RESUMEN
BACKGROUND: Irreversible airflow obstruction in Chronic Obstructive Pulmonary Disease (COPD) is thought to result from airway remodelling associated with aberrant inflammation. Patients who experience frequent episodes of acute deterioration in symptoms and lung function, termed exacerbations, experience a faster decline in their lung function, and thus over time greater disease severity However the mechanisms by which these episodes may contribute to decreased lung function are poorly understood. This study has prospectively examined changes in sputum levels of inflammatory cells, MMP-9 and TIMP-1 during exacerbations comparing with paired samples taken prior to exacerbation. METHODS: Nineteen COPD patients ((median, [IQR]) age 69 [63 to 74], forced expiratory volume in one second (FEV1) 1.0 [0.9 to 1.2], FEV1% predicted 37.6 [27.3 to 46.2]) provided sputa at exacerbation. Of these, 12 were paired with a samples collected when the patient was stable, a median 4 months [2 to 8 months] beforehand. RESULTS: MMP-9 levels increased from 10.5 microg/g [1.2 to 21.1] prior to exacerbation to 17.1 microg/g [9.3 to 48.7] during exacerbation (P < 0.01). TIMP-1 levels decreased from 3.5 microg/g [0.6 to 7.8] to 1.5 microg/g [0.3 to 4.9] (P = 0.16). MMP-9/TIMP-1 Molar ratio significantly increased from 0.6 [0.2 to 1.1] to 3.6 [2.0 to 25.3] (P < 0.05). Neutrophil, eosinophil and lymphocyte counts all showed significant increase during exacerbation compared to before (P < 0.05). Macrophage numbers remained level. MMP-9 levels during exacerbation showed highly significant correlation with both neutrophil and lymphocyte counts (Rho = 0.7, P < 0.01). CONCLUSION: During exacerbation, increased inflammatory burden coincides with an imbalance of the proteinase MMP-9 and its cognate inhibitor TIMP-1. This may suggest a pathway connecting frequent exacerbations with lung function decline.
Asunto(s)
Recuento de Leucocitos , Metaloproteinasa 9 de la Matriz/análisis , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Esputo/citología , Esputo/inmunología , Inhibidor Tisular de Metaloproteinasa-1/análisis , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Many of the leukocytes which migrate into the tissue following allergen challenge can undergo a respiratory burst producing reactive oxygen species causing tissue damage and distorting proteinase/antiproteinase balance. The reactive oxygen species have extremely short half lives and so cannot be measured in vivo, but the protein carbonyl residues which result from protein oxidation can be measured in biological fluids. METHODS: We examined protein oxidation in bronchoalveolar lavage after allergen challenge in 12 patients with atopic asthma by measuring protein carbonyl residues using a sensitive Western blotting technique. RESULTS: We found that the median level of protein carbonyls per molecule of protein rose from 0.09 in bronchoalveolar lavage (BAL) obtained 18 h after saline challenge to 0.23 in BAL taken 10 min after segmental allergen challenge, reaching a median of 0.82 in samples obtained 18 h later (p<0.01 compared with saline control and the earlier time point). The number of protein carbonyl residues correlated strongly with the number of eosinophils recovered in the BAL (rho = 0.574, p<0.05) but not with the number of neutrophils (rho = 0.228, p = NS) or macrophages (rho = 0.178, p = NS). Western blotting showed that the majority of the modified protein comigrated with authentic alpha1-antitrypsin at 53 kD. In contrast, BAL samples from patients with chronic obstructive pulmonary disease, which is characterized by an influx of neutrophils, showed that the main oxidized protein colocalized with human serum albumin, the predominant protein in the BAL. CONCLUSION: Our results suggest that the recruitment and activation of eosinophils accounts for much of the protein oxidation found in the BAL following allergen challenge. The main oxidized protein appears to be alpha1-antitrypsin, a key antiproteinase in the airways. Inactivation of alpha1-antitrypsin by oxidation may distort the proteinase/antiproteinase balance leaving the lung vunerable to proteolytic damage. Intriguingly, we have evidence to suggest that other airways diseases, characterized by recruitment of other inflammatory cells, may result in the oxidation of alternative targets.
Asunto(s)
Asma/metabolismo , Eosinófilos/metabolismo , Proteínas/metabolismo , Adulto , Asma/inmunología , Líquido del Lavado Bronquioalveolar , Endopeptidasas/metabolismo , Femenino , Humanos , Immunoblotting , Masculino , Oxidación-Reducción , Inhibidores de Proteasas/metabolismoRESUMEN
Renal nerves are thought to play an important role in cardiovascular regulation under both normotensive and hypertensive conditions. In the present study the effect of renal denervation on the changes in plasma renin activity (PRA) after aortic baroreceptor deafferentation (tADN) were investigated in the rat. Bilateral renal denervation did not alter arterial pressure (AP, 100 +/- 4 mmHg; 1 mmHg = 133.32 Pa), heart rate (HR, 363 +/- 12 bpm), or PRA (2.9 +/- 0.6 ng.mL-1.h-1) compared with the respective sham renal denervation values of 106 +/- 3 mmHg (AP), 385 +/- 13 bpm (HR), and 3.3 +/- 0.7 ng.mL-1.h-1 (PRA). On the other hand, bilateral tADN resulted in significant increases in AP, HR, and PRA. One and 3 days after tADN, AP was 130 +/- 4 and 127 +/- 6 mmHg, HR was 461 +/- 15 and 463 +/- 20 bpm, and PRA was 9.1 +/- 3.0 and 11.9 +/- 4.5 ng.mL-1.h-1, respectively. Renal denervation before tADN prevented the increases in AP and PRA, but it did not affect the increase in HR. These data indicate that renal denervation does not alter basal PRA in normotensive animals but prevents the increased renin release observed in neurogenic hypertension. These data suggest that the increased PRA may be one of several factors that contributes to the elevated AP after tADN.
Asunto(s)
Aorta/inervación , Desnervación , Riñón/inervación , Presorreceptores/fisiología , Renina/sangre , Animales , Frecuencia Cardíaca , Masculino , Neuronas Aferentes/fisiología , Ratas , Ratas EndogámicasRESUMEN
The effect of chronic angiotensin I converting enzyme inhibition on the pressure-natriuresis relation was studied in Wistar-Kyoto and spontaneously hypertensive rats. Enalapril maleate (25 mg.kg-1.day-1 in drinking water) was started at 4-5 weeks of age. At 7-9 weeks of age, the pressure-natriuresis relation was studied while the rats were under Inactin anesthesia 1 week after the right kidney and adrenal gland were removed. Neural and hormonal influences on the remaining kidney were fixed by surgical renal denervation, adrenalectomy, and infusion of a hormone cocktail (330 microliters.kg-1.min-1) containing high levels of aldosterone, arginine vasopressin, hydrocortisone, and norepinephrine dissolved in 0.9% NaCl containing 1% albumin. Changes in renal function resulting from alterations in renal artery pressure were compared between enalapril-treated and control rats. Mean arterial pressure (+/- SEM) under anesthesia was 118 +/- 5, 94 +/- 4, 175 +/- 3, and 124 +/- 2 mm Hg for control Wistar-Kyoto (n = 10), enalapril-treated Wistar-Kyoto (n = 10), control spontaneously hypertensive (n = 9), and enalapril-treated spontaneously hypertensive (n = 9) rats, respectively. When renal artery pressure was set at values above approximately 125 mm Hg, control spontaneously hypertensive rats excreted less sodium and water than control Wistar-Kyoto rats. Enalapril treatment resulted in a significant and similar shift to the left of the pressure-natriuresis relation in both strains of rats so that a lower renal artery pressure was required to excrete a similar amount of sodium when compared with their respective untreated controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Enalapril/farmacología , Natriuresis/efectos de los fármacos , Ratas Endogámicas SHR/fisiología , Animales , Ingestión de Líquidos/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas WKY , Arteria Renal , Circulación Renal/efectos de los fármacosRESUMEN
To determine whether enhanced sympathetic tone contributes to the maintenance of chronic angiotensin II (A II, 10 ng/min i.v. for 10 days) hypertension in rats, sympathetic activity was assessed in hypertensive and control rats by measuring norepinephrine (NE) turnover (alpha-methyl-p-tyrosine) in peripheral organs and by measuring depressor responses to ganglionic blockade in conscious rats. Pressor responses to methoxamine (1-8 micrograms/min) and arginine vasopressin (0.5-4 ng/min) were also obtained in rats with ganglionic blockade. Chronic A II infusion produced significant hypertension (mean +/- S.E. tail cuff pressure: 176 +/- 5 vs. 134 +/- 2 mm Hg in controls; n = 23 each group) but there were no significant differences in NE turnover in heart, kidney, skeletal muscle, or intestine in hypertensive rats compared with controls. Ganglionic blockade produced a significantly larger decrease in mean arterial pressure in A II-treated rats when compared with controls (73 +/- 7 vs. 38 +/- 2 mm Hg, n = 18 for each group). Dose-response curves for methoxamine and vasopressin were not significantly different between groups. The results suggest that the maintenance of chronic A II hypertension does not involve postsynaptic interactions between A II and the sympathetic system. The NE turnover data do not support the hypothesis that rats with chronic A II hypertension have enhanced sympathetic tone.
Asunto(s)
Angiotensina II/farmacología , Hipertensión/inducido químicamente , Sistema Nervioso Simpático/fisiopatología , Agonistas alfa-Adrenérgicos/farmacología , Angiotensina II/metabolismo , Animales , Arginina Vasopresina/farmacología , Presión Sanguínea/efectos de los fármacos , Bloqueadores Ganglionares/farmacología , Hemodinámica/efectos de los fármacos , Hipertensión/fisiopatología , Masculino , Metoxamina/farmacología , Metiltirosinas/farmacología , Norepinefrina/metabolismo , Ratas , Ratas Endogámicas , Tirosina 3-Monooxigenasa/antagonistas & inhibidores , Vasoconstrictores/farmacología , Equilibrio Hidroelectrolítico/efectos de los fármacos , alfa-MetiltirosinaRESUMEN
The role of the renal nerves in the electrolyte excretion of rats fed or fasted overnight was determined in conscious rats and anesthetized (Inactin) and surgically prepared rats. In conscious rats sodium excretion, as measured in a 1-h urine collection period after feeding or fasting overnight, was decreased with fasting with or without renal nerves. Renal nerve activity, as measured by norepinephrine turnover (inhibition of tyrosine hydroxylase by alpha-methyl-p-tyrosine), was not different between conscious fed or fasted rats and increased to the same extent in fed and fasted rats when anesthetized and surgically prepared. Anesthetized, surgically prepared rats infused with 5.0% glucose showed a denervation natriuresis if rats were fed overnight, but not if they had been fasted overnight. Potassium excretion in conscious and anesthetized rats was lower in fasted rats than fed rats with or without renal nerves. These data suggest (i) renal nerves are not involved in the renal response to an overnight fast in conscious rats, and (ii) in anesthetized, surgically prepared rat renal sympathetic tone is enhanced and denervation natriuresis occurs if rats are fed but not if fasted. Potassium excretion is a reflection of whether rats are fed or fasted and not whether they have renal nerves.
Asunto(s)
Anestesia , Electrólitos/orina , Riñón/inervación , Animales , Desnervación , Ayuno/fisiología , Masculino , Norepinefrina/metabolismo , Ratas , Ratas EndogámicasRESUMEN
To determine the contribution of renal nerves to natriuresis produced by selective alpha-2 adrenergic receptor activation in volume-loaded. Inactin-anesthetized rats, responses to B-HT 933 (20 micrograms/kg/min, i.v.) were compared in the chronically denervated kidney with responses in the contralateral innervated kidney. Plasma vasopressin concentration was maintained at high physiological levels by constant infusion of arginine vasopressin (170 pg/kg/min, i.v.). Control rats received arginine vasopressin and saline only. Arterial pressure and heart rate were decreased significantly by B-HT 933 (12 mm Hg and 80 beats/min. respectively). Glomerular filtration rate was not altered in innervated or denervated kidneys, whereas renal blood flow was decreased slightly, but significantly, in denervated but not innervated kidneys. B-HT 933 increased urine flow and total and fractional sodium excretion significantly in innervated kidneys but not in denervated kidneys when compared with control animals. Urine osmolality was also decreased significantly in innervated kidneys, but remained hyperosmotic to plasma. The data indicate that, in the presence of fixed levels of arginine vasopressin, chronic renal denervation prevented the natriuretic and diuretic effect of B-HT 933 in anesthetized rats. These results suggest that central and/or peripheral effects of alpha-2 adrenergic receptor activation were involved in producing natriuresis in the innervated kidney by decreasing renal sympathetic nerve influence on tubular sodium reabsorption.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Azepinas/farmacología , Diuresis/efectos de los fármacos , Riñón/inervación , Natriuresis/efectos de los fármacos , Receptores Adrenérgicos alfa/efectos de los fármacos , Animales , Arginina Vasopresina/farmacología , Riñón/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas , Sodio/orinaRESUMEN
Angiotensin I converting enzyme inhibitors are typically classified as peripheral vasodilators. We studied the effect of captopril and a known vasodilator, hydralazine, on arterial pressure-urinary output relationships in adult spontaneously hypertensive rats to determine whether these drugs produced similar changes in this relationship. Tail-cuff pressure and 24-hour urine output and sodium excretion were measured under steady state conditions during ingestion of tap water or saline (1% NaCl) ad libitum. Sodium intake increased seven to nine times when rats drank saline, but in the absence of drug treatment, tail-cuff pressure was not altered significantly (water, 213 +/- 3 vs saline, 220 +/- 5 mm Hg). Daily administration of captopril (100 mg/kg p.o.) or hydralazine (15 mg/kg p.o.) for 2 weeks lowered tail-cuff pressure significantly (175 +/- 3 and 166 +/- 3 mm Hg, respectively; p less than 0.01) while rats drank tap water. Continued administration of hydralazine plus 2 weeks of drinking saline did not alter tail-cuff pressure (162 +/- 4 mm Hg), but with the addition of saline during captopril treatment, tail-cuff pressure was elevated significantly (210 +/- 5 mm Hg; p less than 0.01). Thus, hydralazine produced a parallel shift of the arterial pressure-urinary output relationship along the pressure axis. In contrast, captopril produced a marked change in the slope of this relationship, making arterial pressure extremely salt-sensitive. The results suggest that the two drugs have different effects on the mechanisms that contribute to the long-term control of arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Captopril/uso terapéutico , Hidralazina/uso terapéutico , Hipertensión/tratamiento farmacológico , Riñón/efectos de los fármacos , Natriuresis/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Hipertensión/fisiopatología , Capacidad de Concentración Renal/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas SHR , Sistema Renina-Angiotensina/efectos de los fármacos , Cloruro de Sodio/administración & dosificación , Resistencia Vascular/efectos de los fármacosRESUMEN
Denervation supersensitivity in chronically denervated kidneys increases renal responsiveness to increased plasma levels of norepinephrine. To determine whether this effect is caused by presynaptic (i.e., loss of uptake) or postsynaptic changes, we studied the effect of continuous infusion of norepinephrine (330 ng/min, i.v.) and methoxamine (4 micrograms/min, i.v.), an alpha 1-adrenergic agonist that is not taken up by nerve terminals, on renal function of innervated and denervated kidneys. Ganglionic blockade was used to eliminate reflex adjustments in the innervated kidney and mean arterial pressure was maintained at preganglionic blockade levels by an infusion of arginine vasopressin. With renal perfusion pressure controlled there was a significantly greater decrease in renal blood flow (-67 +/- 9 vs. -33 +/- 8%), glomerular filtration rate (-60 +/- 9 vs. -7 +/- 20%), urine flow (-61 +/- 7 vs. -24 +/- 11%), sodium excretion (-51 +/- 15 vs. -32 +/- 21%), and fractional excretion of sodium (-50 +/- 9 vs. -25 +/- 15%) from the denervated kidneys compared with the innervated kidneys during the infusion of norepinephrine. During the infusion of methoxamine there was a significantly greater decrease from the denervated compared with the innervated kidneys in renal blood flow (-54 +/- 10 vs. -30 +/- 14%), glomerular filtration rate (-51 +/- 11 vs. -19 +/- 17%), urine flow (-55 +/- 10 vs. -39 +/- 10%), sodium excretion (-70 +/- 9 vs. -59 +/- 11%), and fractional excretion of sodium (-53 +/- 10 vs. -41 +/- 10%).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Riñón/efectos de los fármacos , Norepinefrina/farmacología , Sinapsis/efectos de los fármacos , Animales , Arginina Vasopresina/administración & dosificación , Arginina Vasopresina/farmacología , Desnervación , Bloqueadores Ganglionares/farmacología , Tasa de Filtración Glomerular/efectos de los fármacos , Compuestos de Hexametonio/farmacología , Riñón/inervación , Masculino , Metoxamina/farmacología , Natriuresis/efectos de los fármacos , Perfusión , Ratas , Circulación Renal/efectos de los fármacosRESUMEN
Vasopressin (AVP) in acute experiments has been shown to influence cardiovascular reflexes, but the effect of a more prolonged administration of AVP on the sympathetic nervous system has not been investigated. Long-Evans rats were treated for 7 days with AVP (Pitressin tannate in oil, with single daily doses of 100 or 500 mU.100 g-1, s.c.) to determine whether AVP alters norepinephrine (NE) turnover in kidney, intestine, or skeletal muscle. Control rats were given equal doses of peanut oil daily. NE turnover was determined by measuring the decline in tissue levels of NE for 8 h after inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine (300 mg.kg-1, i.p. every 4 h). Measurements of water intake, urine output, and urine osmolality showed that chronic administration of the high dose, but not the low dose, of AVP produced maintained increases in urine osmolality and decreases in water intake and urine output. Body weight, plasma osmolality, plasma electrolytes, and hematocrit were not significantly altered by AVP treatment, but mean arterial pressure was elevated significantly (control, 105 +/- 3 mmHg versus AVP, 119 +/- 4 mmHg, p less than 0.05) (1 mmHg = 133.3 Pa) in the high dose group. Plasma renin activity was decreased slightly, but significantly in rats treated with the high dose of AVP. Compared with results in control animals, there were no statistically significant changes in NE turnover after chronic administration of either the low or the high dose of AVP. The results indicate that administration of AVP for 7 days to rats in normal fluid balance does not result in a decrease in NE turnover in peripheral organs.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Norepinefrina/metabolismo , Vasopresinas/farmacología , Animales , Líquidos Corporales/metabolismo , Peso Corporal/efectos de los fármacos , Ingestión de Líquidos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Ratas , Vasopresinas/administración & dosificaciónRESUMEN
The effect of norepinephrine (NE) infusion (10, 100, and 330 ng/min, iv) on renal blood flow (RBF), glomerular filtration rate (GFR), urine flow, and sodium excretion was studied during ganglionic blockade in Inactin-anesthetized Wistar rats with one kidney innervated and the contralateral kidney denervated 7-10 days before the experiment. During the NE infusions, steady-state mean arterial pressure was 73 +/- 3, 91 +/- 5, and 117 +/- 2 mmHg, whereas plasma NE concentration averaged 3.9 +/- 1.2, 26.4 +/- 3.2, and 78.1 +/- 4.8 pmol/ml, respectively. At the lowest dose, RBF and GFR were decreased significantly in both kidneys but were significantly lower in the denervated kidneys than in the innervated kidneys. Urine flow and total and fractional sodium excretion increased significantly from the innervated kidneys but not from the denervated kidneys during the 100 and 330 ng/min infusion of NE. When renal perfusion pressure was controlled at the level found after ganglionic blockade, RBF and GFR decreased significantly in both kidneys but to a greater extent in the denervated kidneys at all doses of NE. Urine flow and total and fractional sodium excretion decreased significantly from the denervated kidneys at all doses of NE but decreased from the innervated kidneys only at the highest dose. These results indicate that in chronically denervated kidneys both tubular and vascular responses to NE are altered. The data support the conclusion that denervation supersensitivity can significantly alter renal responses to increased plasma concentration of NE.
Asunto(s)
Riñón/efectos de los fármacos , Norepinefrina/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Desnervación , Resistencia a Medicamentos , Bloqueadores Ganglionares/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Riñón/metabolismo , Riñón/fisiología , Masculino , Norepinefrina/sangre , Ratas , Ratas Endogámicas , Circulación Renal , Factores de Tiempo , Ácido p-Aminohipúrico/metabolismoRESUMEN
The possibility that sympathetic nervous system activity may be altered in Brattleboro rats with diabetes insipidus (DI) was studied using the norepinephrine (NE) turnover technique. Female DI and Long-Evans rats were used. NE turnover in peripheral organs was calculated by measuring the decline in tissue [NE] after inhibition of tyrosine hydroxylase with alpha-methyltyrosine. NE turnover was increased significantly in the kidney of DI rats but was not significantly altered in other peripheral organs examined (heart, duodenum, skeletal muscle). Both NE and epinephrine concentrations in the adrenal gland were significantly higher in the DI rats. Treatment of DI rats for 7 days with vasopressin tannate (Pitressin, 100 mU/100 g) or 1-deamino-[8-D-arginine] vasopressin (DDAVP, 250 ng X kg-1 X day-1) reversed the changes in renal NE turnover and also decreased the turnover in other tissues. The results of these studies suggest that, compared with Long-Evans rats, DI rats have a selective increase in NE turnover in the kidney and the potential to release more catecholamines from the adrenal glands. The apparently nonspecific effect of antidiuretic therapy on NE turnover in DI rats is probably mediated by the epithelial receptor for vasopressin, because both Pitressin and DDAVP produced similar results.
Asunto(s)
Diabetes Insípida/fisiopatología , Riñón/fisiopatología , Norepinefrina/fisiología , Ratas Brattleboro/fisiología , Ratas Mutantes/fisiología , Glándulas Suprarrenales/metabolismo , Animales , Desamino Arginina Vasopresina/farmacología , Diuresis/efectos de los fármacos , Duodeno/metabolismo , Femenino , Ventrículos Cardíacos/metabolismo , Músculos/metabolismo , Ratas , Vasopresinas/farmacología , Equilibrio Hidroelectrolítico/efectos de los fármacosRESUMEN
We have used a model for measuring renal clearances in the undisturbed rat to assess the role of the renal nerves in the depression of renal function during sodium pentobarbital anesthesia. One group of rats was studied with renal nerves intact and a second group was studied 7-9 days after bilateral renal denervation. Rats were prepared by placement of cannulae an average of 5 days prior to the clearance experiments. Renal function was measured before and after the injection of saline as the control vehicle and 2-3 days later, before, and after the injection of sodium pentobarbital (50 mg/kg) in the same rat. Sodium pentobarbital produced comparable decreases in glomerular filtration rate, para-aminohippuric acid clearance, urine flow rate, and sodium excretion in rats with denervated or innervated kidneys. Injection of saline resulted in no differences in measured variables between the rats with intact or sectioned renal nerves. Sodium pentobarbital caused a drop in arterial pressure in the denervated group but not in the innervated group. In a second series of experiments rats with denervated kidneys were implanted with an inflatable occluder around the aorta. This occluder was inflated to limit the drop in arterial pressure during anesthesia. When the blood pressure to the kidneys was maintained, renal function did not decrease during sodium pentobarbital anesthesia. These experiments suggest that the renal nerves are involved in the decrease in renal function during sodium pentobarbital anesthesia.
Asunto(s)
Anestesia , Riñón/efectos de los fármacos , Pentobarbital/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Desnervación , Frecuencia Cardíaca/efectos de los fármacos , Riñón/inervación , Masculino , Ratas , Ratas Endogámicas , Sodio/sangreRESUMEN
The role of renal nerves in influencing the control of arterial pressure was studied in Wistar rats with aortic depressor nerve (ADN) transection. Renal denervation prevented or reversed the normal increase in arterial pressure seen after ADN transection. This effect was not due to an effect on the renin-angiotensin system, as the elevated arterial pressure after ADN section in rats with renal nerves intact was shown to be due to increased alpha-adrenergic activity. Food and water intake and urine output decreased significantly in both renal-denervated and sham-denervated rats after ADN section, suggesting that a pressure diuresis mechanism was not responsible for preventing the rise in pressure in renal-denervated rats. In another study, the concentration of norepinephrine in skeletal muscle and hypothalamus at 0 and 8 hours after inhibition of tyrosine hydroxylase with alpha-methyltyrosine was used as an index of norepinephrine turnover. Norepinephrine turnover in skeletal muscle was increased significantly over control values by ADN transection in sham renal-denervated rats, but was not significantly different from controls in renal-denervated rats with ADN section. In the hypothalamus, there was a significant difference between the turnover of norepinephrine in the two groups of ADN-sectioned rats. The results taken together suggest that renal denervation prevents the arterial pressure response to ADN transection by altering the central mechanisms governing sympathetic outflow. It is suggested that this effect may be due to elimination of information carried by afferent renal fibers.
Asunto(s)
Aorta/inervación , Presión Sanguínea , Riñón/inervación , Norepinefrina/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Captopril/farmacología , Desnervación , Hipotálamo/metabolismo , Masculino , Músculos/metabolismo , Fentolamina/farmacología , Ratas , Ratas Endogámicas , Sistema Renina-Angiotensina , Tirosina 3-Monooxigenasa/metabolismo , Equilibrio HidroelectrolíticoRESUMEN
Previous studies of noradrenergic mechanisms in spontaneously hypertensive rats (SHR) have yielded conflicting results, as many have used: 1) rats of only one age; 2) a single organ such as heart or brain; or 3) either Wistar-Kyoto (WKY) or an outbred normotensive control rat. We have studied the turnover of norepinephrine (NE) in three brain areas (cortex, hypothalamus, brain stem) and three peripheral organs (duodenum, skeletal muscle, kidney) of SHR, WKY, and Wistar rats at 5, 9, and 18 weeks of age. The rate of decline of norepinephrine [NE] in tissue was determined with a fluorescence assay at 0, 2, 4, and 8 hours after inhibition of tyrosine hydroxylase with alpha-methyltyrosine. Differences in NE turnover were inferred by comparing slopes of regression lines calculated for the plot of log [NE] (expressed as a percent of the initial concentration) vs time. Systolic arterial pressure of SHR was similar to that of WKY and Wistar rats at 5 weeks of age, but increased to 150 mm Hg by 9 weeks and reached an average of 190 mm Hg by 18 weeks. The turnover of NE in 5-week-old SHR compared to two normotensive strains was significantly lower in the cortex and significantly higher in the kidney and skeletal muscle. By 9 weeks, in SHR, NE turnover had increased significantly in the hypothalamus and brain stem, while decreasing significantly in the kidney and duodenum. No such changes were seen in these organs of WKY or Wistar rats when comparing turnover of NE at 5 and 9 weeks. At 18 weeks, there were no further differences in the organs of SHR when compared to values obtained at 9 weeks. These data support the hypothesis that the turnover of NE may be altered in central and peripheral organs of young SHR, and may initiate or contribute to the development of hypertension. Changes in turnover of NE in the brain and peripheral organs between 5 and 9 weeks in SHR suggest compensatory responses to increasing arterial pressure; however, similar changes in turnover were not seen between 9 and 18 weeks, although arterial pressure continued to increase.
Asunto(s)
Envejecimiento , Encéfalo/metabolismo , Hipertensión/metabolismo , Norepinefrina/metabolismo , Animales , Duodeno/metabolismo , Riñón/metabolismo , Metiltirosinas/farmacología , Músculos/metabolismo , Ratas , Ratas Endogámicas , Tirosina 3-Monooxigenasa/antagonistas & inhibidoresRESUMEN
Renal norepinephrine (NE) concentration was measured at 2-week intervals after bilateral denervation of the kidneys in 5-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Sham-operated rats of both strains served as controls. Renal denervation significantly delayed but did not prevent the development of hypertension in SHR. Kidney NE concentration in renal-denervated SHR was 13, 25, 33, and 35% of that found in sham-operated SHR at 2, 4, 6, and 8 weeks, respectively, after denervation. Similarly, kidney NE concentration in renal-denervated WKY rats was 11, 24, 32, and 34% of controls but arterial pressure was not significantly altered. Renal-denervated SHR subjected to a second denervation operation 3 weeks after the initial operation continued to develop hypertension similar to those having only one operation. The results of this study support the hypothesis that renal nerves are involved in the hypertensive process in SHR during the early stages and suggest that renal reinnervation may occur within several weeks after denervation; however, the delayed rise in arterial pressure in renal-denervated SHR is not due to renal reinnervation.
Asunto(s)
Presión Sanguínea , Hipertensión/metabolismo , Riñón/inervación , Norepinefrina/metabolismo , Animales , Desnervación , Riñón/metabolismo , Masculino , Ratas , Factores de TiempoRESUMEN
The time course for functional reinnervation and development of supersensitivity to norepinephrine (NE) in the denervated rat kidney was studied using an in situ kidney preparation perfused at constant flow. Changes in perfusion pressure were measured during renal nerve stimulation (RNS, 1-10 Hz) and after administration of NE (1-50 ng, ia) up to 8 wk after unilateral renal denervation or a sham operation. During the first 2 wk after denervation, supersensitivity to NE was present, but there was no response to RNS. Between 24 and 32 days after denervation, RNS produced responses averaging 40% of control in denervated kidneys and supersensitivity to NE was still present. A fluorescence assay was used to determine that the NE concentration in kidneys 24-32 days after denervation was less than 30% of that found in control kidneys. At 8 wk, average responses to RNS in denervated kidneys were not significantly different from innervated kidneys, while supersensitivity to NE was still present. These results indicate that functional reinnervation of the renal vasculature begins to occur between 14 and 24 days after denervation, and that complete return of function may occur by 8 wk. The response to RNS during reinnervation appears to be due to a combination of regeneration of nerve fibers and denervation supersensitivity to NE.
Asunto(s)
Riñón/inervación , Norepinefrina/farmacología , Regeneración , Animales , Desnervación , Relación Dosis-Respuesta a Droga , Hipersensibilidad a las Drogas , Inyecciones Intraarteriales , Riñón/fisiología , Masculino , Norepinefrina/administración & dosificación , Ratas , Factores de TiempoRESUMEN
Renal norepinephrine (NE) concentration was measured in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) at 7, 9, 11, and 13 weeks of age. Although the weight of kidneys was similar in the two strains of rats, renal NE concentration was significantly lower in SHR at all ages (147 +/- 9 to 175 +/- 13 ng/g for SHR, and 216 +/- 8 to 262 +/- 17 ng/g for WKY rats). The difference in renal NE concentration during this time of rapidly increasing arterial pressure in the SHR suggests that renal NE may in some way be related to the development of hypertension.
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Hipertensión/metabolismo , Riñón/metabolismo , Norepinefrina/metabolismo , Envejecimiento , Animales , Masculino , Tamaño de los Órganos , RatasRESUMEN
The involvement of the renal nerves in the development of hypertension in Okamoto spontaneously hypertensive rats (SHR) was investigated by performing bilateral renal denervation in a group (n = 7) of SHR at 8 weeks of age. A sham-operated group (n = 7) of SHR served as surgical controls. Systolic arterial pressure was recorded twice a week until 14 weeks of age using a tail cuff method. Renal denervation significantly (P less than 0.01) altered the time course for development of hypertension, although both groups eventually developed hypertension. During the 6-week observation period, there were no significant differences in body weight, average 24-h food and fluid intake, urine output, or Na+ and K+ excretion between the two groups. At 20 weeks of age there were no significant differences in systolic pressure, average fluid intake, or urine output between the sham and denervated groups. These results suggest that the renal nerves may be involved in the early phase of development of hypertension in the SHR. The possibility that altered renal function may be the mechanism of the above effects is discussed.
Asunto(s)
Hipertensión/fisiopatología , Riñón/inervación , Animales , Presión Sanguínea , Desnervación , Diuresis , Ingestión de Líquidos , Masculino , Ratas , Factores de TiempoRESUMEN
Sodium intake and sodium output were measured in rats before and after lesioning of the anterior hypothalamus. Both parameters were lower than control rats following the lesioning procedure. When an amount of sodium was given orally to these lesioned rats to make up the deficit in sodium intake, no difference was found in sodium intake or output between the rats with lesions and normal rats. Rats with anterior hypothalamic lesions were able to increase their sodium intake following a period of sodium deprivation or adrenalectomy. When presented with concentrations of sodium chloride ranging between 0.9 and 2.5% rats with lesions decreased their intake of sodium in a manner similar to control rats except that the level of intake in the lesioned rats was lower for all concentrations. Control rats and those with lesions were not different in their intakes of KC1 solutions. These findings suggest that the anterior hypothalamus is important in setting the absolute intakes of sodium but does not interfere with the control mechanisms regulating the sodium intake.