RESUMEN
Acute transplant rejection is the leading cause of graft loss in the first months after kidney transplantation. Lipoxygenase products mediate pro- and anti-inflammatory actions and thus we aimed to correlate the histological reports of renal transplant biopsies with urinary lipoxygenase products concentrations to evaluate their role as a diagnostic marker. This study included a total of 34 kidney transplant recipients: 17 with an acute transplant rejection and 17 controls. LTE4, LTB4, 12-HETE and 15-HETE concentrations were measured by enzyme immunoassay. Urinary lipoxygenase product concentrations were not significantly changed during an acute allograft rejection. Nevertheless, LTB4 concentrations correlated significantly with the body temperature (P ≤ 0.05) 3 months after transplantation, and 12- and 15-HETE concentrations correlated significantly with renal function (P ≤ 0.05) 2 weeks after transplantation. In conclusion, our data show a correlation for LTB4 with the body temperature 3 months after transplantation and urinary 12- and 15-HETE concentrations correlate positively with elevated serum creatinine concentrations but do not predict acute allograft rejection.
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Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/orina , Temperatura Corporal , Rechazo de Injerto/orina , Ácidos Hidroxieicosatetraenoicos/orina , Riñón/fisiología , Leucotrieno B4/orina , Leucotrieno E4/orina , Enfermedad Aguda , Adulto , Femenino , Rechazo de Injerto/enzimología , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Humanos , Trasplante de Riñón/efectos adversos , Lipooxigenasa/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: The renin-angiotensin-aldosterone system (RAAS) plays an integral role in the regulation of blood pressure, electrolyte and fluid homeostasis in mammals. The capability of the different nephron segments to form components of the RAAS is only partially known. This study therefore aimed to characterize the nephron-specific expression of RAAS components within the mouse kidney. MATERIALS AND METHODS: Defined nephron segments of adult C57B/16 mice were microdissected after collagenase digestion. The gene expression of renin, angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin II receptors 1a (AT1a), 1b (AT1b), and 2 (AT2) was assessed by reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Renin mRNA was present in glomeruli, in proximal tubules, in distal convoluted tubules (DCT) and cortical collecting ducts (CCD). AGT mRNA was found in proximal tubules, descending thin limb of Henle's loop (dTL) and in the medullary part of the thick ascending limb (mTAL). ACE mRNA was not detectable in microdissected mouse nephron segments. AT1a, AT1b and AT2 mRNA was detected in glomeruli and proximal convoluted tubules. CONCLUSIONS: Our data demonstrate a nephron-specific distribution of RAAS components. All components of the local RAAS - except ACE - are present in proximal convoluted tubules, emphasizing their involvement in sodium and water handling.
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Nefronas/metabolismo , Sistema Renina-Angiotensina/genética , Angiotensinógeno/genética , Angiotensinógeno/metabolismo , Animales , Cartilla de ADN/metabolismo , Túbulos Renales Colectores/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microdisección , Nefronas/enzimología , Especificidad de Órganos/genética , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/metabolismo , Renina/genética , Renina/metabolismoRESUMEN
Cyclooxygenases (COX) are known to be involved in inflammatory kidney diseases. However, there are no data available about the expression of COX-1 and only preliminary reports about the expression of COX-2 in biopsies of patients undergoing acute renal allograft rejection. We conducted this prospective study to analyze the expression, distribution, and cellular localization of COX-1 and -2 and thus to elucidate the role of COX in human kidney transplantation. One hundred forty-four biopsies were included from patients without rejection and unaltered morphology (n = 60), with acute interstitial rejection (n = 7), with acute vascular rejection (n = 21), with chronic allograft nephropathy (n = 16), without rejection but with various other lesions (n = 40). COX-1 and -2 expression was localized in each biopsy by immunohistochemistry. We found a highly significant up-regulation of COX-1 in vessels and in infiltrating interstitial cells of patients with acute allograft rejection compared with biopsies with well-preserved tissue. Also, COX-2 expression was significantly elevated in infiltrating interstitial cells of biopsies with acute rejection. This is the first prospective study demonstrating a significant induction of both COX-1 and -2 in human allograft biopsies with acute rejection after renal transplantation.
Asunto(s)
Ciclooxigenasa 1/biosíntesis , Ciclooxigenasa 2/biosíntesis , Trasplante de Riñón , Riñón/enzimología , Adulto , Anciano , Arteriosclerosis/patología , Biopsia , Femenino , Expresión Génica , Regulación Enzimológica de la Expresión Génica , Rechazo de Injerto , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
Although the regulation of cyclooxygenase-2 (COX-2) expression in the kidney cortex has been extensively characterized, the physiological control mechanisms of COX-2 expression at the level of the kidney and at the level of the tubular cells are not well understood. Based on the current hypothesis that tubular salt transport might be a crucial regulator of COX-2 expression, this study aimed to determine the impact of salt delivery to the tubules (glomerular filtration) for the regulation of COX-2 in the kidney cortex in vivo. To this end, glomerular filtration of the right kidney was abrogated by the ligation of the right ureter of male Sprague-Dawley rats. After 1 wk of ligation, the animals were treated with subcutaneous infusions of furosemide (12 mg x kg(-1) x day(-1)) or with a low-salt or a high-salt diet (0.02% wt/wt; 8% wt/wt), and COX-2 as well as renin mRNA expression were determined in the ligated and the nonligated contralateral kidney. During ureteral ligation, hydronephrosis developed with a reduction of medullary mass, while the cortex was preserved. Expressions of the Na-K-2Cl cotransporter isoforms A and B were both reduced in the hydronephrotic cortex to 70 and 35% of the corresponding contralateral intact kidney. Despite the abrogation of glomerular filtration, detected by inulin clearance measurements, renocortical COX-2 mRNA abundance was stimulated by furosemide treatment (3.2-fold) or low-salt diet (2.9-fold) to similar degrees compared with the intact contralateral kidney (2.7-fold for both treatments), whereas a high-salt diet did not significantly suppress COX-2 mRNA in the macula densa region of either kidney. Renin mRNA expression was regulated strictly in parallel in both kidneys, a low-salt diet or furosemide treatment stimulating and a high-salt diet suppressing it. We conclude from these findings that salt delivery to the tubules is not an essential requirement for the upregulation of COX-2 by salt deficiency or by loop diuretics in the rat kidney cortex nor is it for chronic stimulation of renin mRNA expression.
Asunto(s)
Tasa de Filtración Glomerular , Isoenzimas/biosíntesis , Corteza Renal/fisiología , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Cloruro de Sodio Dietético , Animales , Ciclooxigenasa 2 , Diuréticos/administración & dosificación , Furosemida/administración & dosificación , Masculino , Ratas , Ratas Sprague-Dawley , Cloruro de Sodio/farmacología , Regulación hacia ArribaRESUMEN
BACKGROUND/AIMS: The role of COX-2 for renal function during renal development, for physiology and pathophysiology of renal diseases and the side effects of available COX-2 inhibitors, has gained increasing interest. We aimed therefore to review the respective role of renal COX-2. METHODS: Review of relevant recent publications in the field, and in addition of in part unpublished data obtained in our laboratories. RESULTS: COX-2 is 'constitutively' localized in the kidney i.e. in macula densa, TALH, interstitial cells, and is of utmost importance for normal renal development. Renal COX-2 is regulated by for example sodium and volume intake, angiotensin II, glucocorticoids often involving specific COX-2 promotor response elements. COX-2 derived prostanoids are required for preservation of renal blood flow and glomerular filtration especially in states of fluid deficit, they promote natriuresis, and furthermore may stimulate renin secretion during low-sodium intake/loop diuretic use. Conversely, COX-2 inhibitors decrease glomerular filtration, and renal perfusion, sometimes even causing acute renal failure. In addition, COX-2 inhibitors cause sodium retention, edema formation, cardiac failure and hypertension. The role of COX-2 derived prostanoids in renal inflammation or failure including diabetic nephropathy and renal transplantation remains at present controversial. CONCLUSION: COX-2 is one of the major players in renal physiology and pathophysiology. One focus of future work should be placed on COX-2 in primary renal diseases.
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Isoenzimas/fisiología , Riñón/enzimología , Prostaglandina-Endoperóxido Sintasas/fisiología , Animales , Ciclooxigenasa 2 , Humanos , Isoenzimas/metabolismo , Riñón/crecimiento & desarrollo , Riñón/fisiología , Enfermedades Renales/fisiopatología , Proteínas de la Membrana , Natriuresis/fisiología , Nefritis/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Renina/metabolismoRESUMEN
BACKGROUND/AIMS: Ultrasonographic determination of gallbladder motility is sparsely performed in clinical practice as the examination is considered to be time consuming and there is uncertainty about a number of parameters possibly influencing the results. The aims of this study were a) to establish normal values for a simple ultrasonographic test and b) to evaluate the influence of different parameters on gallbladder motility. METHODOLOGY: In 62 systematically age- and sex-matched healthy volunteers, ultrasonographic measurements of gallbladder volume (ellipsoid method, planimetry and sum-of-cylinders method) were performed fasting and 5, 10, 20, 30, 40, 50, 60, 70 and up to 75 min after stimulation with a standardized high-caloric liquid meal. RESULTS: Using the ellipsoid method, gallbladder fasting volume (V0) reached a mean value (+/- SD) of 24.6 +/- 10.0 mL with an ejection fraction of 65.9 +/- 19.1%. Age, gender and hair color did not influence parameters of gallbladder contraction. Body mass index showed a weak correlation with V0 but not with ejection fraction. There was a highly significant correlation between the ellipsoid method and longitudinal planimetry and the sum-of-cylinders method, respectively. CONCLUSIONS: Ultrasonographic measurement of gallbladder motility in healthy volunteers shows a very wide scattering of normal values. In the interpretation of gallbladder emptying, age, gender and body mass index do not have to be considered. Determination of gallbladder motility may be performed by a rather simple approach with oral stimulation and ellipsoid method or longitudinal planimetry as easily applicable ultrasonographic measurements.
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Vesícula Biliar/fisiología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Femenino , Vesícula Biliar/diagnóstico por imagen , Vaciamiento Vesicular/fisiología , Color del Cabello , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Factores Sexuales , UltrasonografíaRESUMEN
Cardiovascular morbidity and mortality is high in patients following renal transplantation. The present analysis assessed major cardiovascular risk factors and estimated the risk of coronary artery disease in the largest present-day comparative trial of tacrolimus vs. microemulsified cyclosporine A. In this 6-month study, 557 patients were randomly allocated to therapy with tacrolimus (n = 286) or cyclosporine A (n = 271) concomitantly with azathioprine and corticosteroids. The primary endpoint was the incidence of and time to acute rejection. Blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose were measured at baseline, and at months 1, 3, and 6. Ten-year risk of coronary heart disease was estimated according to the Framingham risk algorithm. Tacrolimus resulted in significantly lower summary measures (time-weighted average) of serum cholesterol (p = 0.0004) and mean arterial blood pressure (p = 0.0156), but in a higher summary measure of blood glucose (p = 0.0028) than cyclosporine. The summary measure of serum triglycerides was not different between treatment groups (p = 0.368). The mean 10-year coronary artery disease risk estimate was significantly lowered in men (p = 0.0032) treated with tacrolimus, but was unchanged in women. Tacrolimus and cyclosporine A microemulsion exert a compound-specific impact on cardiovascular risk factors and appear to affect the predicted rate of cardiovascular morbidity in different manners.
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Inhibidores de la Calcineurina , Enfermedad de la Arteria Coronaria/etiología , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Tacrolimus/uso terapéutico , Ciclosporina/efectos adversos , Humanos , Inmunosupresores/efectos adversos , Fallo Renal Crónico/cirugía , Estudios Prospectivos , Factores de Riesgo , Análisis de Supervivencia , Tacrolimus/efectos adversosRESUMEN
Eurotransplant offers a Senior Program to extend the donor pool for renal transplantation. The study comprised 14 patients of the ET Senior ("Old For Old") Program. Kidneys from five cadaveric donors were transplanted in pairs to ten recipients with a difference in cold ischemia time (CIT) of >4 h, and grouped according to CIT (group 1: patients that underwent transplantation first; group 2: patients that underwent transplantation second). CIT was shorter (5.5+/-2.0 h vs. 11.7+/-3.1 h, P<0.01), and the first day diuresis was higher (287.4 ml/h vs. 134.8 ml/h, P<0.05) in group 1 than in group 2. No patient in group 1 required dialysis, 3/5 patients in group 2. Rejection episodes occured more often in group 2 (5/5 vs. 3/5), and the hospital stay tended to be shorter in group 1 (33.0 days (27-43) vs. 54.2 days (27-112)). Our study confirms the positive effect of ultra-short CIT on early graft function in marginal donors, despite overall short CIT. The increase in delayed graft function (DGF) may lead to an extended hospital stay and dialysis requirements. Efforts to realize simultaneous transplantation in two recipients seem necessary to optimize results.
Asunto(s)
Trasplante de Riñón , Obtención de Tejidos y Órganos/métodos , Anciano , Estudios de Casos y Controles , Criopreservación , Femenino , Rechazo de Injerto/etiología , Humanos , Trasplante de Riñón/mortalidad , Tiempo de Internación , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
1 It is known that nonselective cyclo-oxygenase (COX) inhibitors have small but significant effects on blood pressure (BP), most notably in hypertensive patients on antihypertensive medication. Whether selective COX-2 inhibitors also interfere with BP regulation is not well understood. Therefore, we aimed to examine the effect of chronic treatment with a selective COX-2 inhibitor (rofecoxib) on systolic blood pressure (sBP) in normotensive Wistar-Kyoto rats (WKY) and on the developmental changes of sBP in young spontaneously hypertensive rats (SHR). In addition, we investigated a possible influence of salt intake on the effects of COX-2 inhibition on BP in these two rat strains. 2 Rofecoxib dose dependently increased sBP and decreased plasma levels of 6-keto prostaglandin (PG)F(1alpha) in WKY rats fed a normal salt diet (0.6% NaCl, wt wt(-1)), without affecting serum thromboxane (TX)B(2) levels. 3 Rofecoxib significantly elevated sBP in both rat strains fed normal salt or high salt diet (8% NaCl, wt wt(-1)), but not in rats on low salt intake (0.02% NaCl, wt wt(-1)). 4 Rofecoxib significantly decreased plasma levels of 6-keto PGF(1alpha) in both rat strains fed normal or high salt diet, but not in rats during low salt intake. 5 Rofecoxib exerted no influence on the changes of body weight nor on water intake. Plasma renin activity (PRA) and renocortical renin mRNA abundance were not changed by rofecoxib, but plasma aldosterone concentration (PAC) was significantly reduced. 6 These results suggest that chronic inhibition of COX-2 causes an increase of blood pressure that depends on prostacyclin synthesis. Furthermore, this increase is independent on genetic predisposition and can be prevented by salt deprivation. Since water intake and body weight gain were not changed by rofecoxib, fluid retention appears not to be a major reason for the development of hypertension. Similarly, an activation of the renin-angiotensin-aldosterone axis appears to be an unlikely candidate mechanism.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/efectos adversos , Lactonas/efectos adversos , 6-Cetoprostaglandina F1 alfa/sangre , Actinas/metabolismo , Aldosterona/sangre , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Hematócrito , Corteza Renal/efectos de los fármacos , Corteza Renal/metabolismo , Masculino , Potasio/sangre , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Renina/sangre , Renina/genética , Renina/metabolismo , Sodio en la Dieta/administración & dosificación , SulfonasRESUMEN
We investigated the effect of cyclooxygenase (COX) activity on the regulation of the renin-angiotensin-aldosterone system by salt intake. Therefore, Sprague-Dawley rats were subjected to different salt diets [0.02, 0.6, and 8% NaCl (wt/wt)] and treated with the selective COX-2 inhibitor rofecoxib (10 mg x kg body wt(-1) x day(-1)) or with ketorolac at a dose selective for COX-1 inhibition (2 mg x kg body wt(-1) x day(-1)) for 3, 7, 14, and 21 days. Rofecoxib and ketorolac caused a similar reduction of renocortical PGE2 formation with a low-salt diet. Rofecoxib did not change plasma renin activity or renocortical renin mRNA abundance with any of the diets but clearly lowered plasma aldosterone concentration. In contrast, ketorolac delayed the increase in plasma renin activity and of renin mRNA in response to low salt intake but did not change plasma aldosterone concentration. Prolonged treatment with rofecoxib but not with ketorolac caused an upregulation of COX-2 expression while COX-1 mRNA abundance remained unchanged. These findings suggest that COX-1-derived, but not COX-2-derived, prostanoids are of relevance for the regulation of the renin system by salt intake.
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Riñón/enzimología , Prostaglandinas/metabolismo , Sistema Renina-Angiotensina/fisiología , Cloruro de Sodio Dietético/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/fisiología , Inmunohistoquímica , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Ketorolaco/farmacología , Lactonas/farmacología , Masculino , Proteínas de la Membrana , Prostaglandina-Endoperóxido Sintasas/genética , Prostaglandina-Endoperóxido Sintasas/metabolismo , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Renina/genética , Sistema Renina-Angiotensina/efectos de los fármacos , SulfonasRESUMEN
BACKGROUND: The incidence of acute renal failure (ARF) after cardiac surgery remains high, despite improvements in surgical techniques and perioperative care, and is associated with an unacceptably high mortality. The adenosine receptor antagonist theophylline has been shown to confer some benefit in experimental and clinical ARF due to ischaemia, contrast media and various nephrotoxic agents. METHODS: In a double-blind, randomized, placebo-controlled trial, the effectiveness of theophylline for prevention of renal impairment after elective coronary artery bypass grafting (CABG) was evaluated. Fifty-six patients with normal renal function received a bolus of 4 mg/kg and a subsequent continuous infusion of 0.25 mg/kg/h theophylline (n=28) or isotonic saline (n=28) for up to 96 h. Serum creatinine concentrations were measured preoperatively and daily until day 5 after surgery, and the glomerular filtration rate (GFR) ([(51)Cr]EDTA-clearance) was determined preoperatively, and at days 1, 3 and 5 after surgery. RESULTS: Serum creatinine and GFR were the same in both groups. The number of patients with increases of serum creatinine > or =0.4 mg/dl were five in the theophylline group and four in the placebo group. Volumes of infused fluid and urine volumes were not different between groups, both ranging from approximately 7.5 to 8 l during the first 24 h after surgery. The number of patients with termination of study medication due to presumed side effects was not different between placebo and theophylline groups. CONCLUSIONS: Theophylline administration for renal protection after CABG appears to be ineffective in a pilot study in well-hydrated patients. However, the statistical power of our study was not sufficient to exclude a possible protective effect of theophylline. The present study demonstrated the feasability of a larger trial with theophylline or one of the new specific adenosine A1 receptor antagonists in the setting of ARF after cardiac surgery.
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Puente de Arteria Coronaria/efectos adversos , Citoprotección , Enfermedades Renales/etiología , Enfermedades Renales/prevención & control , Teofilina/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Creatinina/sangre , Diuresis/efectos de los fármacos , Método Doble Ciego , Ingestión de Líquidos/efectos de los fármacos , Estudios de Factibilidad , Tasa de Filtración Glomerular/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Proyectos Piloto , Antagonistas de Receptores Purinérgicos P1 , Teofilina/sangre , Insuficiencia del TratamientoRESUMEN
Salt restriction leads to parallel increases of renin, cyclooxygenase-2 (COX-2), and neuronal nitric oxide synthase (nNOS) gene expression in the juxtaglomerular apparatus of rat kidneys. Because the upregulation of these genes is strongly enhanced if salt restriction is combined with inhibition of the renin-angiotensin-aldosterone system, our study aimed to find out whether the juxtaglomerular expressions of renin, COX-2, and nNOS are subject to a common direct negative feedback control by ANG II. For this purpose, male Sprague-Dawley rats were fed a low-salt diet (0.02% wt/wt) with or without additional treatment with the ANG I-converting enzyme (ACE) inhibitor ramipril (10 mg x kg body wt(-1) x day(-1)) for 1 wk, and renocortical renin, COX-2, and nNOS mRNAs were assayed. To narrow down possible indirect effects of the ACE inhibitor that may result from insufficient aldosterone production, the animals received mineralocorticoid substitution with fludrocortisone (6 mg. kg body wt(-1) x day(-1)). Thus mineralocorticoid substitution prevented the fall of systolic blood pressure and of glomerular filtration induced by ramipril in rats on low-salt diet. Although fludrocortisone had no effect on basal renin, COX-2, and nNOS mRNA, it clearly attenuated the threefold increases of both renin and COX-2 mRNA in response to low-salt diet. In rats on low-salt diet, ramipril further increased renin mRNA ninefold, COX-2 mRNA fourfold, and nNOS 2.5-fold in the absence of fludrocortisone. In the presence of fludrocortisone, ramipril increased renin mRNA 10-fold, COX-2 mRNA 2.5-fold, and nNOS mRNA 2.5-fold. These data indicate that mineralocorticoid substitution lowers the overall expression of juxtaglomerular renin and COX-2 during low-salt intake and attenuates a further rise of COX-2 expression by ACE inhibition, but it does not change the stimulatory effect of ACE inhibition on renin and nNOS expression. We conclude that the expression of renin, COX-2, and nNOS in the juxtaglomerular apparatus during low-salt diet is markedly limited by a direct feedback inhibition through ANG II.
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Retroalimentación Fisiológica/fisiología , Isoenzimas/metabolismo , Corteza Renal/metabolismo , Óxido Nítrico Sintasa/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Renina/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Creatinina/metabolismo , Ciclooxigenasa 2 , Dieta Hiposódica , Retroalimentación Fisiológica/efectos de los fármacos , Fludrocortisona/farmacología , Isoenzimas/genética , Corteza Renal/efectos de los fármacos , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/metabolismo , Masculino , Mineralocorticoides/farmacología , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo I , Prostaglandina-Endoperóxido Sintasas/genética , ARN Mensajero/metabolismo , Ramipril/farmacología , Ratas , Ratas Sprague-Dawley , Renina/sangre , Renina/genéticaRESUMEN
BACKGROUND/AIMS: Published data regarding the effects of common cardiovascular diseases, i.e. aortic stenosis on renal regulation of major vasoconstrictive (renin, endothelins) and vasodilatory systems (NO) are controversial. Therefore we aimed to evaluate the effects of chronic aortic stenosis on the renal renin-angiotensin, endothelin and NO systems. METHODS: Experimental supravalvular aortic stenosis was induced by using silver clips with a 0.6 mm internal diameter on the ascending aorta of weanling rats. Renal endothelin-1 (ET-1), endothelin-3 (ET-3), renin, AT(1a), AT(1b), eNOS, and bNOS gene expression were assessed by RNase protection assay. RESULTS: Renal renin gene expression increased twofold in rats with aortic stenosis. In contrast, renal ET-1, ET-3, eNOS, bNOS, and AT(1a), AT(1b) gene expression were unchanged in rats with aortic stenosis. CONCLUSION: Our study demonstrates that in rats with severe experimental supravalvular aortic stenosis only renal renin gene expression is stimulated. This contrasts with severe heart failure where endothelins and NO synthases are also upregulated. Different patterns of regulation of renal vasoactive mediators may be of importance for the extent of the renal impairment associated with aortic stenosis, and may be correlated with the severity of congestive heart failure.
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Estenosis Aórtica Supravalvular/metabolismo , Endotelinas/biosíntesis , Riñón/metabolismo , Óxido Nítrico Sintasa/biosíntesis , Receptores de Angiotensina/biosíntesis , Renina/biosíntesis , Animales , Expresión Génica , Insuficiencia Cardíaca/metabolismo , Masculino , Óxido Nítrico Sintasa/genética , ARN Mensajero/biosíntesis , Ratas , Ratas WistarAsunto(s)
Antidepresivos/uso terapéutico , Sistema Enzimático del Citocromo P-450/biosíntesis , Hypericum , Inmunosupresores/efectos adversos , Trasplante de Riñón/inmunología , Riñón/patología , Oxigenasas de Función Mixta/biosíntesis , Fitoterapia , Preparaciones de Plantas/uso terapéutico , Tacrolimus/efectos adversos , Anciano , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Monitoreo de Drogas , Inducción Enzimática/efectos de los fármacos , Alemania , Humanos , Riñón/efectos de los fármacos , Masculino , Tacrolimus/sangre , Tacrolimus/farmacocinéticaRESUMEN
Naftidrofuryl, a 5-hydroxytryptamine 2 (5-HT 2 ) serotonergic receptor antagonist with vasodilator effects, has successfully been used for intermittent claudication, some forms of dementia, and glaucoma. Recently, an additional mode of action of naftidrofuryl (i.e., mixed endothelin receptor antagonism) has been suggested. However, in the current study naftidrofuryl was unable to block endothelin-3-induced free intracellular calcium increases, in contrast to a mixed endothelin receptor antagonist, bosentan. The inhibition of forskolin-induced renin secretion by endothelin-3 in primary cultures of mouse juxtaglomerular cells and by endothelin-1 in the isolated perfused rat kidney could not be blocked by naftidrofuryl. Naftidrofuryl was unable to block marked endothelin-1-induced renal vasoconstriction in isolated perfused rat kidney. In contrast, naftidrofuryl markedly attenuated serotonin-induced renal vasoconstriction and nearly completely blocked serotonin's renin inhibitory properties in isolated perfused rat kidney. The present results suggest that naftidrofuryl is a potent antagonist of serotonin's renal effects, but has no endothelin receptor-blocking properties.