RESUMO
The effects of nifedipine and enalapril on age-associated renal interstitial fibrosis were investigated in 60 CF1 female mice. Mice received 20 mg enalapril (ENAL) per L (N = 20), or 40 mg nifedipine (NIF) per L (N = 20) in their drinking water. Control (CONT) mice received tap water ad libitum. The percentages of both interstitial peritubular sclerosis (IPS) in cortex and interstitial medullary sclerosis (IMS) were determined. Kidney tissue was studied using immunological techniques and optical (OM) and electron microscopy (EM) to analyze the expression of renin. alpha-SM-actin and vimentine expression were also evaluated. The results showed that blood pressure levels in ENAL or NIF animals were not different from those of CONT. Renin expression was observed in arcuate vessels (AV) in ENAL animals, whereas no renin staining in AV was found in either NIF or CONT animals. Renin immunoreactivity in the juxtaglomerular apparatus was more intense in ENAL mice, as compared with NIF or CONT animals. Laboratory testing showed the following values: proteinuria (mg/mL): CONT 6.1 +/- 0.6, NIF 11.2 +/- 2.3, and ENAL 1.0 +/- 0.6 (P < 0.05); creatinine: CONT 1.37 +/- 0.24, NIF 0.87 +/- 0.16, and ENAL 0.63 +/- 0.1 (P < 0.01). The percentages of interstitial sclerosis were: %IPS: CONT 18.12 +/- 1.1, NIF 17.40 +/- 0.9, and ENAL 3.42 +/- 1.3 (P < 0.01); %IMS: CONT 23.41 +/- 1.5, NIF 21.80 +/- 1.9, and ENAL 6.12 +/- 1.2 (P < 0.01). Percentages of alpha-SM-actin expression were: CONT 13.10 +/- 1.9, NIF 13.80 +/- 0.2, and ENAL 1.00 +/- 0.1 (P < 0.01). Vimentine staining showed no differences among the groups. It was concluded that enalapril reduces the peritubular and medullar interstitial fibrosis, whereas nifedipine has no effect.
Assuntos
Envelhecimento/patologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Enalapril/uso terapêutico , Rim/patologia , Nifedipino/uso terapêutico , Actinas/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Biomarcadores , Bloqueadores dos Canais de Cálcio/farmacologia , Enalapril/farmacologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Fibrose , Rim/efeitos dos fármacos , Camundongos , Nifedipino/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Esclerose , Vimentina/metabolismoRESUMO
We have characterized the effect of angiotensin converting enzyme (ACE) inhibitors on the activity of CuZn-superoxide dismutase (CuZn-SOD), Mn-superoxide dismutase (Mn-SOD), catalase, and selenium-dependent glutathione peroxidase (Se-GPx). CF1 mice (4-month-old females) were administered water containing enalapril (20 mg/l) or captopril (50 mg/l), during 4 to 11 weeks. After 11 weeks, enalapril treatment caused an increase in the activity of CuZn-SOD, Mn-SOD and Se-GPx, from 19 +/- 4 to 46 +/- 7, 2.1 +/- 0.2 to 3.8 +/- 0.2 units/mg protein and 27 +/- 3 to 54 +/- 3 milliunits/mg protein, respectively. After 11 weeks, captopril treatment increased the activities (P < 0.05) of CuZn-SOD, MnSOD and Se-GPx to 35 +/- 4, 2.9 +/- 0.2 units/mg protein, and 38 +/- 2 milliunits/mg protein, respectively. Catalase activity was not affected by the treatments. These results suggest that ACE inhibitors may protect cell components from oxidative damage by increasing the enzymatic antioxidant defenses.
Assuntos
Captopril/farmacologia , Enalapril/farmacologia , Glutationa Peroxidase/metabolismo , Fígado/enzimologia , Superóxido Dismutase/metabolismo , Animais , Catalase/metabolismo , Feminino , Fígado/efeitos dos fármacos , CamundongosRESUMO
We studied four groups of 20 female mice to evaluate the long-term effect of an angiotensin-converting enzyme on myocardium and vessels during the natural process of aging. Three groups received enalapril in water from weaning to 24 months of age (group A, 20 mg/L; group B, 10 mg/L; group C, 5 mg/L); group D served as a control. Animals surviving after 24 months were killed, and morphometric studies were performed. Total corporal weight was higher in animals receiving enalapril. Cardiac weight relative to total body weight was lower in the treated groups than in the control group. Cardiac morphometric studies showed lower myocardiosclerosis in animals receiving angiotensin-converting enzyme inhibitor (groups A through D, respectively, 0.9 +/- 0.6%, 1.1 +/- 0.2%, 1.03 +/- 0.1%, and 9.5 +/- 4.3%; P < .01, groups A, B, and C versus D). The number of mitochondria per myocardiocyte was higher in the groups receiving enalapril (A through D, respectively, 85 +/- 7, 85 +/- 6, 83 +/- 8, and 58 +/- 8; P < .01, groups A, B, and C versus D). At the vascular level, vessel diameters were not significantly different between the groups receiving angiotensin-converting enzyme inhibitor and the control group, whereas differences were seen in arterial tunica media thickness (wall-lumen ratio) (groups A through D, respectively, aorta: 0.13 +/- 0.02, 0.11 +/- 0.02, 0.12 +/- 0.01, 2.81 +/- 0.35; intrapulmonary: 0.9 +/- 0.43, 0.6 +/- 0.41, 0.8 +/- 0.46, 1.9 +/- 0.51; intracerebral: 2.18 +/- 0.46, 2.29 +/- 0.45, 2.46 +/- 0.43, 3.30 +/- 0.41; intrarenal: 2.28 +/- 0.46, 2.73 +/- 0.48, 2.70 +/- 0.51, 3.23 +/- 0.41; intracariaciac: 2.27 +/- 0.44, 2.59 +/- 0.41, 2.80 +/- 0.43, 3.68 +/- 0.47; P < .001, groups A, B, and C versus D).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Envelhecimento/fisiologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Fenômenos Fisiológicos Cardiovasculares , Sistema Cardiovascular/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Animais , Vasos Sanguíneos/patologia , Sistema Cardiovascular/patologia , Enalapril/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos , Miocárdio/patologia , Fatores de TempoRESUMO
To evaluate the effects of angiotensin-converting enzyme inhibition on renal aging, enalapril was administered in the drinking water to three groups of CF1 mice at doses of 20 mg/L (Group A), 10 mg/L (Group B), and 5 mg/L (Group C). These experimental groups were compared with 20 CF1 mice not receiving enalapril (Group D). At 2 yr, total body weight was 48.1 +/- 7.5 g in Group A, 47.7 +/- 7.1 g in Group B, 47.6 +/- 4.6 g in Group C, and 35.1 +/- 5.4 g in Group D. The ratio of kidney to total body weight, in percentages, was 1.8 +/- 0.3, 1.6 +/- 0.3, 1.9 +/- 0.2, and 1.5 +/- 0.1 in Groups A, B, C, and D, respectively. Morphometric studies of the kidneys revealed the glomerular diameter to be 86.7 +/- 18.0 microns, 96.9 +/- 6.3 microns, 91.1 +/- 11.4 microns, and 106.8 +/- 9.3 microns in Groups A, B, C, and D, respectively. The number of glomeruli per square millimeter of renal cortex was 9.6 +/- 3.7, 12.3 +/- 2.7, 12.4 +/- 8.6, and 3.2 +/- 1.5 in Groups A, B, C, and D, respectively. The mesangial area per glomerulus, in percentages, was 11.6 +/- 4.8, 13.9 +/- 2.9, 14.2 +/- 3.1, and 20.6 +/- 1.9 in Groups A, B, C, and D, respectively. The percentage of glomeruli with sclerosis was 0.1 +/- 0.1, 0.3 +/- 0.1, 0.6 +/- 0.2, and 11.6 +/- 1.9 in Groups A, B, C, and D, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Enalapril/farmacologia , Glomerulosclerose Segmentar e Focal/prevenção & controle , Envelhecimento/patologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Feminino , Mesângio Glomerular/efeitos dos fármacos , Mesângio Glomerular/patologia , Glomerulosclerose Segmentar e Focal/patologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
To determine whether chronic treatment with enalapril initiated early in life prevents glomerular injury secondary to normal aging, CF1 mice received enalapril (20 mg/L, n = 10) or nifedipine (40 mg/L, n = 10) in their drinking water from the time of weaning to 12 months of life. Control mice (n = 10) received tap water ad libitum. Immunocytochemical detection of renin confirmed that angiotensin-converting enzyme inhibition resulted in recruitment of renin-containing cells along the preglomerular vessels. Morphometric analysis of glomeruli included assessment of glomerular diameter and the percentage of mesangial area per glomerulus. Glomerular diameter and mesangial area were higher in control mice (99.7 +/- 0.5 microns, 12.7 +/- 0.3%) than in enalapril-treated mice (88 +/- 0.8 microns, 8.6 +/- 0.6%) (P < .05). Glomerular diameter and mesangial area in the nifedipine-treated group (99.1 +/- 0.9 microns, 12.4 +/- 0.9%) were not different from control mice. These results demonstrate that angiotensin-converting enzyme inhibition prevents the glomerular enlargement and mesangial expansion observed during natural aging. In addition, control glomeruli expressed alpha-smooth muscle actin in a mesangial distribution. This effect was prevented by enalapril treatment but not by nifedipine. We conclude that long-term treatment with enalapril from early life prevents the early changes associated with glomerular injury and expression of alpha-smooth muscle actin in the glomerulus. alpha-Smooth muscle actin may participate in and serve as an early marker of the glomerular injury during the normal aging process.
Assuntos
Actinas/metabolismo , Envelhecimento/metabolismo , Glomérulos Renais/metabolismo , Músculo Liso/metabolismo , Animais , Enalapril/farmacologia , Camundongos , Camundongos Endogâmicos , Nifedipino/farmacologia , Valores de Referência , Distribuição TecidualRESUMO
A study was performed on renin synthesis in order to evaluate changes that occur in renal cells during angiotensin-converting enzyme chronic inhibition of Ang I in mice. Immediately after weaning, 20 CF1 mice received 20 mg/l enalapril maleate in drinking water during 16 months; this group was compared with a control group. Kidney tissue was processed and studies using optical and electron microscope immunochemical techniques were performed. An antirenin antibody was used, and in situ hybridization was performed to keep track of renin mRNA with a digoxygenin-marked probe. We calculated the number of juxtaglomerular apparatus (JGA), afferent arterioles (AA) and arcuate vessels (AV) immunomarked (IM) with antirenin and antidigoxygenin. These parameters were rendered in JGA rates (%IMJGA) and AA (%IMAA) and AV (%IMAV) marked rates (%AV), and in the rate of JGA (%SJGA), AA (%SAA) and AV (%SAV) hybridization signs. Electron microscope readings were used to determine the number of gold particles per renin granule. An increase in the number of renin-producing cells was observed in animals having received enalapril chronically, beyond AJG and AA, since marking was observed in arcuate vessels. The mean %MJGA value was lower in control animals (65.6% +/- 2.4) than in treated animals (94.2% +/- 3 p < 0.05). Similar findings occurred with %MAA: 23.6% +/- 3, (control animals) vs. 41.6% +/- 2.3, p < 0.05 (treated animals). AV were not marked in the control group, as they were in treated animals where %MAV was 4.4% +/- 1.6. The mRNA distribution was different in animals with RAS inhibition as compared with control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Angiotensina II/farmacologia , Angiotensina I/antagonistas & inibidores , Enalapril/farmacologia , Rim/citologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Renina/biossíntese , Animais , Feminino , Rim/efeitos dos fármacos , Rim/metabolismo , Camundongos , Sistema Renina-Angiotensina/fisiologiaRESUMO
A study was performed on renin synthesis in order to evaluate changes that occur in renal cells during angiotensin-converting enzyme chronic inhibition of Ang I in mice. Immediately after weaning, 20 CF1 mice received 20 mg/l enalapril maleate in drinking water during 16 months; this group was compared with a control group. Kidney tissue was processed and studies using optical and electron microscope immunochemical techniques were performed. An antirenin antibody was used, and in situ hybridization was performed to keep track of renin mRNA with a digoxygenin-marked probe. We calculated the number of juxtaglomerular apparatus (JGA), afferent arterioles (AA) and arcuate vessels (AV) immunomarked (IM) with antirenin and antidigoxygenin. These parameters were rendered in JGA rates (
IMJGA) and AA (
IMAA) and AV (
IMAV) marked rates (
AV), and in the rate of JGA (
SJGA), AA (
SAA) and AV (
SAV) hybridization signs. Electron microscope readings were used to determine the number of gold particles per renin granule. An increase in the number of renin-producing cells was observed in animals having received enalapril chronically, beyond AJG and AA, since marking was observed in arcuate vessels. The mean
MJGA value was lower in control animals (65.6
+/- 2.4) than in treated animals (94.2
+/- 3 p < 0.05). Similar findings occurred with
MAA: 23.6
+/- 3, (control animals) vs. 41.6
+/- 2.3, p < 0.05 (treated animals). AV were not marked in the control group, as they were in treated animals where
MAV was 4.4
+/- 1.6. The mRNA distribution was different in animals with RAS inhibition as compared with control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
RESUMO
To investigate the effects of angiotensin-converting enzyme (ACE) inhibitors on the cellular function and structure in a variety of organs during the aging process, one hundred CF1 mice were divided into four groups of 25 animals each. Groups A, B, and C received enalapril in drinking water from weaning until the age of 24 mo. Doses administered were (in mg/l): group A, 20; group B, 10; group C, 5. Group D is the control. Animals were killed, and morphometric studies were performed in heart, kidney, liver, and spleen. As a result, there was a decrease of renal and myocardial sclerosis and an increase in the number of mitochondria in heart and liver cells, which is associated with a significant increase in survival of animals receiving ACE inhibitors. These findings lead us to think that natural aging mechanisms have been altered in those animals.