Effect of spironolactone and captopril on nitric oxide and S-nitrosothiol formation in kidney of L-NAME-treated rats

Although angiotensin-converting enzyme (ACE) inhibitors are well-established drugs in the treatment of hypertension, they are not supposed to be sufficient in the inhibition of aldosterone formation. The present study analyzes the effect of aldosterone receptor antagonist, spironolactone and ACE inhibitor, captopril on nitric oxide (NO) and S-nitrosothiol formation in the kidney of N(G)-nitro-L-arginine methyl ester (L-NAME)-treated rats. Male Wistar rats were divided into six groups: (1) controls, (2) L-NAME (40 mg/kg/day), (3) spironolactone (200 mg/kg/day), (4) captopril (100 mg/kg/day), (5) L-NAME+spironolactone, and (6) L-NAME+captopril. After 4 weeks, NO synthase (NOS) activity, protein expression of endothelial NOS, inducible NOS and concentration of thiol and S-nitrosothiol groups were determined in the kidney. Besides the increase in systolic blood pressure (by 32%) and the decrease in NOS activity (by 37%), L-NAME treatment lowered the concentration of thiols (by 32%) and S-nitrosothiols (by 36%) in the renal tissue. Simultaneous treatment with spironolactone preserved NOS activity and S-nitrosothiols on the control level, whereas captopril did not affect these parameters modified by L-NAME treatment. Moreover, spironolactone increased expression of endothelial NOS protein without affecting inducible NOS protein expression. In conclusion, both captopril and spironolactone prevented L-NAME-induced hypertension and the decline of the antioxidant potential of the kidney tissue. However, only spironolactone improved NOS activity which led to the S-nitrosothiols formation. Both NO itself and S-nitrosothiols may contribute to the preventive effect of spironolactone against development of L-NAME-induced hypertension.     

Renal haemodynamics and organ damage in young hypertensive patients with different plasma renin activities after ACE inhibition.

We describe our observations concerning differences in two groups of young hypertensive patients according to their renin activities after ACE inhibition. Seventeen of these patients (age 26 +/- 7 years), so far untreated, were investigated prospectively for hormone levels (renin, aldosterone, vasopressin), microalbuminuria, renal haemodynamics (inulin and PAH clearance) and signs of organ damage (echocardiography, fundoscopy). Secondary forms of hypertension were excluded by routine methods, including angiography. We differentiated two groups of young hypertensive patients. Group 1 (n = 9) had a false positive captopril test with elevated renin activities after ACE inhibition with captopril (8.4 +/- 5 ng/ml per hour) compared to group 2 (renin activity: 2.2 +/- 1.3 ng/ml per hour) or an increase of greater than 400% of renin activity after ACE inhibition. Baseline renin activities and sodium excretion did not differ between the groups. Group 1 also showed significantly greater GFR, FF, and microalbuminuria, as well as signs of organ damage, with left ventricular hypertrophy and hypertensive changes in fundoscopy. There were no differences between the groups concerning mean arterial blood pressure and duration of hypertension. In conclusion, we were able to demonstrate that patients with highly stimulated renin activities showed signs of visceral organ damage and renal hyperfiltration compared to the normal renin activity group after ACE inhibition. Investigations of the renin-angiotensin-aldosterone system with ACE inhibitors might constitute a helpful indicator of renal changes and organ damages in young hypertensive patients.     

EFFECTS OF NITRIC OXIDE SYNTHESIS INHIBITION ON FK506-INDUCED NEPHROTOXICITY IN RATS

This study was designed to evaluate the role of nitric oxide (NO) in FK506-induced nephrotoxicity by administering an inhibitor of NO synthesis, Nω-nitro-L-arginine methyl ester (L-NAME) to rats treated with FK506. After one week of treatment with FK506 (3.2 mg/kg/day, intramuscularly) and/or L-NAME (5 mg/100 mL of L-NAME in the drinking water), the arterial pressure, urinary NOx, and parameters for renal function were measured, and histological analysis of the kidney was made. In the L-NAME without FK506 group, L-NAME administration effectively inhibited urinary NOx excretion and increased mean arterial pressure (MAP) without any change in renal function. In the FK506 without L-NAME group, FK506 treatment showed increase in urinary NOx excretion and mild renal dysfunction. In the FK506 with L-NAME group, urinary NOx excretion was decreased by L-NAME administration and renal function was significantly worsened than FK506 without L-NAME group. The plasma creatinine, BUN and urinary N-acetyl-β-D-glucosaminidase increased 2-, 3-, and 3-fold, respectively and the creatinine clearance was reduced by 50% as compared with that in the FK506 without L-NAME group. Histological analysis revealed severe interstitial fibrosis and tubular atrophy in the FK506 + L-NAME treatment group. Thus, results suggest that NO synthesis is enhanced in the kidney during FK506-induced nephrotoxicity and that NO synthesis inhibition aggravates FK506-induced nephrotoxicity. NO may play a protective role attributable to the balance of vasoactive substances in FK506-induced nephrotoxicity.     

Reduction of albuminuria after angiotensin converting enzyme inhibition in various renal disorders

The urinary albumin excretion measured by the albumin creatinine clearance ratio (Calb/Ccreat) and the mean supine arterial blood pressure (MAP) were studied before the start of ACE inhibition, at the start and during up to 1 year of ACE inhibition with Captopril or Enalapril in 35 patients with various chronic proteinuric renal disorders with or without renal failure, arterial hypertension and nephrotic syndrome. Before the start of ACE inhibition mean Calb/Ccreat, MAP, s-albumin and s-creatinine did not change. During ACE inhibition the Calb/Ccreat was reduced from 75% (p less than 0.05) in patients with minimal albuminuria to 41% (p less than 0.005) in patients with extensive albuminuria. Average reduction of albuminuria was 44% at one year's observation time. Serum albumin increased 9% (p less than 0.05), serum creatinine did not change significantly and MAP showed a slight, not uniformly significant decrease. The reduction of Calb/Ccreat was of the same order in the different renal disorders studied and was independent of the renal function, presence or absence of nephrotic syndrome and treatment with antihypertensive or immunosuppressive drugs. The decrease in Calb/Ccreat during ACE inhibition was related to the reduction in MAP at most time intervals, but Calb/Ccreat decreased also when MAP was unchanged or increased. Thus the decrease in Calb/Ccreat during ACE inhibition does not only seem to be a consequence of a decrease in the systemic arterial blood pressure but reasonably also due to changes in the intra-renal hemodynamics and most probably a decrease in the glomerular capillary pressure.     

Reversal of renal lesions following interruption of nitric oxide synthesis inhibition in transgenic mice.

BACKGROUND: Renal fibrosis, a common complication of hypertension and diabetes is considered as a non-curable disease and is characterized by the abnormal accumulation of collagen I within the kidney. Chronic inhibition of nitric oxide (NO) synthesis is a model of hypertension associated with the development of nephroangiosclerosis. The present study investigated whether halt of NO inhibition leads to the regression of renal sclerotic lesions. METHODS: The NO deficiency (N(G)-nitro-L-arginine methylester; L-NAME) model of hypertension was applied in transgenic mice harbouring the luciferase reporter gene under the control of the collagen I-alpha2 chain promoter. RESULTS: Systolic pressure gradually increased following the administration of L-NAME, and reached 160 mmHg after 8-10 weeks. Activation of collagen I gene within the renal vasculature preceded the blood pressure increase and was accompanied by the appearance of sclerotic glomeruli and tubulointerstitial infiltration. After renal lesions had been established (20 weeks), animals were divided in three subgroups for an additional experimental period of 10 weeks: first group continued to receive L-NAME, in the second, L-NAME administration was stopped to allow endogenous NO synthesis and in the third the removal of L-NAME was combined with endothelin receptor antagonism. Removal of L-NAME decreased, without normalizing, systolic pressure and collagen I gene activity; renal morphology was substantially improved, and tubulointerstitial infiltration disappeared. Combination of L-NAME removal with endothelin antagonism normalized collagen I gene expression and further improved renal morphology without further decreasing blood pressure. CONCLUSION: Manipulating the balance between NO/vasoconstrictors in favour of NO could provide a curative approach against renal inflammatory and fibrotic complications associated to hypertension.     

Comparison of the influence of general and regional anesthesia on basic haemodynamic parameters during carotid endarterectomy

Carotid endarterectomy (CEA) is a preventive operation to reduce the incidence of embolic and thrombotic cerebral stroke. CEA carries a significant perioeperartive mortality rate from stroke and myocardial infarction, which may even approach 5%. Thus, anesthetic and surgical techniques are constantly under scrutiny to try to reduce this relatively high incidence of morbidity and mortality. Anesthetic technique for CEA is divided to general (GA) and regional (RA) anesthesia, performed by cervical plexus block. The aim this study was to examine changes of basic haemodynamic parameters, which routinely fallows during CEA in condition of GA and RA. After obtaining institutional approval and informed consent, we randomized 50 patients scheduled for CEA (Tab. 1) in two groups (GA and RA). We fallow blood pressure: systolic (BPs), mean (BPm), diastolic (BPd), heart rate (HR), and RPP index at the examined patients. The examination performed in six control times: before induction of anesthesia (T1), 10 minutes after beginning of operation (T2), 5 minutes after cross clamping of arteria carotis (T3), 5 minutes after declamping arteria carotis (T4), 10 minutes (T5) and 2 hours after operation (T6). The results of study shows significant changes of blood pressure (BPs and BPm) and RPP index in T2 time in patinets undergoing GA. The changes occurred under influence of induction agent thiopental. These changes were in homeostatic range. In RA patinets, no haemodynamic changes registrated in control times. Therefore, from haemodynamic aspect RA was superior to GA.     

Effects of nitric oxide synthesis inhibition on FK506-induced nephrotoxicity in rats

This study was designed to evaluate the role of nitric oxide (NO) in FK506-induced nephrotoxicity by administering an inhibitor of NO synthesis, N omega-nitro-L-arginine methyl ester (L-NAME) to rats treated with FK506. After one week of treatment with FK506 (3.2 mg/kg/day, intramuscularly) and/or L-NAME (5 mg/100 mL of L-NAME in the drinking water), the arterial pressure, urinary NOx, and parameters for renal function were measured, and histological analysis of the kidney was made. In the L-NAME without FK506 group, L-NAME administration effectively inhibited urinary NOx excretion and increased mean arterial pressure (MAP) without any change in renal function. In the FK506 without L-NAME group, FK506 treatment showed increase in urinary NOx excretion and mild renal dysfunction. In the FK506 with L-NAME group, urinary NOx excretion was decreased by L-NAME administration and renal function was significantly worsened than FK506 without L-NAME group. The plasma creatinine, BUN and urinary N-acetyl-beta-D-glucosaminidase increased 2-, 3-, and 3-fold, respectively and the creatinine clearance was reduced by 50% as compared with that in the FK506 without L-NAME group. Histological analysis revealed severe interstitial fibrosis and tubular atrophy in the FK506 + L-NAME treatment group. Thus, results suggest that NO synthesis is enhanced in the kidney during FK506-induced nephrotoxicity and that NO synthesis inhibition aggravates FK506-induced nephrotoxicity. NO may play a protective role attributable to the balance of vasoactive substances in FK506-induced nephrotoxicity.     

Converting enzyme inhibition in chronic renal failure

Ten patients with chronic renal failure whose hypertension was controlled with triple drug therapy consisting of propranolol-hydralazine-furosemide were switched to the angiotensin-converting enzyme (ACE) inhibitor captopril for a period of 12 months. Control of hypertension was similar with both antihypertensive regimens. Clearance of inulin and of paraaminohippuric acid increased during the first 3 months of captopril therapy and remained stable thereafter. Moreover, the decline in the reciprocal of serum creatinine over time observed during triple drug therapy was arrested during therapy with the ACE inhibitor. If the salutary effects of captopril are sustained, the results obtained in the current studies would suggest that control of hypertension by ACE inhibition may be effective in slowing progression of renal failure. Future studies to answer this important question are necessary.     

Physical training increases renal injury in rats with chronic NOS inhibition

Nitric oxide (NO) is involved in regulation of vascular tone and renal hemodynamics. Inhibition of NO synthase (NOS) by Nomega-nitro-L-arginine methyl ester (L-NAME) promotes systemic hypertension and glomerular damage. Exercise is effective in reducing elevated blood pressure in hypertensive individuals and rats treated with L-NAME. We investigated the effects of regular aerobic exercise on renal injury in hypertensive rats with NOS inhibition. Adult Wistar rats were divided into four groups: sedentary or exercising, nonhypertensive (two groups) and hypertensive, sedentary or exercising (two groups). Treadmill running exercise was prolonged for 4 weeks (60 min.day(-1), 5 days/week, 20 m.min(-1), no incline), and hypertension was induced by L-NAME given orally to rats for 4 weeks (25 mg.kg(-1).day(-1) in drinking water). Blood pressure was monitored at baseline and then once a week throughout L-NAME administration. Kidney sections were examined for renal histopathology. Hypertensive animals exhibited elevated blood pressure, and exercise partly prevented this elevation. Renal injury observed as arteriolar wall thickening, focal tubular atrophy, and interstitial inflammatory infiltration was apparent in hypertensive animals, and exercise induced further renal damage in hypertensive animals. The present training protocol exacerbates renal insufficiency in NOS-blockage hypertension in rats.     

Role of nitric oxide in the renal hemodynamic response to unilateral nephrectomy

Reduction of renal mass by unilateral nephrectomy results in an immediate increase in renal blood flow (RBF) to the remnant kidney, followed by compensatory renal hypertrophy. Whether the increase in RBF after unilateral nephrectomy is mediated by nitric oxide (NO) was tested. It was found that immediately after nephrectomy, blood flow to the remaining kidney increased by 8% (P < 0.01), and inhibition of NO synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME) blocked the increase in RBF. In addition, 2 d after nephrectomy, there was a 49% increase in RBF (corrected per gram of kidney weight), a 25% increase at 7 and 14 d, and a 16% increase after 28 d. Acute inhibition of NO synthesis with L-NAME in uninephrectomized rats caused a greater decrease in RBF on days 2 and 7 compared with controls, whereas by 14 and 28 d, the response to L-NAME was similar to controls. Urinary excretion of cyclic guanosine monophosphate, a marker for renal NO production, increased 2.5-fold by 2 d after uninephrectomy (P < 0.005) and remained at this level through 28 d. Pretreating rats chronically with a subpressor dose of L-NAME beginning 2 d before nephrectomy blocked the increase in RBF seen at 2 and 7 d and retarded the renal hypertrophy that should have developed by 7 d. It is concluded that after unilateral nephrectomy, immediate and sustained increases in RBF are mediated at least in part by NO. The hypertrophic response to unilateral nephrectomy may be partially initiated by the signal of hemodynamic changes.     

Comparison of captopril and enalapril in the treatment of hypertension in patients with non-insulin dependent diabetes mellitus and nephropathy

Eighteen patients with non-insulin dependent diabetes mellitus (NIDDM), hypertension and nephropathy were randomized to receive captopril or enalapril for 6 months. Two patients with serum creatinine of >400 μmol/l had to be excluded from the study because of rapidly deteriorating renal function after starting treatment. Of the remaining patients, 7 received captopril and 9 received enalapril. Blood pressure control was achieved in about 50% of patients with either drug alone. Serum creatinine and creatinine clearance were unchanged in both groups but there was a greater tendency for the former to increase in patients with higher pretreatment values. Proteinuria was reduced at 1 month only in the enalapril group which also showed a significant elevation of serum potassium after treatment. Captopril and enalapril have only a modest antihypertensive action in patients with NIDDM and nephropathy. Their use in patients with renal insufficiency must be balanced against the risk of further aggravating the deterioration of renal function.     

Temporary losartan or captopril in young SHR induces malignant hypertension despite initial normotension

BACKGROUND: Exposure of normotensive rats to angiotensin-converting enzyme (ACE) inhibitors in early life causes hypertrophy of intrarenal arteries. Similar defects have been found in knockout mice lacking angiotensinogen, ACE, or angiotensin II type 1 (AT1) receptors. On the other hand, transient inhibition of the renin-angiotensin system from 2 weeks of age in spontaneously hypertensive rats (SHR), either with ACE inhibitors or with AT1 receptor antagonists partially prevents the increase in blood pressure. However, permanent treatment of SHR from conception onwards with ACE inhibitors completely prevents hypertension. Although these studies demonstrated protection from hypertension-induced changes in the heart and large arteries, renal arteries were not studied and follow-up did not extend beyond 6 months of age. We postulated that while brief exposure to ACE inhibitors or AT1 receptor antagonists in young SHR would temporarily decrease blood pressure, it would also be associated with development of intrarenal arterial malformation, and ultimately have deleterious effects. METHODS: Direct effects on intrarenal arterial morphology of an ACE inhibitor (captopril, 100 mg/kg/day) and an AT1 receptor antagonist (losartan, 50 mg/kg/day), administered from the last week of gestation until 8 weeks of age were examined in SHR. After stopping treatment at 8 weeks, we continued to monitor blood pressure until spontaneous death. RESULTS: Systolic blood pressure at 8 weeks was normalized by captopril and losartan (SHR control 187 +/- 8 mm Hg; captopril 118 +/- 5 mm Hg; and losartan 120 +/- 9 mm Hg). However, by 30 weeks, blood pressure had increased to control SHR levels. At 4 weeks, the media of renal arteries and arterioles was hypertrophied. Marked smooth muscle cell hyperplasia of cortical arteries resulted in significantly increased wall thickness by 8 weeks, despite similar external diameter. Arterial wall structure was disrupted, with fragmentation of elastic fibers and irregular distribution of collagen type I fibers. After stopping treatment, the rats gradually began to show poor health and all had died by 1 year of age, while all 1-year-old control SHR females were in good health. The cause of morbidity and mortality in the rats treated in early life was clearly malignant hypertension. Severe hypertrophy of renal arterioles was found, as well as cerebral hemorrhage. CONCLUSION: Despite initial normalization of blood pressure interference with the renin-angiotensin system during a crucial stage of development in SHR can initiate marked smooth muscle cell hyperplasia and disruption of the wall structure of the intrarenal arteries. Subsequent progression of this intrarenal process after cessation of treatment suggests an independent process that eventually results in malignant hypertension and early death.     

Captopril, an angiotensin I-converting enzyme inhibitor, decreases proteinuria in hypertensive patients with renal diseases

A crossover study was planned in order to compare the effects of captopril and slow channel calcium entry blocker (Ca antagonist) on urinary protein excretion in 7 hypertensive patients with renal diseases, including 4 with IgA nephropathy, 2 with lupus nephritis and 1 with benign nephrosclerosis. Captopril decreased urinary protein excretion by 52% without any change in creatinine clearance, while Ca antagonist was having a slight effect on proteinuria even though the drug showed an equivalent antihypertensive effect as captopril. These results suggest that the attenuation of proteinuria induced by captopril may be related to an inhibition of angiotensin II formation and/or a direct action of this drug on protein permeability of glomerular basement membrane.     

Renal angiotensin converting enzyme (ACE) expression in diabetic rats: the effect of ACE inhibitors]

Renal excreted angiotensin converting enzyme (ACE) inhibitor captopril, and renal.hepatic bile excreted ACE inhibitor temocapril, were compared by monitoring serum ACE and renal ACE expression (protein and mRNA) in streptozotocin-induced diabetic rats. Serum ACE levels did not change in untreated diabetic rats or in those treated with temocapril, compared with normal control rats. However, serum ACE levels significantly increased in diabetic rats treated with captopril after 3 months (153.8 +/- 23.0 vs. 43.5 +/- 5.5 IU/l/37 degrees C, p < 0.01) and 6 months (113.6 +/- 9.3 vs. 36.9 +/- 2.9 IU/l/37 degrees C, p < 0.01) compared with normal control rats. Compared with normal control rats (3.6 +/- 0.4), proximal tubular ACE protein expression significantly (p < 0.01) decreased in untreated diabetic rats (1.6 +/- 1.1), but significantly (p < 0.01) increased in diabetic rats treated with captopril (3.7 +/- 0.3) and temocapril (3.5 +/- 0.4). Renal ACE mRNA levels decreased in untreated diabetic rats (125.5 +/- 20.3 vs. 313.3 +/- 53.4, p < 0.01) compared with normal control rats for 6 months. Renal ACE mRNA levels tended to increase in diabetic rats treated with captopril (184.4 +/- 51.2 vs. 125.5 +/- 20.3) and temocapril (165.4 +/- 43.2 vs. 125.5 +/- 20.3) compared with untreated diabetic rats for 6 months. In conclusion, diabetic rats had lower proximal tubular ACE protein expression and lower renal ACE mRNA levels compared with normal control rats. Furthermore, both ACE inhibitors increased renal ACE protein and mRNA expression, but differed in their effect on serum ACE levels.     

Studies on the mechanism of action of angiotensin converting enzyme inhibitors on the dog kidney]

The effects of angiotensin-converting enzyme (ACE) inhibitors, rampipril, captopril and enalapril, on the renal circulation and function were examined in normotensive dogs, in relation to the renin-angiotensin-aldosterone (R-A-A) and kallikrein-kinin (K-K) systems and prostaglandins (PGs). These inhibitors markedly decreased renal vascular resistance (RVR) in parallel with a reduction in systemic blood pressure, and increased renal blood flow (RBF). Captopril exerted its effects rapidly, but its disappearance was also rapid. The onset of ramipril's effects was slightly delayed, but its antihypertensive and RVR-decreasing effects were fairly prolonged. Ramipril showed more potent and longer-lasting RBF-increasing effect and induced marked Na diuresis. Enalapril had no diuretic effect, and captopril's effect was only temporary. Plasma renin activity was increased similarly by the three inhibitors, but only ramipril significantly decreased plasma aldosterone concentration. This aldosterone secretion inhibition by ramipril may be partly involved in the diuretic effect. Involvement of the K-K system and PGs in ramipril's effects on the dog kidney was examined. When systemic PG biosynthesis was inhibited by indomethacin pretreatment, ramipril-induced increases in RBF and urine volume were inhibited about 50%. Inhibition of the K-K system by aprotinin pretreatment resulted in marked inhibition of urine volume increase, but scarcely affected RBF increase. These results indicate that ramipril produces the most potent effect on the renal circulation and function of the dog among the three ACE inhibitors and that its diuretic action is mostly due to kinins and kinin-induced PGs in the kidney and the RBF increase, due to the R-A-A system and PGs.     

Reversal of high-dose fentanyl anesthesia by naloxone: analysis of factors attenuating respiratory and hemodynamic responses to naloxone

The respiratory and hemodynamic responses to postoperative reversal by naloxone of high-dose fentanyl anesthesia were studied in 101 patients after open heart surgery. Respiratory and hemodynamic changes after drip infusion of naloxone were minimum. Change of systolic blood pressure (BPs), mean blood pressure (BPm), CVP and PO2 were statistically significant. BPs increased for 3.8 +/- 14.0 mmHg, BPm increased for 1.6 +/- 8.2 mmHg. CVP decreased for 0.4 +/- 2.1 mmHg, and PO2 decreased for 8.6 +/- 3.4 mmHg. Severe side effect was not observed. Multi-factorial analysis revealed that the abrupt recovery of consciousness from anesthesia and acidosis were the most important factors that attenuate hemodynamic response to naloxone.     

Renal antioxidant status in rats with hypertension induced by N sup omega nitro-L-arginine methyl ester

Nitric oxide (NO) has a role in the etiopathogenesis of hypertension. Relaxation of vascular smooth muscles is failed when NO production is reduced leading to increased vascular peripheral resistance. N sup omega nitro-L-arginine methyl ester (L-NAME) is one of the inhibitors of NO production. The aim of this study was to investigate oxidant-antioxidant systems of renal tissue in rats with hypertension induced by L-NAME. Rats were divided into three groups: control group and study groups treated with 100 or 500 mg/l L-NAME in drinking water for 15 days. The activities of catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), and the levels of malondialdehyde (MDA) and NO were studied in the renal tissue after hypertension induction. Arterial blood pressure was increased in both L- NAME groups. CAT activity of 500-mg L-NAME group was higher than control. GSH-Px activity of 500-mg L-NAME group was decreased compared with 100-mg ones. NO level was lower in 500-mg L-NAME group than control. MDA levels in both L-NAME groups were decreased compared with control. In conclusion, hypertension was induced with oral L-NAME treatment. Increased CAT activity was compensated with decreased GSH-Px activity in 500-mg L-NAME group. Both study groups were protected from lipid peroxidation with NO inhibition.     

Evidence for renal vasodilation in pre-dialysis patients during correction of anemia by erythropoietin.

Results from animal experiments have suggested that treatment with recombinant human erythropoietin (rHuEPO) causes changes in renal hemodynamics which are detrimental to renal function. Therefore, the effects of correction of the anemia by rHuEPO on glomerular filtration rate (GFR; inulin clearance) and effective renal plasma flow (ERPF; PAH clearance) were studied in eight pre-dialysis patients. The studies were done before (Hct 0.24 +/- 0.05 liter/liter) and at 89 +/- 19 days after the start of rHuEPO therapy (Hct 0.39 +/- 0.03 liter/liter). To further evaluate the effects of ACE inhibition, 25 mg of captopril was given orally after baseline values had been obtained. Baseline GFR, renal blood flow (RBF) and filtration fraction (FF) did not change during rHuEPO therapy. At low hematocrit (Hct) captopril induced a significant increase in ERPF and RBF, and a decrease in MAP. After correction of the hematocrit the blood pressure lowering effect of captopril remained unchanged. However, captopril no longer induced changes in ERPF and RBF. We conclude that the increase in hematocrit had no adverse effects on GFR. The results suggest that changes in hematocrit may influence the effects of ACE inhibition on efferent vascular resistance. Therefore, the hematocrit should be taken into account when evaluating studies on the effects of ACE inhibition in the progression of chronic renal failure.     

Gentamicin reduces serum ACE activity in patients with normal kidney function

AIMS: We evaluated serum angiotensin-converting enzyme (ACE) as an indicator of gentamicin toxicity and compared it with N-acetyl-beta-D-glucosaminidase (NAG) and creatinine. METHODS: 20 bone fracture in-patients receiving gentamicin 80 mg TDS for 3 days. Subjects had normal kidney function and had no history or sign of hypertension. Serum and urine samples were collected before and 3 days after drug administration. Samples analyzed for ACE, NAG, BUN, creatinine, sodium, and potassium. RESULTS: Our results showed that urine NAG activity increased significantly at the 3rd day. Serum creatinine level and glomerular filtration rate (GFR) while still at a normal range showed slight but significant changes at this time. This may indicate some renal damage. Serum ACE activity decreased significantly at the 3rd day. CONCLUSION: These results indicate serum ACE can be used as a good indicator of renal damage in patients receiving gentamicin.     

Study of serum and tissues angiotensin converting enzyme (ACE) activity in rat with gentamicin induced renal toxicity

PURPOSE: In this research ACE activity (as a marker of epithelial injury) was studied in rats with gentamicin induced renal toxicity. METHODS: Male Sprague-Dawley rats were sacrificed 1, 3, 5, and 7 days after gentamicin injection, 100 mg/kg/day for 1, 3, 5, and 7 consecutive days. ACE activity was measured in serum, kidney and lung. These data were compared with normal saline-treated rats. Histological scoring of renal cortical pathology was performed on days 1, 3, 5, and 7. RESULTS: Treatment of rats with gentamicin resulted in renal damage evidenced by proteinuria, polyuria, and decreased creatinine clearance. The damage to the kidney proximal tubule was evident by (a) the histological analysis at light microscopy and (b) the augmentation in the urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG). Kidney ACE activity decreased while lung and serum ACE activity didn't change until day 7. Lung ACE activity increased significantly on day 7. Kidney and serum ACE activity increased too. Blood pressure increased significantly on day 7. This corresponded well with the lung ACE activity increment. CONCLUSION: These data suggest that kidney ACE activity decreased significantly just one day after gentamicin administration and prior to kidney NAG decrease.