RESUMEN
The purpose of this study was to determine the long-term impact of obesity and related metabolic abnormalities in the absence and presence of hypertension on renal injury and salt-sensitivity of blood pressure. Markers of renal injury and blood pressure salt sensitivity were assessed in 52- to 55-wk-old normotensive melanocortin-4 receptor-deficient (MC4R-/-) mice and lean C57BL/6J wild-type (WT) mice and in 22-wk-old MC4R-/- and WT mice made hypertensive by N(G)-nitro-L-arginine methyl ester (L-NAME) in the drinking water for 8 wk. Old MC4R-/- mice were 60% heavier, hyperinsulinemic, and hyperleptinemic but had similar mean arterial pressure (MAP) as WT mice (115 +/- 2 and 117 +/- 2 mmHg) on normal salt diet (0.4% NaCl). A high-salt diet (4.0% NaCl) for 12 days did not raise MAP in obese or lean mice [DeltaMAP: MC4R (-/-) 4 +/- 2 mmHg; WT, 2 +/- 1 mmHg]. Obese MC4R-/- mice had 23% greater glomerular tuft area and moderately increased GFR compared with WT mice. Bowman's space, total glomerular area, mesangial matrix, urinary albumin excretion (UAE), renal TGF-beta and collagen expression were not significantly different between old MC4R-/- and WT mice. Renal lipid content was greater but renal macrophage count was markedly lower in MC4R-/- than WT mice. Mild increases in MAP during L-NAME treatment (approximately 16 mmHg) caused small, but greater, elevations in UAE, renal TGF-beta content, and macrophage infiltration in MC4R-/- compared with WT mice without significant changes in glomerular structure. Thus despite long-term obesity and multiple metabolic abnormalities, MC4R-/- mice have no evidence of renal injury or salt-sensitivity of blood pressure. These observations suggest that elevations in blood pressure may be necessary for obesity and related metabolic abnormalities to cause major renal injury or that MC4R-/- mice are protected from renal injury by mechanisms that are still unclear.
Asunto(s)
Presión Sanguínea , Hipertensión/fisiopatología , Enfermedades Renales/etiología , Riñón/fisiopatología , Obesidad/fisiopatología , Receptor de Melanocortina Tipo 4/deficiencia , Factores de Edad , Albuminuria/fisiopatología , Animales , Biomarcadores/sangre , Peso Corporal , Modelos Animales de Enfermedad , Tasa de Filtración Glomerular , Frecuencia Cardíaca , Hiperinsulinismo/fisiopatología , Hipertensión/complicaciones , Hipertensión/metabolismo , Hipertensión/patología , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/fisiopatología , Enfermedades Renales/prevención & control , Leptina/sangre , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/patología , Receptor de Melanocortina Tipo 4/genética , Cloruro de Sodio Dietético/administración & dosificaciónRESUMEN
OBJECTIVE: We recently showed that leptin has powerful central nervous system (CNS)-mediated antidiabetic and cardiovascular actions. This study tested whether the CNS melanocortin system mediates these actions of leptin in diabetic rats. RESEARCH DESIGN AND METHODS: A cannula was placed in the lateral ventricle of Sprague-Dawley rats for intracerebroventricular infusions, and arterial and venous catheters were implanted to measure mean arterial pressure (MAP) and heart rate 24 h/day and for intravenous infusions. After recovery from surgery for 8 days, rats were injected with streptozotocin (STZ), and 5 days later, either saline or the melanocortin 3 and 4 receptor (MC3/4R) antagonist SHU-9119 (1 nmol/h) was infused intracerebroventricularly for 17 days. Seven days after starting the antagonist, leptin (0.62 microg/h) was added to the intracerebroventricular infusion for 10 days. Another group of diabetic rats was infused with the MC3/4R agonist MTII (10 ng/h i.c.v.) for 12 days, followed by 7 days at 50 ng/h. RESULTS: Induction of diabetes caused hyperphagia, hyperglycemia, and decreases in heart rate (-76 bpm) and MAP (-7 mmHg). Leptin restored appetite, blood glucose, heart rate, and MAP back to pre-diabetic values in vehicle-treated rats, whereas it had no effect in SHU-9119-treated rats. MTII infusions transiently reduced blood glucose and raised heart rate and MAP, which returned to diabetic values 5-7 days after starting the infusion. CONCLUSIONS: Although a functional melanocortin system is necessary for the CNS-mediated antidiabetic and cardiovascular actions of leptin, chronic MC3/4R activation is apparently not sufficient to mimic these actions of leptin that may involve interactions of multiple pathways.
Asunto(s)
Sistema Nervioso Central/fisiología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Hipoglucemiantes/uso terapéutico , Leptina/uso terapéutico , Melanocortinas/fisiología , Hormonas Estimuladoras de los Melanocitos/uso terapéutico , Receptores de Corticotropina/antagonistas & inhibidores , Animales , Apetito/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Ratas , Ratas Endogámicas WKY , Ratas Sprague-DawleyRESUMEN
This study examined the importance of direct central nervous system (CNS) actions and increased adrenergic activity in mediating the chronic antidiabetic and cardiovascular actions of leptin. Insulin-deficient rats (streptozotocin, 50 mg/kg) were used to examine the effects of leptin on glucose homeostasis independent of changes in insulin. Male Sprague-Dawley rats were instrumented with arterial and venous catheters and intracerebroventricular cannula for 24-h/day blood pressure (BP) and heart rate (HR) monitoring and intravenous and intracerebroventricular infusions. Insulin-deficient diabetes was associated with marked hyperglycemia, hyperphagia, decreased BP, and pronounced fall in HR. Leptin treatment, intravenous or intracerebroventricular, completely restored to control values plasma glucose levels (384+/-58 to 102+/-28 and 307+/-38 to 65+/-7 mg/dl, respectively), food intake, BP, and HR (304+/-8 to 364+/-7 and 317+/-13 to 423+/-9 bpm, respectively). Combined blockade of alpha1-, beta1-, and beta2-adrenergic receptors attenuated the rise in HR by 30 to 50% but had no effect on the antidiabetic and dietary actions of leptin. Blockade of beta3-adrenergic receptors did not attenuate the chronic cardiovascular or metabolic effects of leptin. These data demonstrate that leptin, via its direct actions in the CNS, has powerful antidiabetic actions in insulin-deficient rats independent of increased peripheral alpha1, beta1, beta2, and beta3-adrenergic activity. Leptin also exerts important long-term cardiovascular actions that are partially mediated via alpha1- and beta1/beta2-adrenergic activation. These findings provide new insights into novel pathways for long-term control of glucose homeostasis and cardiovascular regulation.
Asunto(s)
Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Sistema Nervioso Central/fisiología , Glucosa/metabolismo , Leptina/farmacología , Receptores Adrenérgicos/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Sistema Nervioso Central/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Hemostasis/efectos de los fármacos , Hemostasis/fisiología , Insulina/sangre , Riñón/efectos de los fármacos , Riñón/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos/efectos de los fármacosRESUMEN
BACKGROUND AND OBJECTIVE: Acute studies suggest that insulin has anorexic and hypertensive actions through direct effects on the central nervous system (CNS). However, the importance of these actions in the long-term regulation of food intake and cardiovascular function is still unclear. The goal of the present study was to determine whether chronic increases in CNS levels of insulin, in the absence of changes in plasma insulin concentration, decrease food intake and raise arterial pressure in rats. METHODS: An intracerebroventricular cannula was placed in the lateral ventricle of male Sprague-Dawley rats for chronic insulin or vehicle (artificial cerebrospinal fluid, 0.5 mul/h) infusion, via osmotic minipump, and arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) and heart rate (HR) 24 h/day and intravenous infusions. After 4 days of control measurements, insulin (6 mU/h, n = 7 or 12 mU/h, n = 6) or vehicle (n = 4) was infused intracerebroventricularly for 7 days. RESULTS: Insulin infusion at 6 or 12 mU/h caused transient decreases in food intake, but did not significantly alter plasma glucose or insulin concentrations. Insulin intracerebroventricular infusion also did not alter MAP or HR (106 +/- 2 and 105 +/- 5 versus 104 +/- 2 mmHg in control; 411 +/- 9 and 407 +/- 9 versus 410 +/- 7 bpm in control, respectively). Food intake, MAP and HR remained unchanged in the vehicle-treated group. CONCLUSIONS: These findings provide no evidence that insulin plays a major role in the long-term regulation of appetite, arterial pressure or HR. However, the CNS actions of insulin may exert modest acute effects on appetite that could play a role in limiting meal size and influencing caloric balance.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Encéfalo/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Hiperinsulinismo/fisiopatología , Hipoglucemiantes/farmacología , Insulina/farmacología , Animales , Encéfalo/fisiopatología , Ingestión de Alimentos/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Hiperinsulinismo/inducido químicamente , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Riñón/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
This study tested whether the melanocortin 4-receptor (MC4R) is essential for the chronic cardiovascular and metabolic actions of leptin. Twenty- to 22-week-old male wild-type (WT) C57BL/6J and obese MC4R (-/-) mice (N=5 to 6 per group) were implanted with radiotelemetric transmitters and catheters for measuring mean arterial pressure (MAP) and heart rate 24 hours per day and intravenous infusions. After a 3-day stable control period, leptin was infused (2 microg/kg per minute IV) for 7 days in WT, obese ad libitum-fed MC4R (-/-), and nonobese pair-fed MC4R (-/-) mice. WT mice receiving vehicle for 7 days served as controls. MC4 (-/-) mice were 30% heavier and had 4- and 11-fold increases in plasma insulin and leptin levels, respectively, compared with WT mice. Despite obesity, MAP and heart rate tended to be lower in MC4R (-/-) mice compared with WT mice. Chronic leptin infusion in the different groups increased plasma leptin levels to 45 to 65 ng/mL. Seven-day leptin infusion in WT mice increased MAP by 12+/-3 mm Hg despite a 35% reduction in food intake and an 8% reduction in body weight. Leptin did not alter plasma glucose but reduced plasma insulin in WT mice (5.9+/-1.0 versus 3.0+/-0.5 microU/mL). These cardiovascular and metabolic actions of leptin were abolished in obese and nonobese MC4R (-/-) mice. These data suggest that MC4R deficiency, and not obesity-induced leptin resistance, abolished the cardiovascular and metabolic actions of leptin in obese MC4R (-/-) mice. Thus, a functional MC4R is essential for the chronic cardiovascular and metabolic actions of leptin.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Leptina/farmacología , Receptor de Melanocortina Tipo 4/fisiología , Adiposidad/efectos de los fármacos , Análisis de Varianza , Animales , Glucemia/metabolismo , Tasa de Filtración Glomerular/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Insulina/sangre , Leptina/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL/fisiología , Ratones Obesos/fisiología , Receptor de Melanocortina Tipo 4/deficiencia , Receptores de LeptinaRESUMEN
Previous studies suggest that blockade of melanocortin 3 and 4 receptors (MC3/4-R) markedly attenuates the chronic hypertensive effects of leptin. Although obesity has been reported to be associated with leptin "resistance," it is unclear whether obesity alters the cardiovascular and metabolic effects of chronic MC3/4-R activation. Therefore, we tested whether the cardiovascular and metabolic actions of MC3/4-R activation are attenuated in Sprague-Dawley rats fed a high-fat diet (HF, n=6) compared with rats fed a standard chow (NF, n=6) for 12 months. A 21G steel cannula was placed in the lateral ventricle for ICV infusion, and arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) 24 hours/day and IV infusions. After a 5-day control period, rats were infused with MC3/4-R agonist melanotan II (10 ng/h, ICV), for 10 days followed by a 5-day recovery period. HF rats were heavier (558+/-21 versus 485+/-13 g) with 140% more visceral fat than NF rats, hyperleptinemic (8.9+/-0.5 versus 2.7+/-0.5 ng/mL), and insulin resistant. HF rats also had higher MAP (109+/-3 versus 100+/-1 mm Hg). Chronic melanotan II infusion significantly increased MAP in HF and NF (7+/-2 and 6+/-1 mm Hg), decreased caloric intake (-32+/-2 and -25 +/-2 kcal/day), and reduced insulin levels in both groups by approximately 50%. Thus, the metabolic and cardiovascular actions of chronic MC3/4-R activation are preserved in diet-induced obesity, supporting a potential role for the hypothalamic melanocortin system in obesity hypertension.
Asunto(s)
Presión Sanguínea , Resistencia a la Insulina , Obesidad/fisiopatología , Receptor de Melanocortina Tipo 3/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Dieta , Ingestión de Energía/efectos de los fármacos , Inyecciones Intraventriculares , Insulina/sangre , Leptina/sangre , Masculino , Melatonina/administración & dosificación , Melatonina/farmacología , Obesidad/sangre , Obesidad/etiología , Isoformas de Proteínas/administración & dosificación , Isoformas de Proteínas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 3/agonistas , Receptor de Melanocortina Tipo 4/agonistasRESUMEN
The purpose of this study was to test whether the melanocortin-4 receptor (MC4R) is critical in the development of hypertension associated with obesity and its metabolic disorders. MC4R-deficient homozygous (-/-) and heterozygous (+/-) and wild-type (WT) C57BL/6J mice 17 to 19 weeks old (n=5 to 7 per group) were implanted with telemetry devices for monitoring 24-hour mean arterial pressure (MAP) and heart rate (HR). After 3-day stable control measurements on normal-salt diet (NSD; 0.4% NaCl), mice received a high-salt diet (HSD; 4% NaCl) for 7 days, followed by 3-day recovery on NSD. MC4R (-/-) mice were severely obese compared with MC4R (+/-) and WT mice (body weight 48+/-1.5 versus 31+/-0.6 and 30+/-0.5 g respectively). On NSD, MAP was similar in all groups of mice (MC4R (-/-) 110+/-3 mm Hg; MC4R (+/-) 109+/-2 mm Hg; WT 114+/-2 mm Hg), and HR in MC4R (-/-) was lower than in WT (604+/-5 versus 645+/-9 bpm; P<0.05) but not different from MC4R (+/-) (625+/-13 bpm) mice. HSD did not significantly alter MAP or HR in any of the groups. Epididymal and retroperitoneal fat weights and plasma leptin levels were several-fold greater in MC4R (-/-) compared with MC4R (+/-) and WT mice. Plasma insulin and glucose levels were also significantly greater in MC4R (-/-) than in MC4R (+/-) and WT mice. These data suggest that despite obesity, visceral adiposity, hyperleptinemia, and hyperinsulinemia, MC4R (-/-) mice are neither hypertensive nor salt sensitive, indicating that a functional MC4R may be necessary for the development of hypertension associated with obesity and its metabolic abnormalities.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Hiperinsulinismo/complicaciones , Hipertensión/etiología , Leptina/sangre , Obesidad/complicaciones , Receptor de Melanocortina Tipo 4/metabolismo , Cloruro de Sodio/farmacología , Tejido Adiposo/patología , Animales , Tamaño Corporal , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos , Ingestión de Alimentos , Frecuencia Cardíaca/efectos de los fármacos , Hormonas/sangre , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/metabolismo , Receptor de Melanocortina Tipo 4/deficiencia , Cloruro de Sodio Dietético/administración & dosificación , Cloruro de Sodio Dietético/farmacología , Vísceras/patología , Aumento de PesoRESUMEN
Oxidative stress plays a pathogenic role in hypertension, particularly the one associated with diabetes and obesity. Here, we test the hypothesis that renal dopamine D1 receptor dysfunction in obese Zucker rats is caused by oxidative stress. One group each from lean and obese Zucker rats received tempol, a superoxide dismutase mimetic in drinking water for 2 weeks. Obese animals were hypertensive, hyperglycemic, and hyperinsulinemic, exhibited renal oxidative stress, and increased protein kinase C activity. Also, there was hyperphosphorylation of D1 receptor, defective receptor-G-protein coupling, blunted dopamine-induced Na+-K+-ATPase inhibition, and diminished natriuretic response to D1 receptor agonist, SKF-38393. However, obese animals had elevated levels of plasma nitric oxide and urinary cGMP. In addition, L-N-nitroarginine and sodium nitroprusside showed similar effect on blood pressure in lean and obese rats. In obese animals, tempol reduced blood pressure, blood glucose, insulin, renal oxidative stress, and protein kinase C activity. Tempol also decreased D1 receptor phosphorylation and restored receptor G-protein coupling. Dopamine inhibited Na+-K+-ATPase activity, and SKF-38393 elicited a natriuretic response in tempol-treated obese rats. Thus in obese Zucker rats, tempol ameliorates oxidative stress and improves insulin sensitivity. Consequently, hyperphosphorylation of D1 receptor is reduced, leading to restoration of receptor-G-protein coupling and the natriuretic response to SKF-38393.
Asunto(s)
Óxidos N-Cíclicos/farmacología , Proteínas de Unión al GTP/metabolismo , Insulina/farmacología , Riñón/fisiología , Obesidad/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Receptores de Dopamina D1/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Insulina/sangre , Riñón/efectos de los fármacos , Masculino , Malondialdehído/sangre , Fosforilación , Proteína Quinasa C/metabolismo , Ratas , Ratas Zucker , Receptores de Dopamina D1/efectos de los fármacos , Marcadores de SpinRESUMEN
Although excess hypothalamic agouti-related peptide (AGRP), an endogenous antagonist of the melanocortin 3/4 receptor, causes hyperphagia and obesity, its role in regulating cardiovascular function is unclear. This study examined control of mean arterial pressure (MAP), heart rate (HR), and metabolism during chronic central administration of AGRP in rats. A cannula was placed in the lateral ventricle for intracerebroventricular infusion, and arterial and venous catheters were implanted for monitoring MAP and HR 24 hours per day, as well as intravenous infusions. After a 5-day control period, rats received AGRP (n=6; 0.02 nmol per hour ICV) or artificial cerebrospinal fluid (aCSF; n=9; 0.02 nmol per hour ICV) for 12 days, followed by a 5-day recovery period. A third group was infused intracerebroventricularly with AGRP and pair-fed to match food intake of control rats (n=7). AGRP produced a peak decrease in MAP and HR of -7+/-2 mm Hg and -68+/-7 bpm, respectively, despite increased food intake (from 23+/-0.5 to 36+/-3 g per day) and weight gain (from 350+/-8 to 454+/-5 g). AGRP also increased glomerular filtration rate, plasma insulin, glucose, and leptin. AGRP infusion in pair-fed rats produced a peak decrease in HR of -70+/-8 bpm but did not alter MAP or other variables. The metabolic effects of AGRP may be secondary to hyperphagia because they were abolished in pair-fed rats. aCSF infusion did not change any of the variables studied. These results demonstrate that increased central nervous system AGRP levels produce chronic reductions in MAP and HR despite marked increases in food intake and weight gain that normally tend to raise arterial pressure.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Sistema Nervioso Central/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/farmacología , Metabolismo/efectos de los fármacos , Hormonas Peptídicas/farmacología , Proteína de Señalización Agouti , Proteína Relacionada con Agouti , Animales , Regulación del Apetito , Ventrículos Cerebrales , Ingestión de Alimentos/efectos de los fármacos , Tasa de Filtración Glomerular/efectos de los fármacos , Hipertensión , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Masculino , Obesidad , Hormonas Peptídicas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Aumento de PesoRESUMEN
Acute studies have shown that MC3/4-R stimulation increases sympathetic activity, but the role of adrenergic activation in mediating the cardiovascular and renal responses to chronic melanocortin 3- and 4-receptor (MC3/4-R) activation is unknown. The present study tested whether chronic MC3/4-R activation raises blood pressure and whether these changes are attenuated by alpha1+beta-adrenergic blockade. Rats were instrumented with an intracerebroventricular (ICV) cannula and arterial and venous catheters for measurements of mean arterial pressure (MAP) and heart rate (HR) 24 hours per day, and intravenous infusions. After control measurements, rats were intravenously infused with either saline vehicle (n=7) or alpha1+ beta-adrenergic antagonists (n=6, terazosin+propranolol, 10 mg/kg per day each) for 21 days. Five days after starting the vehicle or adrenergic blockade, the MC3/4-R agonist, MTII (10 ng/h), was infused ICV for 11 days followed by a 5-day recovery period. Another group of rats was infused with the adrenergic antagonists for 21 days but received the saline vehicle ICV for 11 days (n=7). MC3/4-R activation decreased food intake from 21+/-1 to 8+/-2 g/d by day 3 of MC3/4-R activation, and increased MAP and HR by an average of 8+/-2 mm Hg and 9+/-5 bpm, respectively. Adrenergic blockade did not alter the MC3/4-R-mediated decrease in food intake but abolished the increases in MAP and HR (1+/-2 mm Hg and -12+/-5 bpm, respectively, compared with control). ICV vehicle infusion during adrenergic blockade did not alter food intake or MAP. Glomerular filtration rate was unchanged in both the vehicle-infused and adrenergic blocked rats during MC3/4-R activation. These results indicate that the chronic actions of MC3/4-R activation on MAP and HR are mediated by adrenergic activation.
Asunto(s)
Antagonistas Adrenérgicos/farmacología , Presión Sanguínea , Receptor de Melanocortina Tipo 3/agonistas , Receptor de Melanocortina Tipo 4/agonistas , alfa-MSH/análogos & derivados , Animales , Presión Sanguínea/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Riñón/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , alfa-MSH/farmacologíaRESUMEN
Endothelial dysfunction has been suggested to play an important role in the development of obesity-induced hypertension. Because endothelin release increases in response to endothelial damage, we examined whether endothelin-1 contributes to increased arterial pressure in a model of visceral obesity produced by feeding Sprague-Dawley rats a high-fat (HF) diet (40% fat w/w, n=6) for 12 months. Arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) and heart rate (HR) 24 hours per day and intravenous infusions. After a 5-day control period, rats were infused with the selective endothelin-1 type A receptor (ET-A) blocker ABT-627 (2.5 mg/kg per day, IV) for 9 days, followed by a recovery period. Rats fed a standard chow (normal fat, or NF, group: n=6) for 12 months were also infused with ET-A blocker and were used as controls. Compared with NF rats, HF rats had higher MAP (113+/-4 versus 98+/-2 mm Hg), increased visceral fat (18.7+/-2.0 versus 10.8+/-1.4 g), and 3.2-fold increase in plasma leptin despite similar total body weight gain. Long-term ET-A blockade markedly reduced MAP in HF (-14+/-3 mm Hg) and NF (-14+/-2 mm Hg), but it had no effect on HR, GFR, or PRA. These results indicate that a long-term HF diet may cause visceral obesity and increased MAP, even in the absence of major changes in total body weight. Endothelin-1 appears to play an important role in the maintenance of arterial pressure in rats fed HF and NF diets, but it does not appear to contribute to increased MAP in this model of diet-induced hypertension.
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Presión Sanguínea , Endotelina-1/fisiología , Hipertensión/fisiopatología , Obesidad/complicaciones , Tejido Adiposo/patología , Animales , Atrasentán , Presión Sanguínea/efectos de los fármacos , Peso Corporal , Ingestión de Alimentos , Antagonistas de los Receptores de la Endotelina A , Grasas/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Hormonas/sangre , Hipertensión/etiología , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Obesidad/etiología , Obesidad/patología , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , VíscerasRESUMEN
Excess weight gain is a major cause of increased blood pressure in most patients with essential hypertension, and also greatly increases the risk for renal disease. Obesity raises blood pressure by increasing renal tubular reabsorption, impairing pressure natriuresis, causing volume expansion due to activation of the sympathetic nervous system and renin-angiotensin system, and by physical compression of the kidneys, especially when visceral obesity is present. The mechanisms of sympathetic nervous system activation in obesity may be due, in part, to hyperleptinemia that stimulates the hypothalamic pro-opiomelanocortin pathway. With prolonged obesity, there may be a gradual loss of nephron function that worsens with time and exacerbates hypertension. Weight reduction is an essential first step in the management of obesity hypertension and renal disease. Special considerations for the obese patient, in addition to adequately controlling the blood pressure, include correction of the metabolic abnormalities and protection of the kidneys from further injury.
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Hipertensión/epidemiología , Enfermedades Renales/epidemiología , Obesidad/epidemiología , Animales , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Enfermedades Renales/fisiopatología , Leptina/sangre , Obesidad/fisiopatología , Obesidad/terapia , Sistema Renina-Angiotensina/fisiología , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
The objective of the present study is to investigate whether plasma insulin levels play a role in the antinatriuretic and vasoconstrictor actions of angiotensin-II (Ang-II). We evaluated antinatriuretic function of endogenous Ang-II using an AT1 receptor antagonist, candesartan in anesthetized Sprague-Dawley rats. In control rats, candesartan produced significant increases in natriuresis and diuresis and these effects were abolished in streptozocin (STZ, 55 mg/kg i.p.) treated rats. Replacement of insulin restored these renal effects of candesartan. In a separate group of rats pretreated with an autonomic ganglionic blocker, pressor responses to Ang-II and norepinephrine (NE) before or after L-NNA, a nitric oxide synthase inhibitor were not affected by STZ treatment. However, insulin replacement greatly augmented these responses. These data provide evidence in vivo showing that insulin can enhance both antinatriuretic and vasoconstrictor actions of Ang-II. Hence exaggerated renal and vascular effects of Ang-II in the obese Zucker rats observed in our previous studies may be related to hyperinsulimemia and this phenomena could contribute to salt-sensitivity and development of sustained hypertension.