enalapril and Atrophy

The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.

Topics: Animals; Antihypertensive Agents; Atrophy; Benzimidazoles; Benzoates; Bone Density; Enalapril; Female; Mice; Mice, Inbred C57BL; Ovariectomy; Propranolol; Telmisartan; Thiazides; Tibia; Tomography, X-Ray Computed; Uterus

Neonatal inhibition of the renin-angiotensin system [angiotensin-converting enzyme (ACE) inhibition] in the rat results in long-term abnormal renal morphology and function, including interstitial inflammation and fibrosis. Hyaluronan (hyaluronic acid, HA) has pathological implications in inflammatory diseases and renal ischaemia-reperfusion injury. The present study aimed at determining if renal cortical HA in the adult rat is correlated to the abnormal morphology and function in rats treated neonatally with the ACE inhibitor enalapril. In adult control rats (23 weeks old), the cortical HA content was very low [about 5 microg g(-1) dry weight (d.w.)] and about 1% of the papillary HA content. In rats treated neonatally with enalapril (days 3-13), the cortical HA level was 15 times that in control rats already at 21 days after birth, and it persisted at this level during adulthood (at 23 weeks). At 13 weeks the enalapril-treated animals showed markedly reduced ability (-53%) to concentrate urine during 24-h thirst provocation. At 21 days as well as at 23 weeks the enalapril-treated kidneys displayed morphological changes, such as papillary atrophy, dilation of the tubules and cellular infiltration of the cortical tissue. Histochemical staining confirmed the HA quantification assay and revealed a patchy staining for HA located in the same regions as the infiltrating cells. In conclusion, neonatal treatment with the ACE inhibitor enalapril results in renal morphological and functional abnormalities during adulthood. Cortical HA levels are already seriously elevated at day 21 and coexist with infiltrating cells. Besides the known effects of angiotensin II in development, the accumulation of HA in these kidneys may be involved in the genesis of at least the cortical abnormalities in enalapril-treated animals because of the proinflammatory effects and water-binding properties of HA.

Topics: Age Factors; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Atrophy; Enalapril; Hyaluronic Acid; Kidney Concentrating Ability; Kidney Cortex; Kidney Tubules; Male; Rats; Rats, Wistar; Thirst

Unilateral ureteral obstruction (UUO) is a model of renal injury characterized by progressive tubulointerstitial fibrosis and renal damage, while relatively sparing the glomerulus and not producing hypertension or abnormalities in lipid metabolism. Tubulointerstitial fibrosis is a major component of several kidney diseases associated with the progression to end-stage renal failure. Here we report that when a critical renal developmental morphogen, osteogenic protein-1 (OP-1; 100 or 300 microg/kg body wt), is administered at the time of UUO and every other day thereafter, interstitial inflammation and fibrogenesis are prevented, leading to preservation of renal function during the first 5 days after obstruction. Compared with angiotensin-converting enzyme inhibition with enalapril treatment, OP-1 was more effective in preventing tubulointerstitial fibrosis and in preserving renal function. The mechanism of OP-1- induced renal protection was associated with prevention of tubular atrophy, an effect not shared with enalapril, and was related to preservation of tubular epithelial integrity. OP-1 blocked the stimulation of epithelial cell apoptosis produced by UUO, which promoted maintenance of tubular epithelial integrity. OP-1 preserved renal blood flow (RBF) during UUO, but enalapril also stimulated RBF. Thus OP-1 treatment inhibited tubular epithelial disruption stimulated by the renal injury of UUO, preventing tubular atrophy and diminishing the activation of tubulointerstitial inflammation and fibrosis and preserving renal function.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Atrophy; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Cell Size; Collagen; Enalapril; Epithelial Cells; Fibrosis; Immunohistochemistry; Inflammation; Kidney; Macrophages; Rats; Rats, Sprague-Dawley; Renal Circulation; Transforming Growth Factor beta; Ureteral Obstruction

Hyperoxaluria is a recognized cause of tubulointerstitial lesions, and this could contribute to development of hypertension and chronic renal failure. Enalapril has been effective against the progression of tubulointerstitial lesions in various animal models. The aim of the present study was to evaluate the usefulness of enalapril on the tubulointerstitial damage produced by oxalates. Two-month-old male Sprague-Dawley rats were separated into 4 groups, control with tap water (G1), hyperoxaluric (G2), hyperoxaluric+enalapril (G3), enalapril (G4), for 4 weeks. G2 and G3 rats were given 1% ethyleneglycol (ETG, precursor for oxalates), and G3 and G4 rats were given enalapril 20 mg/L in drinking water. At the end of the study, we evaluated renal tubulointerstitial lesions by a semiquantitative score. Urine albumin excretion, serum and urine nitric oxide production, tubulointerstitial immunostaining by alpha-smooth muscle actin, transforming growth factor-beta1, and collagen type III were measured. Rats belonging to the hyperoxaluric group treated with enalapril (G3) showed fewer tubulointerstitial lesions (1.3+/-0.2 versus 3+/-0.2; P<0.01), lower urine albumin excretion (8+/-2 mg/d versus 25+/-2 mg/d; P<0.01), less percentage of alpha-smooth muscle actin in renal interstitium (2+/-0.4% versus 13.5+/-2.4%; P<0.01), less percentage of transforming growth factor-beta1 in tubulointerstitial area (3.3+/-1% versus 13.3+/-2. 1%; P<0.01), less percentage of collagen type III interstitial deposition (0.7+/-0.5% versus 7+/-2.6%; P<0.01), and increased NO production in serum as well as urine (both P<0.01), when compared with the hyperoxaluric group not treated with enalapril (G2). Considering these data, we believe that enalapril, by several mechanisms of action, could provide an important benefit in the prevention of inflammatory response, transforming growth factor-beta1 tubulointerstitial production, collagen type III interstitial deposition, and finally, the progressive tubulointerstitial fibrosis caused by oxalates.

Topics: Animals; Atrophy; Blood Pressure; Enalapril; Hyperoxaluria; Kidney Tubules; Male; Nephritis, Interstitial; Oxalates; Rats; Rats, Sprague-Dawley; Time Factors

The inability to separate irreversible lesions of tubular epithelia from reversible tubular atrophy constitutes a major problem in histopathology and in decisions for revascularization of shrunken kidneys with renal artery stenosis. In order to characterize reversible tubular atrophy ('kidney hibernation') we studied the physiological and biochemical parameters and morphology including histochemistry in rat kidneys made atrophic by renal artery stenosis and treatment with the angiotensin-converting enzyme inhibitor, enalapril. Renal artery stenosis was induced by a 0.2-mm clip around the left renal artery. Following 7 weeks of clipping and 2 concomitant weeks of enalapril treatment, the kidney length decreased from 17.8 +/- 0.3 to 13.7 +/- 0.7 mm (mean +/- SEM). Renal blood flow and glomerular filtration rate decreased to 39 +/- 3% and to approximately 3% of control values, respectively. The activities of the intracellular proteolytic enzymes cathepsin B and L and of Na-K-ATPase in microdissected proximal tubular segments decreased to values below 50 and 10%, respectively. All changes were significant (p < 0.05). Histochemical staining for ATPase activity in the distal tubule segments remained unchanged. Tubular cells were atrophic but not necrotic. Histochemical staining of alkaline phosphatase in the tubular brush border and of acid phosphatase and peroxidase in lysosomes was greatly reduced. All observed changes were reversible within 2-3 weeks following removal of the clip and withdrawal of enalapril either with or without contralateral nephrectomy. Thus, a form of kidney hibernation with readily reversible tubular atrophy has been described. Based on this description it may be possible in consecutive experiments to differentiate between reversible and irreversible tubular atrophy.

Topics: Acid Phosphatase; Alkaline Phosphatase; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrophy; Cathepsins; Enalapril; Glomerular Filtration Rate; Hemodynamics; Hibernation; Hypertension, Renovascular; Kidney; Kidney Tubules; Male; Rats; Rats, Wistar; Renal Artery Obstruction; Renal Circulation; Sodium-Potassium-Exchanging ATPase

Earlier experiments have shown that in sodium depleted hypertensive rats with bilaterally constricted renal arteries the arterial pressure normalized after blockade of the renin-angiotensin system; simultaneously acute renal failure occurred. In hypertensive rats with unilateral renal artery stenosis an impaired excretory function of the clipped kidney can be expected, but may not be detectable by conventional tests of renal function. Male Wistar rats with chronic two kidney, one clip hypertension were fed a low sodium diet. After 7 days the rats were treated with vehicle, with the vasodilator dihydralazine, or with the angiotension converting enzyme inhibitor MK 421 for 2 weeks. During the 14-day treatment period a continuous blood pressure reduction was achieved in dihydralazine and MK 421 treated rats. Overall excretory kidney function (plasma creatinine concentration) was well maintained in all three groups until the end of the antihypertensive drug treatment. At the end of drug therapy mean glomerular filtration rates of the left clipped kidneys were significantly lower in both treated groups compared to hypertensive controls, and mean glomerular filtration rate of the left clipped kidneys of dihydralazine treated rats was significantly higher than in MK 421 treated rats: controls (N = 6) 1.03 +/- 0.03, dihydralazine-group (N = 10) 0.28 +/- 0.07, MK 421-group (N = 9) 0.03 +/- 0.01 ml/min. Renal blood flows were comparable in both treated groups. Only the left kidneys of rats treated with MK 421 showed a prominent tubular atrophy. Seven days after declipping of the left renal artery and right nephrectomy a considerable restitution of the tubular structure had occurred in the MK 421-group. The recovery of tubular epithelial cells was paralleled by a rise in glomerular filtration rate: MK 421 group (N = 7) 1.25 +/- 0.08 ml/min. Thus, the clipped kidney in two kidney, one clip hypertensive rats showed functional and morphological signs of impairment when systemic arterial pressure was reduced to the normal range. The alterations of the clipped kidney were most pronounced in rats with renin-angiotensin system-blockade.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrophy; Creatinine; Dihydralazine; Enalapril; Epithelium; Glomerular Filtration Rate; Hypertension, Renovascular; Kidney; Kidney Tubules; Male; Microscopy, Electron; Rats; Rats, Inbred Strains; Renal Circulation; Urea