RESUMO
The present study was designed to measure angiotensin-converting enzyme (ACE) activity in the human ovary and in serum and to relate this activity to age, serum estradiol levels, and uterine and endometrial pathology. ACE activity was determined in 56 females by a radiometric assay using [3H]hippuryl-glycyl-glycine as substrate. Ovarian ACE activity, but not serum ACE, was found to increase with age (P < 0.01) and was significantly greater in postmenopausal subjects (n = 31; 1.35 +/- 0.05 nmol/mg.min) than in subjects with active ovaries (n = 21; 0.65 +/- 0.2 nmol/mg.min; P = 0.0033). Ovarian ACE activities in fertile women in the preovulatory phase (n = 14) and the postovulatory phase (n = 7) were not statistically different (0.66 +/- 0.23 and 0.63 +/- 0.17 nmol/mg.min, respectively). Serum ACE activities were similar in females with active and nonactive ovaries (87.6 +/- 5.0 vs. 81.7 +/- 5.3 nmol/mL-min, respectively). Serum estradiol levels in fertile women were significantly higher than those in postmenopausal women (P = 0.0023). Serum estradiol levels were negatively correlated with age (r = -0.46; P = 0.0041) and were not correlated with either serum ACE activity (r = 0.080; P = NS) or ovarian ACE activity. In summary, human ovarian ACE activity, but not serum ACE, is positively correlated with age. Serum estradiol levels decrease with age, but are not correlated with either ovarian or serum ACE activity. Endogenous serum estradiol levels had no apparent effect on ovarian or serum ACE activity. The presence of uterine pathology affects ovarian ACE activity. The cause of the increased ovarian ACE activity is not clear, but may be related to the aging process.
Assuntos
Envelhecimento/metabolismo , Estradiol/sangue , Ovário/enzimologia , Peptidil Dipeptidase A/metabolismo , Doenças Uterinas/metabolismo , Adulto , Idoso , Carcinoma/metabolismo , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Renina/sangueRESUMO
Studies in animal models have indicated that ramipril is a potent inhibitor of angiotensin converting enzyme (ACE) in serum and tissue. In our study, the normal range of ACE activity and the inhibitory effect of short-term oral administration of ramipril on ACE activity in human serum and tissue samples of renal cortex, heart and blood vessels were determined. ACE activity in the renal cortex (125.2 +/- 11.5 nmol/mg per min) was greater than 600 times that of the heart (0.20 +/- 0.01 nmol/mg per min), greater than 500 times that of the veins (0.23 +/- 0.09 nmol/mg per min) and greater than 150 times that of the arteries (0.80 +/- 0.23 nmol/mg per min). ACE activity in the renal cortex and arteries 2 h after last dosing was almost completely inhibited by ramipril whereas ACE activity in the veins and heart was inhibited to a lesser extent. Our results demonstrate in man, for the first time, an inhibition of tissue ACE following short-term oral treatment with an ACE inhibitor.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Peptidil Dipeptidase A/metabolismo , Administração Oral , Angiotensina II/sangue , Feminino , Humanos , Córtex Renal/enzimologia , Masculino , Pessoa de Meia-Idade , Miocárdio/enzimologia , Ramipril , Valores de Referência , Renina/sangue , Procedimentos Cirúrgicos Operatórios , Fatores de TempoRESUMO
Nephrotoxicity is the most troublesome complication of cyclosporine (CSA) therapy. The present study was designed to investigate the effects of chronic treatment with CSA on the 24-hr urinary excretion of prostanoids (PGs) and thromboxane (Tx) and on the renal function in the absence or presence of indomethacin. CSA administration to Wistar rats (20 mg/kg/day, i.p.) for 14 days caused a significant increase in plasma creatinine, blood urea nitrogen (BUN), urine osmolality, fractional excretion of sodium and potassium and a reduction in creatinine clearance (CCr) and urine volume. These changes were associated with a significant reduction in urinary excretion of PGE2 (21.1 +/- 3.3 vs 33.0 +/- 2.5 ng/24 hr) and PGF2 alpha (13.4 +/- 1.4 vs 27.9 +/- 3.8 ng/24 hr) and an increase in TxB2 (12.1 +/- 3.0 vs 4.6 +/- 0.5 ng/24 hr), and 6-keto PGF1 alpha (56.2 +/- 7.7 vs 27.7 +/- 1.9 ng/24 hr). However, the synthesis of TxB2 and 6-keto PGF1 alpha by renal medullary and cortical slices prepared from CSA treated rats was not different from values obtained for vehicle treatment. In contrast, PGE2 synthesis by cortical slices prepared from the CSA group was increased. A single injection of indomethacin (10 mg/kg) to vehicle and CSA treated rats resulted in a significant reduction in PGs and TxB2 excretion. This, was associated with a further reduction in CCr (0.81 +/- 0.06 vs 1.03 +/- 0.04 ml/min) and an increase in BUN (38.5 +/- 5.2 vs 28.2 +/- 1.4 mg%) only in the CSA group. We suggest that the vasodilating PGs attenuate the renal toxic effects induced by CSA.
Assuntos
Ciclosporinas/toxicidade , Rim/patologia , Prostaglandinas/urina , Tromboxano B2/urina , Animais , Técnicas In Vitro , Rim/efeitos dos fármacos , Rim/fisiopatologia , Córtex Renal/patologia , Medula Renal/patologia , Masculino , Ratos , Ratos Endogâmicos , Valores de ReferênciaRESUMO
This study was designed to investigate the effects of chronic treatment with cyclosporin A (CSA) on the endogenous synthesis of prostanoids (PGs) and thromboxane (Tx) by renal isolated medullary and cortical mitochondria. The administration of CSA, dissolved in 10% ethanol in olive oil, to male Wistar rats (20 mg kg-1 day-1 i.p.) for 14 days resulted in alterations in mitochondrial biosynthesis of immunoreactive PGs. The endogenous synthesis of thromboxane by medullary and cortical mitochondria isolated from CSA-treated rats was significantly enhanced by 120 and 55%, respectively, whereas the synthesis of prostaglandin E2 by medullary mitochondria was reduced by 35%. The synthesis of prostaglandin F2 alpha and prostacyclin was not affected by CSA treatment. The conversion of exogenous arachidonic acid to PGs and Tx by cortical mitochondria isolated from CSA-treated rats was significantly increased. In addition, CSA treatment resulted in i) a reduced acylation of arachidonic acid into medullary phospholipids by 25% and into medullary and cortical triglycerides by 33 and 27%, respectively, and ii) an increase in cortical and medullary triglycerides. We suggest that the alterations in the endogenous mitochondrial production of PGs and Tx caused by CSA, may play a role in the impairment of membrane mediated functions.
Assuntos
Ciclosporinas/farmacologia , Rim/metabolismo , Mitocôndrias/metabolismo , Prostaglandinas/biossíntese , Tromboxanos/biossíntese , Animais , Ácidos Araquidônicos/metabolismo , Técnicas In Vitro , Rim/efeitos dos fármacos , Córtex Renal/efeitos dos fármacos , Córtex Renal/metabolismo , Testes de Função Renal , Medula Renal/efeitos dos fármacos , Medula Renal/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Ratos , Ratos EndogâmicosRESUMO
Nephrotoxicity and arterial hypertension are the most common side effects of treatment with cyclosporin A (CSA). Its effects on angiotensin converting enzyme (ACE) activity in the renal cortex, lung and serum of nephrotoxic rats have been investigated. Wistar rats were treated with CSA (20 mg kg-1 day-1 i.p.) or vehicle (olive oil containing 10% ethanol) for 14 days. On day 15, the rats were killed and ACE activity determined by radiometric assay using [3H]hippuryl-glycyl-glycine as substrate. CSA treatment resulted in a decrease in creatinine clearance, urine flow and body weight and a significant increase in serum and lung ACE activities (436 +/- 9 vs 391 +/- 7 nmol mL-1 min-1, P less than 0.001; 184 +/- 8 vs 142 +/- 10 nmol mg-1 min-1 P less than 0.01, respectively). In contrast, renal cortex ACE activity was reduced in the CSA-treated rats (0.35 +/- 0.02 vs 0.51 +/- 0.02 nmol mg-1 min-1, P less than 0.01). ACE activities in the renal cortex and serum were not affected by treatment with gentamicin (80 mg kg-1 day-1) for 11 days. In rats treated simultaneously with CSA and captopril (50 mg kg-1 day-1) ACE activity in the serum, lung and renal cortex was inhibited by 95, 93 and 92%, respectively. These changes in ACE activity were associated with a decreased systolic blood pressure in the rats receiving CSA and captopril. Therefore, ACE activity in the serum and lung of CSA-treated rats was increased, while its activity in the renal cortex was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Ciclosporinas/uso terapêutico , Córtex Renal/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Animais , Captopril/farmacologia , Creatinina/sangue , Creatinina/urina , Ciclosporinas/antagonistas & inibidores , Injeções Intraperitoneais , Córtex Renal/enzimologia , Pulmão/enzimologia , Masculino , Peptidil Dipeptidase A/sangue , Ratos , Ratos EndogâmicosRESUMO
It has been estimated that proximal tubule are responsible for about 7.5% of total kidney prostaglandin PGE2 production. In the present report we investigated the production of prostanoids and thromboxane by rabbit renal proximal tubule brush border membrane. PGF2 alpha was the major endogenous prostaglandin produced under basal condition. The addition of exogenous arachidonic acid increased only PGE2 production. No PGE2 production was found when vesicles were incubated with indomethacin or at 4 degrees C, suggesting the involvement of the PGH2 synthase and PGE2 isomerase enzymes. Addition of angiotensin II at 10(-6) and 10(-9) mol l-1 did not affect the endogenous PGE2 production by brush border membrane. Thus, results of our study demonstrates that the renal proximal tubule brush border membrane has the capacity to produce prostanoids and thromboxane.
Assuntos
Angiotensina II/farmacologia , Rim/metabolismo , Prostaglandinas/biossíntese , Tromboxanos/biossíntese , Animais , Técnicas In Vitro , Rim/efeitos dos fármacos , Microvilosidades/efeitos dos fármacos , Microvilosidades/metabolismo , CoelhosRESUMO
Diabetes Mellitus in its early stages, is associated with kidney enlargement and increased glomerular filtration rate in humans and in rats. The present study was designed to clarify the direct effect of diabetes on serum and tissue angiotensin converting enzyme (ACE) activity in streptozotocin-induced diabetic rats. Serum ACE activity, as determined using a radiometric assay, was significantly increased in the diabetic rats (n = 15) 14 days after induction of diabetes (670 +/- 31 vs. 506 +/- 14 nmol ml-1 min-1). Lung ACE activity, but not renal, was significantly elevated at 7 and 14 days by 29 and 46%, respectively. Plasma renin activity in the diabetic rats was decreased at 7 and 14 days by 41 and 78%, respectively. Incubations of lung slices in the presence of glucose at different concentrations did not affect in-vitro release of the enzyme. Administration of insulin (8 units kg-1) to diabetic rats (n = 6) on the 4th day for 11 days reduced ACE activity to values below control. Thus, serum and lung ACE activity is increased in the diabetic rat and reduced upon insulin treatment.
Assuntos
Diabetes Mellitus Experimental/enzimologia , Rim/enzimologia , Pulmão/enzimologia , Peptidil Dipeptidase A/metabolismo , Animais , Insulina/farmacologia , Masculino , Peptidil Dipeptidase A/sangue , Ratos , Ratos Wistar , Renina/sangueRESUMO
Serum angiotensin-converting enzyme (ACE) was measured in 150 insulin-dependent diabetes mellitus (IDDM) patients and 72 healthy subjects by radioassay, using [3H]-hippuryl-glycyl-glycine as a substrate. Mean (SD) serum ACE activity in diabetic patients was 120 +/- 33 nmol ml-1 min-1 (range 46-215) and was significantly increased by 56% compared to control values (77 +/- 23 nmol ml-1 min-1, range 46-125, P < 0.001). ACE activity > 125 nmol ml-1 min-1 was observed in 60 of 150 IDDM patients. 96 IDDM patients were normoalbuminuric (< 22 mg 24 h-1) and 49 patients were micro- or macroalbuminuric (range 22-6010 mg 24 h-1). Micro- and macroalbuminuric IDDM patients were found to have significantly greater ACE activity values than normoalbuminuric patients (128 +/- 36 vs. 115 +/- 30 nmol ml-1 min-1, P = 0.025). Metabolically well-controlled IDDM patients (glycosylated haemoglobin < or = 8%) had lower ACE activity values than the patients with glycosylated haemoglobin greater than 8% (109 +/- 20 vs. 127 +/- 32 nmol ml-1 min-1, P < 0.02). A significant correlation between degree of metabolic control and ACE activity was found (r = 0.435, P < 0.001) so that an increase in one glycosylated quartile unit is accompanied by an increase in ACE activity of 10.5 nmol ml-1 min-1. Thus ACE activity in the serum of IDDM patients was increased by 56% in 40% of the patients. It was increased in IDDM patients without complications and in patients with retinopathy or nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Diabetes Mellitus Tipo 1/enzimologia , Nefropatias Diabéticas/enzimologia , Retinopatia Diabética/enzimologia , Peptidil Dipeptidase A/sangue , Adolescente , Adulto , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologia , Retinopatia Diabética/sangue , Retinopatia Diabética/etiologia , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Serum and lung angiotensin-converting enzyme (ACE) activity is increased in the streptozotocin (STZ)-diabetic rat. In the present study, the effect of insulin treatment on this increased ACE activity in the STZ-diabetic rat was investigated. Serum and tissue ACE activity was determined by radiometric assay using [3H]-Hippuryl-glycyl-glycine as substrate. Fifteen days after onset of diabetes (n = 16), 8 rats received insulin daily (6-12 units/kg, s.c.) for 33 days, 8 diabetes rats remained untreated. Control, non-diabetic, rats (n = 8) received saline. The baseline serum ACE activity in the control group was 595 +/- 13 nmol/ml/min and did not change significantly throughout the study. However, serum ACE activity in the untreated diabetic rats increased significantly as of day 14 post-STZ (650 +/- 24 nmol/ml/min, p < 0.001) compared to the corresponding values of the control group and compared to baseline values. Insulin administration to diabetic rats starting on day 15 post-STZ caused a gradual reduction in serum ACE activity to basal values, being (527 +/- 22 nmol/ml/min) at day 47. ACE activity in lungs of untreated diabetic rats was increased by 46%, 47 days post-STZ. Insulin treatment reduced lung ACE activity to values similar to those observed in non-diabetic rats. These changes were associated with reduced kidney weight and urine volume. In summary, insulin administration to hyperglycaemic rats resulted in a reduction in the enhanced serum and lung ACE activity to values seen in non-diabetic rats. Normalizing the activity of the renin-angiotensin system may slow or prevent the glomerular hypertension, a major factor in the development of diabetic nephropathy.