Effects of nitrendipine on sodium balance during changes in sodium intake and low-dosage ANP.

We found previously that calcium entry blockade with nitrendipine enhanced the natriuretic effect of high-dose atrial natriuretic peptide (ANP). It is unknown whether nitrendipine also influences the effect of physiological changes in ANP. We therefore studied the effect of nitrendipine on cumulative sodium balance during changes in sodium intake as well as on natriuresis after low-dosage ANP infusion during low and high sodium (LS and HS, respectively) intake. In eight healthy volunteers, sodium balance was recorded after the switch from LS (20 mmol/day) to HS (300 mmol/day) diet. Cumulative sodium balance was equal with (441 +/- 45 mmol) or without (458 +/- 45 mmol) nitrendipine treatment. The body weight curves were also fully congruent. ANP (0.005 micrograms/kg/min for 3 h) was administered during maximal water diuresis on both sodium intake levels with and without nitrendipine. Infusion of ANP increased sodium excretion (mumol/min) from 30 +/- 7 to 81 +/- 12 (LS) and from 316 +/- 27 to 469 +/- 46 (HS). During nitrendipine, similar increments (from 36 +/- 7 to 98 +/- 24 mumol/min, HS) were found. ANP had no effect on inulin clearance and fractional excretion of lithium, but consistently depressed diluting segment reabsorption. This pattern was also similar during nitrendipine. Apparently, under the conditions of this study in normal subjects, nitrendipine has no effect on sodium balance. ANP, in physiological concentrations, increases natriuresis mainly by depressing sodium reabsorption in the distal nephron, an effect not enhanced by nitrendipine.     

EFFECT OF ENALAPRIL ON HANDLING OF A SODIUM CHLORIDE LOAD BY GENETICALLY HYPERTENSIVE AND NORMOTENSIVE RATS

1. Enalapril was given in the drinking water (300 mg/L) for 4.5 days to normotensive (N) and genetically hypertensive (GH) rats on zero sodium intake. An intraperitoneal NaCl load was given 12 h after enalapril was started. 2. Enalapril did not increase the maximum rate of sodium excretion, but caused the rats to excrete more than the load in the first 24 h and then to have a slow fall in body sodium while on a sodium-free diet. 3. In terms of the Strauss et al. (1958) concept of body sodium, enalapril appears to lower the basal level. However, in addition it causes a slow leak of sodium which becomes apparent when sodium intake is very low.     

Acute and chronic effects of a novel dihydrobenzofuran analogue and enalapril on blood pressure and plasma and tissue angiotensin converting enzyme activity in the sodium deficient normotensive rat

1. Changes occurring in plasma and tissue angiotensin converting enzyme (ACE) activity have been examined in relation to blood pressure response following acute and chronic administration of N-[N-[[4-(2,3-dihydro-2-benzofuranyl)-1- (ethoxycarbonyl)]-butyl]-(s)-alanyl]-(s)-proline (BRL 36378) and enalapril in the sodium deficient normotensive rat. 2. Both BRL 36378 and enalapril produced a reduction in blood pressure which was evident at 2 and 24 h after acute administration, or at 24 h after chronic (21 days) administration. This was accompanied by inhibition of ACE activity in both plasma and tissues. 3. The magnitude of ACE inhibition was greater following enalapril administration than achieved after BRL 36378 treatment; this was reflected by the greater fall in blood pressure evoked by enalapril. 4. Removal of the respective ACE inhibitors revealed an apparent increase in total enzyme in the plasma of animals dosed chronically with BRL 36378 and enalapril. The onset of this increase in total enzyme was rapid, as it was apparent in plasma at 24 h after a single oral dose of BRL 36378 and enalapril. 5. The increase in total enzyme in plasma may be related to the degree of ACE inhibition, since the increase in total enzyme was of greater magnitude after 21 days treatment with enalapril than following corresponding dosing with BRL 36378. 6. No consistent effects on total enzyme were observed in tissues following acute and chronic administration with the ACE inhibitors. 7. Stimulation of drinking behaviour was observed throughout the periods of chronic (7 and 21 days) administration with both BRL 36378 and enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of salt balance on the renal and hemodynamic actions of benazepril in normal men

Renal and hemodynamic effects of diet alone and of single oral doses of the nonsulphydryl angiotensin converting enzyme (ACE) inhibitor, benazepril (10 mg), were investigated in eight healthy volunteers under stable conditions of high salt intake (300 mmol NaCl/day) and low salt intake (10 mmol NaCl/day), in a double blind, placebo controlled study. There were no changes in blood pressure between the two dietary extremes either during the run-in period or once sodium balance had been achieved. Mean renal plasma flow was higher, by approximately 10% and renal vascular resistance lower by 15%, on high salt diet compared to low salt diet. Glomerular filtration rates were found to be similar irrespective of the state of salt balance. Both plasma urate concentration and plasma renin activity were significantly elevated in the low salt compared to high salt state. Benazepril caused a greater fall in blood pressure in the sodium depleted state. Significant increases in the mean renal plasma flow, in the order of 15-20%, were seen over 6 h postbenazepril when compared with placebo response, regardless of the level of salt intake. Glomerular filtration rate over the same period remained unaltered. Benazepril doubled the urinary excretion of sodium over the first 4 hours after dosing whilst on the low salt diet; the equivalent increase during salt loading was approximately 20%. These results suggest that benazepril may exert direct effects on renal tubular function additional to those achieved through ACE blockade.     

Cardiac hypertrophy and salt status in chronic myocardial infarction in the rat: effects of enalapril versus salt restriction

The effects of salt restriction and the ACE inhibitor enalapril were compared in a model of chronic myocardial infarction in the rat. Total exchangeable sodium was measured by an isotopic dilution technique to quantitate the effects of the low salt diet and ACE inhibitor on body sodium and extracellular fluid. Rats with infarction developed a marked increase in cardiac weight (4.29 +/- 0.18 mg/g body weight) compared with control rats (3.64 +/- 0.08 mg/g, p less than 0.01). There was hypertrophy of both left and right ventricles. Salt restricted rats with infarction developed identical cardiomegaly (4.30 +/- 0.11 mg/g), although total exchangeable body sodium fell by 10% (p less than 0.001). In contrast, rats with infarction receiving enalapril developed significantly less cardiomegaly (3.97 +/- 0.10 mg/g) while body sodium remained unchanged. Rats with infarction had a significant increase in lung weight which was not changed by salt restriction but which was abolished by enalapril. These results suggest that salt restriction does not prevent the progression of cardiomegaly in chronic left heart failure. In contrast our results confirm the ability of ACE inhibitors to prevent progressive cardiomegaly and left heart failure without affecting long-term changes in sodium balance.     

Natriuretic action of ANP is blunted by ACE inhibition in humans

We investigated the impact of angiotensin I-converting enzyme (ACE) inhibition by enalapril (3 X 2.5 mg p.o.) on the renal action of acute intravenous (i.v.) infusion of atrial natriuretic peptide (1-28-hANP 0.1 micrograms/kg/min for 30 min) in 10 normal subjects. During the control infusion of ANP, urinary sodium excretion rose from 4.5 +/- 0.8 to 11.2 +/- 2.2 mEq/min and urine volume from 32 +/- 14 to 115 +/- 34 ml/30 min. This increment in urinary volume and sodium output during ANP infusion was almost completely reduced by ACE inhibition. ANP plasma levels before and during the infusion and stimulation of urinary cGMP excretion were unaltered by ACE inhibition. However, enalapril treatment reduced systolic blood pressure (SBP) from 112 +/- 3 to 106 +/- 3 mm Hg and diastolic blood pressure (DBP) from 71 +/- 2 to 66 +/- 3 mm Hg. The small rise in glomerular filtration rate (GFR) during the control infusion of ANP was not observed after pretreatment with enalapril. The study demonstrates the importance of the renin-angiotensin system for the natriuretic and diuretic action of ANP in normal humans.     

Evidence for a vasodepressor effect of the angiotensin-converting enzyme inhibitor, MK421 (enalapril), independent of blockade of angiotensin II formation

The effects of acute and chronic angiotensin-converting enzyme (ACE) inhibition with MK421 (enalapril maleate) on angiotensin II formation were studied in sodium-restricted rats. Male Sprague-Dawley rats were placed on a low-sodium diet (less than 0.04 mEq Na+/24 h) with daily injections of furosemide (1 mg/kg i.p.) for 5 days, and were studied at either 5 days or 3 weeks. Half the rats were given MK421 (300 mg/L) in the drinking water. Parallel groups of rats were fed a standard diet (0.26 mEq Na+/24 h) without MK421. As expected, rats maintained on the low-sodium regimen for either 5 or 21 days had marked stimulation of plasma renin activity and increased angiotensin I, angiotensin II, and aldosterone formation. When MK421 was added to the drinking water, there was inhibition of angiotensin II formation at 5 days (low sodium, 99.4 +/- 25.8 pg/ml; low sodium + MK421, 26.3 +/- 10.5 pg/ml; p less than 0.02), but angiotensin II formation at 3 weeks was not different from the control group (low sodium, 499 +/- 147 pg/ml; low sodium + MK421, 306 +/- 110 pg/ml). Plasma aldosterone levels closely paralleled those of angiotensin II in all groups (r = 0.94, p less than 0.05) compatible with angiotensin II stimulation of aldosterone production, even in the face of ACE inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiotensin-converting enzyme responses following enalapril in the sodium deficient rat

The relationship between blood pressure lowering activity and inhibition of plasma and tissue angiotensin-converting enzyme (ACE) has been studied in the sodium deficient normotensive rat at 24, 48 and 96 h after the administration for 21 days of enalapril (MK-421, 10 mg/kg per day p.o.). Blood pressure was reduced and plasma ACE activity inhibited at 24 and 48, but not 96 h, after cessation of dosing. Tissue ACE activity (aorta, lung, mesenteric bed) was inhibited up to 96 h post dose when blood pressure had returned to control values. ACE production (activity following removal of inhibitor) was increased in plasma at 24, 48 and 96 h post dose but in tissues (adrenal glands, renal arteries and mesenteric bed) only at 48 h post dose. There was no tendency for ACE production to increase in the lung, the largest source of the enzyme in the rat. Thus it appears that inhibition of ACE activity in both plasma and tissue contributes to the blood pressure lowering activity of enalapril in the sodium deficient normotensive rat.     

Omapatrilat increases renal endothelin in deoxycorticosterone acetate-salt hypertensive rats

Vasopeptidase inhibitors are a new class of antihypertensive drugs that are single molecules having dual inhibitory action on angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The best known drug in this class is omapatrilat, which has been proposed to be more efficacious than ACE inhibitors because of its ability to inhibit NEP and prevent the breakdown of atrial peptides and bradykinin. However, survival of endothelin (ET) may also be enhanced and therefore, NEP inhibitors may have limited efficacy under conditions of low renin and high ET production. The purpose of the current study was to contrast the effects of the ACE inhibitor, enalapril, with omapatrilat in a model of established hypertension where ACE inhibitors are ineffective, the deoxycorticosterone acetate (DOCA)-salt-treated rat. Two weeks after starting DOCA-salt treatment, rats were given either enalapril (10 mg/kg/day) or omapatrilat (30 mg/kg/day) for 5 days. Mean arterial pressure (MAP) measured by radiotelemetry in untreated DOCA-salt rats increased from 102 +/- 2 to 181 +/- 12 mm Hg (P<.05) as a result of DOCA-salt treatment for 3 weeks. MAP was unaffected by either enalapril (189 +/- 3 mm Hg) or omapatrilat (184 +/- 8 mm Hg). DOCA-salt treatment significantly increased urinary ET excretion compared to baseline (1.6 +/- 0.2 vs. 0.5 +/- 0.1 pmol/day). Administration of omapatrilat significantly increased urinary ET excretion in DOCA-salt rats (2.9 +/- 0.4 pmol/day) compared to enalapril-treated (1.6 +/- 0.2 pmol/day) or untreated (1.5 +/- 0.1 pmol/day) rats. These results indicate that combined ACE/NEP inhibition does not lower blood pressure in a model of established hypertension with high ET activity. These results also support the hypothesis that combined ACE/NEP inhibition can increase renal ET production.     

Renin–angiotensin–aldosterone responsiveness to low sodium and blood pressure reactivity to angiotensin-II are unrelated to cholesteryl ester transfer protein mass in healthy subjects

Background: The blood pressure increase associated with the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib is probably attributable to an off-target effect but it is unknown whether activation of the renin–angiotensin–aldosterone system (RAAS) may be related to variation in the plasma CETP level. We questioned whether the plasma CETP level would affect RAAS responsiveness to low sodium diet and the blood pressure response to angiotensin-II infusion in healthy subjects. Methods: RAAS parameters and blood pressure were determined during liberal sodium diet (200 mmol/24 h) and low sodium diet (50 mmol/24 h) in 67 healthy men. Blood pressure response to incremental angiotensin-II infusion was assessed in 34 subjects during liberal sodium diet. Correlation analysis was performed to test whether RAAS responsiveness and blood pressure were related to plasma CETP mass, high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I measured during liberal sodium diet. Results: CETP mass ranged from 1.29 to 2.95 mg/l. No significant differences in (changes) in mean arterial pressure, aldosterone and active plasma renin concentration in response to low sodium were observed between the lowest and highest tertiles of CETP mass, HDL-C and apolipoprotein A-I. These outcome variables were also not significantly correlated with CETP, HDL-C and apolipoprotein A-I, except for a modest relation of aldosterone measured during low sodium with apolipoprotein A-I (r = 0.28, p = 0.022). Blood pressure response to angiotensin-II was similar between CETP tertiles. Conclusions: Mineralocorticoid and blood pressure responsiveness to dietary salt intake are not significantly related to physiological interindividual differences in plasma CETP. We suggest that a lower CETP mass does not exert adverse effects on blood pressure regulation.     

The renin angiotensin aldosterone system and frusemide response in congestive heart failure.

1. To test the hypothesis that basal renin angiotensin aldosterone system (RAAS) activity impairs the acute natriuretic response to frusemide in patients with mild or moderate congestive heart failure (CHF), we studied eight adult volunteers with preserved renal function, stable New York Heart Association Class II or III CHF, and echocardiographic evidence of left ventricular dysfunction due to myocardial infarction, hypertension, or both causes. 2. All patients received three dosing regimens administered in random order: (a) intravenous frusemide: 40 mg bolus then 40 mg h-1 for 3 h, (b) captopril: two 12.5 mg oral doses separated by 2 h, (c) combined dosing: the first captopril dose preceded the frusemide bolus by 30 min. Sodium balance on an 80 mmol day-1 sodium diet was documented prior to each dosing regimen. Sodium excretion was quantitated in urine collected at intervals until 3.5 h after initiating drug administration. During this time, urine output was replaced intravenously with an equivalent volume of 0.45% saline. 3. Captopril significantly lowered plasma angiotensin converting enzyme (ACE) activity and plasma aldosterone concentration, and raised inulin clearance. The drug had essentially no effect on the time course of magnitude of frusemide's natriuretic effect. Maximal fractional sodium excretion during frusemide infused by itself and in combination with captopril was 24.7 +/- 1.9% vs 28.2 +/- 3.8%, respectively (difference 3.5%; 95% CI, -4.0 to 11.0%; P > 0.05). Cumulative sodium excretion ending at 3.5 h was 429 +/- 53 mmol when frusemide was given alone and 455 +/- 69 mmol when captopril was added (difference, 26 mmol; CI, -121 to 174 mmol; P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

MODERATE SODIUM RESTRICTION AND POTASSIUM SUPPLEMENTATION IN ESSENTIAL HYPERTENSION

Continuous 24 h arterial blood pressure and vasoactive hormones were measured in twelve patients with essential hypertension after 4 weeks on a control sodium intake (180 mmol/day) and after similar periods of sodium restriction (80 mmol/day) and potassium supplementation (200 mmol/day). Sodium restriction was associated with variable blood pressure changes in individual patients and a small reduction in 24 h mean pressure of 4/3 mmHg. The greatest fall in blood pressure with sodium restriction was seen in those patients with the least rise in renin. Potassium supplementation was associated with variable individual blood pressure changes and a trivial reduction in mean 24 h pressures (0.1/0.8 mmHg). Mean 24 h plasma aldosterone concentration was significantly higher during sodium restricted and potassium-supplemented diets, compared to control levels, but other vasoactive hormones were unchanged.     

Effects of repeated doses of enalapril on renal function in man.

Ten healthy subjects received 10 mg oral enalapril (MK 421) daily for a period of 8 days. Renal clearances of electrolytes, urate and phosphate were monitored and factored for glomerular filtration rate, as measured by creatinine clearance, with particular emphasis on the first and eighth day of treatment. Apart from a fall of around 10% in creatinine clearance between 1-2 h on both days 1 and 8, GFR remained unchanged throughout the study. Fractional sodium excretion increased in a biphasic manner by approximately 50% over control between 1-2 h and 4-8 h on day 1. Significant chloruresis (+39.0 +/- 12.9%) and kaluresis (+26.5 +/- 10.3%) occurred between 4-8 h. Urinary pH increased between 0-1 h (+0.29 +/- 0.12; P less than 0.05), and between 4-8 h (+0.50 +/- 0.08; P less than 0.01). The biphasic saluretic effect was also seen between 1-2 h and 4-8 h on day 8. Enalapril caused significant increases in urate and phosphate excretion on day 8 of therapy. There was a biphasic increase in fractional urate excretion at 1-2 h (+28.1 +/- 6.9%; P less than 0.05) and at 4-8 h (+21.0 +/- 6.0% P less than 0.01). Significant phosphaturia (+36.8 +/- 5.2%; P less than 0.05) was also observed at 4-8 h on day 8. Urinary drug excretion was also biphasic; over the first 2 h the predominant drug form was unchanged enalapril, whilst the peak excretion of the diacid metabolite, enalaprilat, occurred at 4-8 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Haemodynamic and hormonal responses to oral enalapril in salt depleted normotensive man.

A combination of dietary sodium restriction (40 mmol day-1) and frusemide pretreatment has been used to activate the renin angiotensin system (RAS) in order to characterise the haemodynamic and hormonal responses to enalapril in young normotensives. Enalapril significantly reduced supine blood pressure with a mean maximum fall of 19 +/- 7.6, compared with 6.5 +/- 6.8 mm Hg with placebo. Similar but greater responses were seen in erect blood pressure. Mean maximal plasma ACE inhibition (78 +/- 5.7%) was associated with a significant increase in PRA from 5.2 +/- 2.1 ngAI ml-1 h-1 to a peak of 29.1 +/- 6 ngAI ml-1 h-1. This simple well tolerated regimen produced consistent RAS activation and gave readily measurable falls in blood pressure following enalapril. This model may be used to undertake detailed assessments of ACE inhibition, renin inhibition and angiotensin receptor blockade.     

The effects of enalapril on urinary protein excretion in patients with idiopathic membranous nephropathy

High doses of the angiotensin converting enzyme inhibitor, captopril, is known to cause significant increases in urinary protein excretion in patients with idiopathic membranous nephropathy. To find whether other angiotensin converting enzyme inhibitors yield similar results, we prospectively examined the effect of enalapril in five consecutive patients with idiopathic membranous nephropathy, elevated arterial pressure, and proteinuria and compared them to age-matched controls receiving clonidine. Glomerular filtration rate, 24-hour urinary protein excretion, and arterial pressure were measured. All patients served as their own controls. Those who received enalapril demonstrated an initial increase in proteinuria (-0.3 +/- 0.7 delta gm/day, clonidine vs 3.9 +/- 0.9 delta gm/day, enalapril: P less than .05) despite similar decreases in arterial pressure (-18 +/- 6 delta mm Hg, clonidine vs -22 +/- 6 delta mm Hg, enalapril: NS) and glomerular filtration rate (-1.1 +/- 0.8 delta mL/min, clonidine vs -1.9 +/- 1.2 delta mL/min, enalapril: NS) when compared to the clonidine group. This increase in proteinuria, however, did not occur when these patients were rechallenged with enalapril. To our knowledge, this is the first report to document a significant increase in preexisting nephrotic range proteinuria following administration of nonsulfhydryl ACE inhibitor. This increase, however, appears to be unique to the initial treatment phase of the disease and does not affect long-term management.     

The effect of saturation of ACE binding sites on the pharmacokinetics of enalaprilat in man.

1. Eight healthy male volunteers received oral enalapril, 10 mg, in the presence and absence of pretreatment with captopril, 50 mg, twice daily for 5 days. 2. Enalaprilat pharmacokinetics were characterised after both doses of enalapril to investigate the effect of saturating ACE binding sites by pretreatment with captopril. 3. The pharmacokinetics of enalaprilat were best described by a one compartment model with zero order input incorporating saturable binding to plasma and tissue ACE. 4. Values of AUC (0.72 h) for enalaprilat were 419 +/- 97 and 450 +/- 87 ng ml-1 h in the presence and absence of captopril, respectively. The difference was not statistically significant nor were there any other differences in model parameters. 5. Induction of ACE by captopril resulting in an increase in the number of ACE binding sites, may have obscured any effect of captopril on the occupancy of ACE binding sites by enalapril.     

Inhibition of angiotensin converting enzyme with enalapril maleate in infants with congestive heart failure.

We studied the inhibition of angiotensin converting enzyme (ACE) in eight infants with congestive heart failure (CHF) poorly controlled with digoxin and diuretics, treated orally with 0.25 mg kg-1 enalapril maleate once a day. Baseline ACE activities were compared between these infants and control children without CHF or ACE inhibitor. Except for one infant who vomited, inhibition of ACE activity was 75.5 +/- 12.2%, 75.5 +/- 10.5% and 51.7 +/- 12.2%, at 4, 12 and 24 h after drug intake respectively. There was no correlation between postnatal age and inhibition of ACE activity. In infants with CHF, mean baseline ACE activity was significantly higher than in control infants (36.4 +/- 7.2 mu ml-1 vs 26.9 +/- 6.9 mu ml-1, P < 0.05). These results were very similar to those seen in adults.     

Feeding but not salt loading is the dominant factor controlling urinary dopamine excretion in conscious rats

Summary We studied urinary dopamine excretion in three different groups of rats after the following treatment regimens: normal chow and tap water (controls, CON), normal chow and 1 % NaCl as drinking water (high salt, HS), and chow with low sodium content plus tap water (low salt, LS). On days 5 and 7 of the respective dietary treatment, rats were placed in metabolic cages. Using a cross over design, chow was given (fed) or withheld (fasted). Urine was collected for 24 h and analyzed for sodium, creatinine, and dopamine.Urinary dopamine excretion did not change in proportion to large differences in sodium excretion in fasted animals. Sodium excretion was enhanced (45%) due to feeding only in the CON group but not in HS and LS rats. However, there was a striking increase in renal dopamine excretion in fed compared to fasted animals, irrespective of their sodium diet: 2.5-fold in CON, 2-fold in HS, and 1.8-fold in LS rats. Urinary creatinine excretion was significantly elevated during the feeding condition compared to fasted animals in all treatment groups.Our results demonstrate that urinary dopamine excretion is dominantly influenced by feeding but not by oral sodium intake in conscious rats. We conclude that (1) the dietary state of the animals should be controlled in experiments on renal dopamine production, (2) renally formed dopamine could be involved in the functional response of the kidney to oral food intake. Correspondence to: B. Mühlbauer     

托拉塞米的利尿作用和安全性

目的 观察健康受试者口服托拉塞米的利尿作用和安全性。方法 19名健康男性受试者单次口服不同剂量托拉塞米5,10和20 mg(n=9)或连续7天每日口服托拉塞米10 mg(n=10)。观察血压,尿量,24 h尿钾、钠、氯和血钾、钠、氯,心率,呼吸,心电图和心电监测,血常规,尿常规,血生化等指标。 结果 5,10,20mg 3组单次服药后24 h总尿量分别为2.24,2.60和3.17 L(P<0.05),24 h尿钾、钠、氯的排泄随托拉塞米剂量增加而略增加(P>0.05)。连续服药,首次药后的24h尿量及尿钾、钠、氯的量最多。单次和连续给药后血钾、钠、氯均未见下降,甘油三脂增加0.1~0.4 mmol.L-1(P<0.05)。4例受试者出现药物不良反应。 结论 在5~20 mg,托拉塞米利尿作用随剂量增加而增加,国人对托拉塞米耐受性良好。     

Renin-angiotensin system blockade prevents the increase in plasma transforming growth factor beta 1, and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat.

INTRODUCTION: Combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) is used to improve renal outcome achieved by monotherapy in diabetic patients. In addition, interference with the renin-angiotensin system (RAS) reduced expression and excretion of transforming growth factor beta 1 (TGF-beta 1) in diabetic nephropathy. The aim of this study was to investigate the effects of interrupting the RAS by ACE inhibitor (ACE-I) or ARB monotherapy or by combination therapy on proteinuria, kidney hypertrophy and plasma TGF-beta 1 in diabetic rats. MATERIALS AND METHODS: Forty-one male Wistar rats were allocated to five groups: 1 = control rats, 2 = diabetic rats (streptozotocin [STZ] 55 mg/kg), 3 = diabetic rats as above receiving enalapril (20 mg/kg/day), 4 = diabetic rats receiving losartan (80 mg/kg/day), 5 = diabetic rats receiving both losartan and enalapril. The study lasted 60 days. RESULTS: Urinary protein excretion, kidney weight, serum ACE activity and plasma TGF-beta1 increased significantly in untreated diabetic rats compared with controls. Administration of losartan, enalapril, or both for 60 days prevented these changes. Furthermore, combined therapy for 30 days normalised urinary protein excretion, while monotherapy did not. Losartan inhibited serum ACE activity both in vivo and in vitro. Plasma TGF-beta 1 levels were positively correlated with blood glucose levels (r=0.4059) and with urinary protein excretion (r=0.3558). CONCLUSIONS: Combination therapy with losartan and enalapril was more effective than monotherapy with either drug in achieving an early antiproteinuric response. Long-term treatment with losartan was as effective as the combined treatment, possibly due to a dual inhibitory effect on the RAS. The antiproteinuric effect may be related, in part, to reduced TGF-beta 1.