RESUMEN
Mesenchymal stem cells (MSC) induced neovascularization and improved renal morphology of the stenotic kidney in 2 kidneys-1 clip (2K-1C) model of renovascular hypertension. The present study evaluated the effects of MSC in the contralateral hypertensive kidney. Three weeks after left renal artery occlusion, MSC were injected into the tail vein of the 2K-1C rats. Renal function and morphology were analyzed in both kidneys. Labeled MSC were found in stenotic and contralateral kidneys. Hypertensive 2K-1C animals presented increased circulating levels of Angiotensin II (Ang II) and renin. MSC prevented the progressive increase of blood pressure and reduced circulating Ang II and renin levels. Stenotic kidney showed reduced renal plasma flow (RPF) and glomerular filtration rate (GFR), whereas the contralateral kidney had a tendency (p > 0.5) of reduction in GFR in spite of unchanged RPF. MSC treatment caused an improvement in GFR with no effect of on RPF in the stenotic kidney. Contralateral kidney showed increased diuresis and natriuresis that were even higher in MSC-treated animals, indicating that cell treatment improved the capacity of the contralateral kidney to excrete sodium. Contralateral kidney expressed higher levels of inflammatory cytokines (IL-6, TNF-α) and signs of fibrosis, which were attenuated by MSC treatment. MSC treatment improved the stenotic kidney function, and it was also beneficial to the contralateral hypertensive kidney because it improved the morphology and preserved its capacity to excrete sodium.
Asunto(s)
Angiotensina II/sangre , Hipertensión Renovascular , Riñón , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Renina/sangre , Animales , Presión Sanguínea/fisiología , Hipertensión Renovascular/fisiopatología , Hipertensión Renovascular/prevención & control , Interleucina-6/metabolismo , Riñón/patología , Riñón/fisiopatología , Pruebas de Función Renal/métodos , Masculino , Ratas , Arteria Renal/cirugía , Eliminación Renal/fisiología , Sodio/metabolismo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Pregnancy is characterized by maternal systemic and intrarenal vasodilation, leading to increases in the renal plasma flow (RPF) and glomerular filtration rate (GFR). These responses are mainly mediated by nitric oxide (NO) and relaxin. The impact of cigarette smoking on the maternal adaptations to pregnancy is unclear. Here we evaluated the effects of chronic exposure to nicotine on systemic and intrarenal parameters in virgin (V) and 14-day pregnant (P) Wistar rats. V and P groups received saline or nicotine (6 mg·kg(-1)·day(-1)) respectively, via osmotic minipumps for 28 days, starting 14 days before pregnancy induction. Nicotine induced a 10% increase in blood pressure in the V group and minimized the characteristic pregnancy-induced hypotension. Renal sympathetic nerve activity (rSNA) and baroreflex sensitivity were impaired by nicotine mainly in the P group, indicating that the effect of nicotine on blood pressure was not mediated by nervous system stimulation. Nicotine had no effect on GFR in the V rats but reduced GFR of the P group by 30%. Renal expression of sodium and water transporters was downregulated by nicotine, resulting in increased fractional sodium excretion mainly in the P group, suggesting that nicotine compromised the sodium and water retention required for normal gestation. There was a reduction in the expression of inducible NO synthase (iNOS) in both the kidney tissue and renal artery, as well as in the expression of the relaxin receptor (LGR7). These results clearly show that nicotine induced deleterious effects in both virgin and pregnant animals, and abolished the maternal capacity to adapt to pregnancy.
Asunto(s)
Adaptación Fisiológica/efectos de los fármacos , Exposición a Riesgos Ambientales/efectos adversos , Tasa de Filtración Glomerular/efectos de los fármacos , Nicotina/efectos adversos , Flujo Plasmático Renal/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Animales , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Femenino , Riñón/fisiopatología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Embarazo , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/biosíntesis , Receptores de Péptidos/biosíntesis , Relaxina/metabolismo , Sistema Nervioso Simpático/fisiología , Vasodilatación/fisiologíaRESUMEN
Angiogenic therapies for critical limb ischemia were tested in a mouse model. The mice were anesthetized and their femoral arteries were ligated. The animals were treated with bone marrow mononuclear cells (BMMCs) alone, BMMCs combined with plasmid vector encoding granulocyte macrophage colony-stimulating factor (GM-CSF), received no treatment, or no intervention (controls). The degree of ischemia was monitored for 4 weeks using a visual scale. Muscle atrophy and strength were assessed at 4 weeks postoperatively; the mice were then killed. In treated animals, total necrosis of the limb was not found, the weight of the gastrocnemius and quadriceps muscles was significantly higher, functional ability and tissue regeneration were significantly increased, and muscle impairment and adipocyte presence were significantly reduced compared with untreated animals. At inducing angiogenesis, the BMMCs alone was more effective than BMMCs combined with plasmid vector encoding GM-CSF. Treated animals showed increased angiogenesis compared with ischemic untreated ones.
Asunto(s)
Trasplante de Médula Ósea , Terapia Genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/biosíntesis , Isquemia/terapia , Neovascularización Fisiológica , Músculo Cuádriceps/irrigación sanguínea , Animales , Células Cultivadas , Enfermedad Crítica , Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Miembro Posterior , Isquemia/genética , Isquemia/metabolismo , Isquemia/fisiopatología , Masculino , Ratones , Ratones Endogámicos BALB C , Fuerza Muscular , Atrofia Muscular/patología , Atrofia Muscular/fisiopatología , Atrofia Muscular/terapia , Necrosis , Músculo Cuádriceps/patología , Músculo Cuádriceps/fisiopatología , Factores de Tiempo , TransfecciónRESUMEN
The exposure of the fetus to a hyperglycemic environment promotes the development of hypertension and renal dysfunction in the offspring at adult age. We evaluated the role of renal nerves in the hypertension and renal changes seen in offspring of diabetic rats. Diabetes was induced in female Wistar rats (streptozotocin, 60 mg/kg ip) before mating. Male offspring from control and diabetic dams were studied at an age of 3 mo. Systolic blood pressure measured by tail cuff was increased in offspring of diabetic dams (146 ± 1.6 mmHg, n = 19, compared with 117 ± 1.4 mmHg, n = 18, in controls). Renal function, baseline renal sympathetic nerve activity (rSNA), and arterial baroreceptor control of rSNA were analyzed in anesthetized animals. Glomerular filtration rate, fractional sodium excretion, and urine flow were significantly reduced in offspring of diabetic dams. Two weeks after renal denervation, blood pressure and renal function in offspring from diabetic dams were similar to control, suggesting that renal nerves contribute to sodium retention in offspring from diabetic dams. Moreover, basal rSNA was increased in offspring from diabetic dams, and baroreceptor control of rSNA was impaired, with blunted responses to infusion of nitroprusside and phenylephrine. Thus, data from this study indicate that in offspring from diabetic mothers, renal nerves have a clear role in the etiology of hypertension; however, other factors may also contribute to this condition.
Asunto(s)
Fibras Adrenérgicas/fisiología , Diabetes Mellitus Experimental/complicaciones , Hipertensión/etiología , Enfermedades Renales/etiología , Riñón/inervación , Animales , Presión Sanguínea , Femenino , Riñón/fisiopatología , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal , Presorreceptores/fisiología , Ratas , Ratas WistarRESUMEN
The birdseed Phalaris canariensis (Pc) is popularly used as an antihypertensive agent. The aqueous extract of Pc (AEPc) was administered in adult normotensive Wistar rats and spontaneously hypertensive rats (SHR) and in prehypertensive young SHR (SHR(Y), 3 weeks old). Animals received AEPc (400 mg·kg(-1)·day(-1), by gavage) for 30 days, then groups were divided into 2 subgroups: one was treated for another 30 days and the other received water instead of AEPc for 30 days. AEPc reduced systolic blood pressure (SBP) in both adult groups; however, treatment interruption was followed by a gradual return of the SBP to baseline levels. SHR(Y) became hypertensive 30 days after weaning. AEPc minimized the increase in SBP in SHR(Y), but blood pressure rose to levels similar to those in the untreated group with treatment interruption. There were no changes in renal function, diuresis, or Na(+) excretion. Pc is rich in tryptophan, and the inhibition of the metabolism of tryptophan to kynurenine, a potential vasodilator factor, prevented the blood pressure reducing effect of AEPc. Moreover, AEPc significantly reduced sympathoexcitation. Data indicate that the metabolic derivative of tryptophan, kynurenine, may be a mediator of the volume-independent antihypertensive effect of Pc, which was at least in part mediated by suppression of the sympathetic tonus.
Asunto(s)
Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Phalaris , Extractos Vegetales/farmacología , Prehipertensión/tratamiento farmacológico , Animales , Antihipertensivos/aislamiento & purificación , Antihipertensivos/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hipertensión/metabolismo , Hipertensión/fisiopatología , Quinurenina/metabolismo , Masculino , Phalaris/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/metabolismo , Prehipertensión/metabolismo , Prehipertensión/fisiopatología , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Factores de Tiempo , Triptófano/metabolismoRESUMEN
Sucrose-fed rats, a model of metabolic syndrome, are characterized by insulin resistance, obesity, hypertension, and high plasma levels of triacylglycerols and angiotensin II (Ang II). However, whether tissue renin-angiotensin system (RAS) is altered in metabolic syndrome is unclear. To study this issue, food ad libitum and water (C) or 20% sucrose solution (SC) were given to adult male Wistar rats, for 30 days. Body weight (BW), blood pressure (BP), epididymal adipose tissue (EPI) mass, rate of in vivo fatty acid (FA) synthesis in EPI, circulating glucose, insulin, leptin, angiotensins I and II, triacylglycerols, and plasma renin (PRA) and angiotensin-converting enzyme (ACE) activities were evaluated. In kidneys and EPI, gene and protein expression of type 1 (AT(1)) and 2 (AT(2)) Ang II receptors, ACE, angiotensinogen (AGT) as well as protein expression of angiotensin-converting enzyme 2 (ACE2) were determined. In both tissues, Ang I, Ang II and Ang-(1-7) contents were also measured by HPLC. In SC rats higher BP, EPI mass, circulating triacylglycerols, insulin, leptin, PRA and, Ang II were found. In EPI, the rate of in vivo FA synthesis was associated with increased Ang-(1-7), protein expression of AT(1) and AT(2) receptors, ACE2, AGT, and gene expression of AGT although a reduction in ACE activity and in adipose Ang I and Ang II contents was observed. In kidneys, AT(1) and AT(2), ACE and AGT gene and protein expression as well as protein expression of ACE2 were unaltered while Ang II, Ang-(1-7) and ACE activity increased. These RAS component changes seem to be tissue specific and possibly are related to enhancement of FA synthesis, EPI mass and hypertension.
Asunto(s)
Tejido Adiposo/metabolismo , Angiotensina I/metabolismo , Fragmentos de Péptidos/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Sacarosa/administración & dosificación , Tejido Adiposo/enzimología , Enzima Convertidora de Angiotensina 2 , Animales , Secuencia de Bases , Glucemia/análisis , Western Blotting , Cromatografía Líquida de Alta Presión , Cartilla de ADN , Masculino , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The aim of this study was to investigate, through the single-cell gel (comet) assay, whether vitamin C is able to protect against renovascular hypertension-induced genotoxicity in multiple organs. A total of 32 male Wistar rats were divided into four groups: negative control (n = 6); animals treated with vitamin C (n = 6); hypertensive rats (n = 10) and hypertensive rats and treated with vitamin C (n = 10). Hypertension was induced as a result of partial obstruction of the left renal artery by means of a silver clip during 6 weeks. Vitamin C was administered at 150 mg/kg during 7 consecutive days before the end of the experimental period. The results showed that vitamin C was able to protect blood cells against hypertension-induced genotoxicity. Brain, liver and heart cells were also protected by vitamin C following hypertension-induced genotoxic damage. Regarding blood pressure, vitamin C reduced the hypertensive state. In conclusion, our results suggest that vitamin C can prevent hypertension-induced DNA damage in blood, liver, brain and heart cells as well as to normalize the blood pressure of rats.
Asunto(s)
Antioxidantes/farmacología , Ácido Ascórbico/farmacología , Daño del ADN/efectos de los fármacos , Hipertensión Renovascular/patología , Estrés Oxidativo/efectos de los fármacos , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Ensayo Cometa , Hipertensión Renovascular/tratamiento farmacológico , Hipertensión Renovascular/prevención & control , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Distribución Aleatoria , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/efectos adversos , Estadísticas no ParamétricasRESUMEN
BACKGROUND: Vascular endothelial growth factor (VEGF) has mostly been tested to treat ischemic diseases, although the outcomes obtained are not satisfactory. Our hypothesis is that the local transient expression of VEGF and stem cell mobilizer granulocyte colony-stimulating factor (G-CSF) genes in ischemic limbs can complement their activities and be more efficient for limb recovery. METHODS: Limb ischemia was surgically induced in mice and 50 microg of VEGF and/or G-CSF genes were locally transferred by electroporation. After 3-4 weeks, evidence of necrosis by visual inspection, capillary density, muscle mass, muscle force and hematopoietic cell mobilization were evaluated. RESULTS: After 4 weeks, 70% and 90% of the animals of the ischemic group (IG) and VEGF-treated group (VG), respectively, presented limb necrosis, in contrast to only 10% observed in the group of mice treated with both VEGF and G-CSF genes (VGG). Recovery of muscle mass and muscle force was higher than 60% in the VGG compared to the non-ischemic group. The mobilization of Sca1+ cells and neutrophils was also higher in the VGG, which may explain the lower level of necrosis observed in this group (22%, in contrast to 70% in the IG). Capillary density and degree of fibrosis were determined in weeks 3 and 4, and also showed a clear benefit as a result of the use of the G-CSF and VEGF genes together. CONCLUSIONS: Gene therapy using VEGF and G-CSF demonstrated a synergistic effect promoting vessel and tissue repair in mouse hind limb ischemia.
Asunto(s)
Extremidades/irrigación sanguínea , Terapia Genética/métodos , Factor Estimulante de Colonias de Granulocitos/genética , Isquemia/terapia , Enfermedades Vasculares Periféricas/terapia , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Isquemia/sangre , Isquemia/etiología , Masculino , Ratones , Ratones Endogámicos BALB C , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/fisiología , Neovascularización Fisiológica/genética , Enfermedades Vasculares Periféricas/complicaciones , Regeneración/genéticaRESUMEN
Previous studies have shown that pharmacological stimulation of a region denominated caudal pressor area (CPA), located in the caudal end of the ventrolateral medulla, induces increases in arterial blood pressure (BP). The aim of this study was to compare the responses on renal sympathetic nerve activity (rSNA) and BP responses mediated by stimulation of CPA or rostral ventrolateral medulla (RVLM), in intact or sino-aortic barodenervated rats. Male Wistar rats (300-350 g, n=15) were anesthetized (urethane 1.2 to 1.4 g/kg, i.v.) and artificially ventilated. The mean arterial pressure (MAP) and rSNA were measured during bilateral glutamate microinjection (10 nmo/100 nl) into the CPA or into the RVLM. Glutamatergic stimulation of the RVLM increased MAP (46+/-7 mm Hg) and rSNA (82+/-21%); during CPA stimulation, MAP and rSNA increased 60+/-7 mm Hg and 93+/-9%, respectively. However, despite the similarity of responses mediated by both regions, the duration of rSNA and blood pressure responses mediated by the CPA were significantly longer than the duration of the responses mediated by the RVLM. After barodenervation, there was an increase in the time-course and magnitude of sympathetic response only in response to RVLM stimulation but not in response to CPA. The results suggest a differential baroreceptor modulation on rSNA mediated by the ventrolateral medulla neurons. Glutamatergic activation of CPA neurons can cause large increases in the rSNA and BP with a weaker baroreceptor modulation when compared to responses mediated by the RVLM neurons.
Asunto(s)
Barorreflejo/fisiología , Bulbo Raquídeo/citología , Neuronas/fisiología , Presorreceptores/fisiología , Análisis de Varianza , Animales , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Ácido Glutámico/farmacología , Riñón/inervación , Masculino , Bulbo Raquídeo/fisiología , Microinyecciones , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Neuronas/efectos de los fármacos , Presorreceptores/efectos de los fármacos , Presorreceptores/efectos de la radiación , Ratas , Ratas Wistar , Sistema Nervioso Simpático/fisiología , Factores de TiempoRESUMEN
The aim of this study was to analyze the cardiovascular effects of chronic stanozolol administration in male rats. The rats were randomly assigned to one of three groups: (1) control (n=12), (2) chronic treatment with low dose of stanozolol (LD, n=18, 5 mg/kgweek) and; (3) treatment with high dose of stanozolol (HD, n=28, 20 mg/kgweek). Mean arterial pressure (MAP) was higher in both HD (128+/-2.2 mmHg) and LD (126+/-2.5 mmHg) than control (116+/-2 mmHg). The LD group showed an increase in cardiac output (control 121+/-2.5, LD 154+/-5.9 ml/min), whereas in the HD group total peripheral resistance increased (control 1.03+/-0.07, HD 1.26+/-0.07 mmHg/ml/min). Acute sympathetic blockade caused a similar decrease in MAP in all groups. In conscious rats, the baroreflex index for bradycardia (control -3.7+/-0.4, LD -2.0+/-0.1 beat/mmHg) and tachycardia (control -3.6+/-0.3, LD -4.7+/-0.2 beat/mmHg) responses changed only in the LD group. Cardiac hypertrophy was observed in both treated groups (P<0.05). In conclusion, hypertension with differential hemodynamic changes and alterations in the reflex control in heart rate is seen at different stanozolol doses, which may be important variables in the cardiovascular effects of anabolic steroids.
Asunto(s)
Anabolizantes/farmacología , Barorreflejo/efectos de los fármacos , Sistema Cardiovascular/efectos de los fármacos , Estanozolol/farmacología , Sistema Nervioso Simpático/efectos de los fármacos , Anabolizantes/administración & dosificación , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Bradicardia , Gasto Cardíaco/efectos de los fármacos , Cardiomegalia/inducido químicamente , Cardiotónicos/farmacología , Estado de Conciencia , Esquema de Medicación , Bloqueadores Ganglionares/farmacología , Hexametonio/farmacología , Inyecciones Subcutáneas , Masculino , Nitroprusiato/farmacología , Tamaño de los Órganos/efectos de los fármacos , Fenilefrina/farmacología , Ratas , Ratas Wistar , Estanozolol/administración & dosificación , Taquicardia , Testosterona/sangre , Resistencia Vascular/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
The aim of the present study was to analyse the haemodynamic effects induced by the hypothalamic disconnection (HD) caudal or rostral to the paraventricular nucleus of the hypothalamus (PVN). Mean arterial pressure (MAP), hindlimb, renal and mesenteric blood flow and vascular conductance (HVC, RVC and MVC, respectively) were measured in urethane (1.2 g/kg, i.v.) anesthetized rats for 60 min after disconnection. HD caudal to the PVN was performed with a double-edged microknife of bayonet shape (R = 1 mm, H= 2 mm) stereotaxically placed, lowered 2.8 mm caudal to the bregma along the midline. The cut was achieved by rotating the microknife 90 degrees right and 90 degrees left. HD rostral to the PVN was performed with the knife placed 0.8 mm caudal to the bregma. Thirty minutes after the hypothalamic disconnection caudal (HD-C), a decrease in MAP was observed (- 14 +/- 3 mm Hg), reaching a 60-min decrease of 30 +/- 3 mm Hg. Hindlimb conductance increased 10 min after HD (156 +/- 14%) and remained elevated throughout the experimental period. On the contrary, we observed a transitory renal vasoconstriction (82 +/- 9%, < or = 20 min) and a late mesenteric vasodilation, starting at 30 min (108 +/- 4%) and reaching 138 +/- 6% at 60 min. In rats with HD rostral to the PVN, we only observed minor changes in the cardiovascular parameters. In the MAP, there was a slight decrease 60 min after the hypothalamic disconnection rostral (HD-R) (-9 +/- 4 mm Hg). There were no significant changes in HVC. RVC and MVC were increased 60 min after the HD-R (116 +/- 12% and 124 +/- 11%, respectively). These results suggest that vasodilation in the hindlimb and in the mesenteric bed could contribute to the observed decrease in MAP in HD caudal to PVN rats.