconditioning in rats after release from the simulation manifested as an altered responsiveness in baroreceptor-heart rate reflex and a lowered blood pressure while the rats are tethered and horizontal. Our results also suggest the counteracting effect of salt loading on cardiovascular deconditioning.
Asunto(s)
Barorreflejo/efectos de los fármacos , Descondicionamiento Cardiovascular/efectos de los fármacos , Sodio en la Dieta/farmacología , Medidas contra la Ingravidez , Simulación de Ingravidez , Animales , Barorreflejo/fisiología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Descondicionamiento Cardiovascular/fisiología , Dieta Hiposódica , Relación Dosis-Respuesta a Droga , Inclinación de Cabeza , Suspensión Trasera , Masculino , Modelos Animales , Ratas , Ratas Sprague-Dawley , Sodio en la Dieta/administración & dosificación , Sodio en la Dieta/uso terapéuticoRESUMEN
To understand the role of nitric oxide in salt-induced hypertension, we evaluated cardiovascular, hemodynamic and biochemical parameters in Dahl salt-sensitive rats fed low (0.3%) and high (8.0%) sodium diets. Two high salt groups received 1.25 and 2.5 g/L l-arginine in their drinking water. After three weeks of treatment, blood pressure was greater in the high salt groups. l-arginine did not modify salt-induced hypertension. Eicosapentaenoic acid (EPA) caused a smaller depressor response compared to normotensive rats. The increase in blood pressure was associated with decreases in aortic and renal blood flows. In renal artery, the reduction was counteracted by both l-arginine doses; whereas in the aorta, only the higher l-arginine one restored blood flow. The salt-induced reduction in aortic cyclic GMP level was only overcome by the higher l-arginine treatment. These data suggest that at the dose levels tested, nitric oxide reverses the reduction in cGMP and blood flow, but not the blood pressure changes associated with salt-induced hypertension.
Asunto(s)
GMP Cíclico/metabolismo , Hipertensión/fisiopatología , Óxido Nítrico/biosíntesis , Sodio en la Dieta/administración & dosificación , Animales , Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/metabolismo , Aorta Abdominal/fisiopatología , Arginina/farmacología , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Ácido Eicosapentaenoico/farmacología , Inhibidores Enzimáticos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Radioinmunoensayo , Distribución Aleatoria , Ratas , Ratas Endogámicas Dahl , Arteria Renal/efectos de los fármacos , Arteria Renal/metabolismo , Arteria Renal/fisiopatologíaRESUMEN
Cardiovascular deconditioning manifested by reduction in mean arterial pressure (MAP) and cardioaccleration are usually observed in astronauts during standing postflight. The head-down tilt (HDT) rat model with "unloaded" hindlimbs has been extensively studied because some of the observed responses mimic observations made during exposure to microgravity. Angiotensin-(1-7) is a biologically active component of the renin-angiotensin system that acts to oppose the pressor and proliferative actions of Angiotensin II. It produces a hypotensive response by either stimulating production of vasodilator prostaglandins (i.e., prostacyclin), increasing nitric oxide or both. In the present study, we have evaluated the role of a specific inhibitor of Ang-(1-7), D-Ala7-Ang-(1-7)[A-779], as a countermeasure against post-suspension hypotension.
Asunto(s)
Angiotensina II/análogos & derivados , Presión Sanguínea/efectos de los fármacos , Suspensión Trasera , Fragmentos de Péptidos/farmacología , Medidas contra la Ingravidez , Angiotensina II/farmacología , Animales , Frecuencia Cardíaca , Hipotensión Ortostática/prevención & control , Masculino , Ratas , Ratas Sprague-Dawley , Simulación de IngravidezRESUMEN
Prolonged exposure to microgravity, in humans, induces cardiovascular deconditioning and impairment of baroreflex activity partially as a result of fluid and electrolyte shifts. Animal models of simulated microgravity have been developed to mimic the above responses. We examined the effects of both 24 hr whole body suspension and 7 day tail-suspension and the subsequent 6 hr post-suspension in salt-loaded (2 wks on 8% NaCl diet) Dahl salt-sensitive rats. In both models, mean arterial pressure (MAP) and heart rate (HR) were unchanged during the suspension period. Upon release from suspension, there was no difference in the MAP or HR responses. Blood flows measured in the lower abdominal aorta and renal artery were not different between suspended and control animals. In both models, there was a similar body weight reduction in all groups. MAP responses to both phenylephrine (PHE) and sodium nitroprusside (SNP) were not affected by simulated microgravity. The HR response to SNP in suspended animals was greater than that of control animals; whereas, PHE-induced responses were not different. These data support the notion that simulated microgravity did not alter the MAP responses to SNP and PHE, however, HR responses were enhanced by SNP in the salt-loaded Dahl rats. In addition, salt-sensitivity/salt-loading prevents the reduction in MAP observed post-suspension in normotensive rats.
Asunto(s)
Presión Sanguínea/fisiología , Descondicionamiento Cardiovascular/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Hemodinámica/fisiología , Cloruro de Sodio Dietético/farmacología , Simulación de Ingravidez , Animales , Aorta Abdominal/fisiología , Presión Sanguínea/efectos de los fármacos , Peso Corporal , Descondicionamiento Cardiovascular/fisiología , Inclinación de Cabeza , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Suspensión Trasera , Hipotensión Ortostática/prevención & control , Masculino , Nitroprusiato/farmacología , Fenilefrina/farmacología , Ratas , Ratas Endogámicas Dahl , Flujo Sanguíneo Regional , Arteria Renal/fisiología , Vasoconstrictores/farmacología , Vasodilatadores/farmacologíaRESUMEN
Dietary salt is a contributing factor to the development of hypertension in individuals who are salt-sensitive. The vitamin D endocrine system has been reported to modulate vascular structure and function. Since elderly hypertensive females with low plasma renin activity, typical of salt-sensitivity, had significantly lower 25-hydroxyvitamin D concentrations compared with normotensive elderly and young females, we have used Dahl salt-sensitive and salt-resistant rats fed high (80 g/kg diet) and low (3 g/kg diet) salt diets as models to examine the relationship between salt-sensitivity and 25-hydroxyvitamin D, the precursor of the hormonal form of vitamin D, 1,25-dihydroxyvitamin D. Plasma 25-hydroxyvitamin D concentrations of salt-resistant rats were unaffected by a high salt diet, but plasma 25-hydroxyvitamin D concentrations of salt-sensitive rats were significantly reduced within three weeks to lower than 25%. There was a negative association between plasma 25-hydroxyvitamin D concentrations of salt-sensitive rats and the number of days that the rats were fed a high salt diet (r = -0.98, P < 0.02) and a positive association between blood pressure and the number of days that the rats were fed a high salt diet (r = 0.97, P < 0.05). An inverse relationship was found between plasma 25-hydroxyvitamin D concentrations and blood pressure (r = -0.99, P < 0.01). Spontaneously hypertensive rats did not have low plasma 25-hydroxyvitamin D concentrations, suggesting that reduction of plasma 25-hydroxyvitamin D concentration might be specific to salt-induced hypertension.
Asunto(s)
Presión Sanguínea/fisiología , Calcifediol/sangre , Sodio en la Dieta , Animales , Dieta Hiposódica , Susceptibilidad a Enfermedades , Hipertensión/sangre , Hipertensión/fisiopatología , Masculino , Ratas , Ratas Endogámicas , Análisis de Regresión , SístoleRESUMEN
We have reported that an inverse relationship exists between blood pressure and plasma concentration of 25-hydroxyvitamin D, the precursor of the hormonal form of vitamin D, for Dahl salt-sensitive rats fed a high salt diet. Plasma 25-hydroxyvitamin D concentrations decreased with time on the diet, as blood pressure increased. Experiments were conducted to determine whether the blood pressure increase of salt-sensitive rats fed a high salt diet could be attenuated by exogenous 25-hydroxycholecalciferol. Dahl salt-sensitive rats were fed a high salt diet and administered exogenous 25-hydroxycholecalciferol via subcutaneously implanted Alzet pumps. Exogenous 25-hydroxycholecalciferol (various doses from 28 to 80 microg/kg body weight-day) had no significant effect on the blood pressure of vitamin D-replete rats fed a high salt diet for 15 days. When exogenous 25-hydroxycholecalciferol (28 and 60 microg/day-kg body weight) was administered to vitamin D-depleted salt-sensitive rats, plasma 25-hydroxyvitamin D concentrations of the rats fed a low salt diet (26 +/- 2 and 59 +/- 6 nM) were proportional to the 25-hydroxycholecalciferol concentration in the pumps. Plasma 25-hydroxyvitamin D concentrations of the rats fed a high salt diet (18 +/- 1 and 23 +/- 3 nM) were not proportional to the 25-hydroxycholecalciferol concentration in the pumps, but were inversely proportional to the blood pressure of the rats. These data indicate no ameliorating effect of exogenous 25-hydroxycholecalciferol on salt-induced hypertension, but accelerated metabolism and/or clearance of 25-hydroxycholecalciferol in salt-induced hypertension.
Asunto(s)
Calcifediol/farmacología , Hipertensión/etiología , Hipertensión/prevención & control , Animales , Presión Sanguínea/efectos de los fármacos , Calcifediol/sangre , Calcifediol/metabolismo , Hipertensión/fisiopatología , Bombas de Infusión Implantables , Masculino , Ratas , Ratas Endogámicas Dahl , Cloruro de Sodio/administración & dosificaciónRESUMEN
Genetic factors, diet, and salt sensitivity have all been implicated in hypertension. To further understand the mechanisms involved in salt-induced hypertension, cardiovascular, hemodynamics, and biochemical parameters in Dahl salt-sensitive rats were evaluated in animals on high- and low-sodium diets. During a 4-week treatment period, blood pressure was significantly elevated in the high (8.0%) salt group compared to the low (0.3%) salt group (p< or =0.05 for weeks 2 and 4, respectively). No significant changes were observed in heart rate. The increase in blood pressure was associated with significant increases in lower abdominal aortic and renal vascular resistance, along with a reduction in blood flow. A fourfold increase in arginine vasopressin was observed in animals on the high-salt diet. In contrast, there was no effect on plasma sodium, potassium, or aldosterone levels during the treatment period. As measured in isolated aortic rings, the high-salt diet also caused a significant elevation in stimulated norepinephrine release and a reduction in cyclic GMP levels. These data suggest that salt-induced elevation in blood pressure is due to activation of both the sympathetic and arginine vasopressin systems via mechanisms involving decreased cyclic GMP generation in vascular smooth muscle.
Asunto(s)
Hipertensión/fisiopatología , Cloruro de Sodio Dietético/administración & dosificación , Aldosterona/sangre , Animales , Aorta/metabolismo , Aorta/fisiopatología , Arginina Vasopresina/sangre , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , GMP Cíclico/metabolismo , Dieta Hiposódica , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/inducido químicamente , Hipertensión/genética , Hipertensión/metabolismo , Técnicas In Vitro , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatología , Norepinefrina/metabolismo , Potasio/sangre , Ratas , Ratas Endogámicas Dahl , Flujo Sanguíneo Regional/efectos de los fármacos , Sodio/sangre , Resistencia Vascular/efectos de los fármacosRESUMEN
We compared cholecalciferol 25-hydroxylation in liver microsomes of male and female rats. The rate of production of 25-hydroxycholecalciferol was similar in liver microsomes from female rats and those from male rats when cholecalciferol concentration ranged from 50 to 200 nmol/L. The liver cytosolic fraction stimulated the 25-hydroxylase activity of the microsomes up to 100% in both male and female rats at 44 nmol/L cholecalciferol. Cytosol metabolized cholecalciferol to a currently unidentified metabolite. At 300 nmol/L cholecalciferol, synthesis of the cytosolic metabolite was 100% greater than at 100 nmol/L and coincided with 32% lower synthesis of 25-hydroxycholecalciferol. These results suggest similar 25-hydroxy-lase activity in liver microsomes from male and female rats and similar ability of liver cytosol from these rats to stimulate 25-hydroxylation at low nanomolar concentrations of cholecalciferol, whereas inhibitory effects of cytosol at higher concentrations of cholecalciferol were shown.
Asunto(s)
Calcifediol/metabolismo , Colecalciferol/metabolismo , Microsomas Hepáticos/metabolismo , Esteroide Hidroxilasas/metabolismo , Animales , Colestanotriol 26-Monooxigenasa , Citosol/metabolismo , Femenino , Hidroxilación , Hígado/metabolismo , Hígado/ultraestructura , Masculino , Microsomas Hepáticos/enzimología , Ratas , Ratas Sprague-Dawley , Caracteres SexualesRESUMEN
25-Hydroxycholecalciferol (25-OHD3) is converted to 8 alpha,25-dihydroxy-3-oxoneocholecalciferol [8,25-(OH)2-3-oxoneo-D3] by liver microsomes, alveolar macrophages and myeloid leukemia cells. The characteristics of this reaction in liver microsomes have been determined. Omission of an NADPH-generating system or NADH resulted in a greater than 75% reduction in the production of 8,25-(OH)2-3-oxoneo-D3. In the absence of the cytosolic fraction, 25-OHD3 was converted to products that comigrated with 8,25-(OH)2-3-oxoneo-D3 on a silica column developed with hexane-isopropanol, thereby preventing quantitation. Production of 8,25-(OH)2-3-oxoneo-D3 was unaffected by EDTA and was stimulated by N,N'-diphenyl-p-phenylenediamine. Both progesterone and pregnenolone inhibited production of 8,25-(OH)2-3-oxoneo-D3; inhibition by progesterone was greater than that by pregnenolone. 8,25-(OH)2-3-Oxoneo-D3 did not bind the thymus receptor for 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] at concentrations 10-fold higher than that of 1,25-(OH)2D3. The lack of affinity of 8,25-(OH)2-3-oxoneo-D3 for the 1,25-(OH)2D3 receptor suggests that this metabolite is a degradative product of 25-OHD3, which might be produced when 25-OHD3 concentrations in the liver are excessive. Synthesis of this metabolite in the liver may be catalyzed by enzymes that also metabolize other steroids.
Asunto(s)
Microsomas Hepáticos/metabolismo , Animales , Antioxidantes/farmacología , Colestenos , Cromatografía en Capa Delgada , Masculino , Microsomas Hepáticos/efectos de los fármacos , NAD/metabolismo , NADP/metabolismo , Fenilendiaminas/farmacología , Pregnenolona/farmacología , Progesterona/farmacología , Ratas , Ratas EndogámicasRESUMEN
The ability of liver microsomes, sites of synthesis of 25-hydroxycholecalciferol, to further metabolize 25-hydroxycholecalciferol has been assessed. When liver microsomes were incubated with 25-hydroxycholecalciferol in the presence of cytosol, a metabolite was isolated that comigrated with 8 alpha,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3- one in three different chromatographic systems. The ultraviolet spectrum (220-350 nm) and mass spectrum of the purified metabolite were identical to that of synthetic 8 alpha,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3-one. This study indicates that liver microsomes convert 25-hydroxycholecalciferol to 8 alpha,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3-one. The significance of this metabolite, which has been shown previously by others to be produced by alveolar macrophages, has yet to be determined.
Asunto(s)
Calcifediol/metabolismo , Colestenos/aislamiento & purificación , Microsomas Hepáticos/metabolismo , Animales , Colestenos/metabolismo , Cromatografía Líquida de Alta Presión , Masculino , Espectrometría de Masas , Ratas , Ratas Endogámicas , Espectrofotometría UltravioletaRESUMEN
Two metabolites have been isolated from rat renal microsomes incubated with 25-hydroxycholecalciferol. Postmitochondrial supernatant fractions from kidneys of thyroidectomized and parathyroidectomized rats were incubated with magnesium acetate, potassium acetate, an NADPH generating system, and 25-hydroxycholecalciferol at a level of 20 micrograms/ml postmitochondrial supernatant for 60 min at 30 degrees C. Lipid extracts of the incubation mixtures were purified by silica gel TLC and HPLC. Two peaks were obtained. Metabolite chi 2 eluted at 18 min and metabolite chi 1 at 23 min when chromatographed on a silica column developed with hexane-isopropanol. Metabolites chi 1 and chi 2 were found to have maximal absorbance at 265 nm. Both metabolites were periodate sensitive, indicating vicinal hydroxyl groups. Mass spectral analysis of metabolite chi 2, which was isolated in greater quantity than metabolite chi 1, indicates that metabolite chi 2 had resulted from hydroxylation of the A ring. Results indicate that 25-hydroxycholecalciferol is hydroxylated on carbon 2 or carbon 4 by renal microsomes. Metabolites chi 1 and chi 2, because of similarity in chromatographic migration and periodate sensitivity, are, perhaps, isomers or 2- and 4-hydroxylated metabolites.
Asunto(s)
Calcifediol/metabolismo , Riñón/metabolismo , Microsomas/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Hidroxilación , Masculino , Espectrometría de Masas , Ratas , Ratas Endogámicas , TiroidectomíaRESUMEN
Metabolism of vitamin K1 in rat liver mitochondria has been studied with succinate as the source of reducing equivalents. A metabolite was isolated that comigrated with vitamin K1 epoxide using four different chromatographic systems. The purified metabolite had an ultraviolet spectrum (200-330 nm) that was identical to that of synthetic vitamin K1 epoxide. The mass spectrum of the purified metabolite was identical to that of synthetic vitamin K1 epoxide. A comparison of production of vitamin K1 epoxide by mitochondrial and microsomal preparations indicates that the mitochondrial production of vitamin K1 epoxide was about 50% of that of the microsomes. Since the mitochondrial preparation was found to have only 3.4% of the glucose-6-phosphatase activity of the microsomal preparation, it can be concluded that the vitamin K1 epoxide isolated from the mitochondrial incubations was due primarily to mitochondrial synthesis. Epoxidation of vitamin K1 in mitochondria suggests that mitochondria might be sites for vitamin K-dependent carboxylation of protein(s).