trandolapril and Kidney-Diseases

Antihypertensive treatment mitigates the progression of chronic kidney disease. Here, we comparatively assessed the effects of antihypertensive agents in normotensive and hypertensive diabetic patients with microalbuminuric kidney disease.. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) comparing oral antihypertensive agents in adult diabetic patients with microalbuminuria. The primary efficacy outcome was reduction in albuminuria, and the primary safety outcomes were dry cough, presyncope, and edema. Random-effects pairwise and Bayesian network meta-analyses were performed to produce outcome estimates for all RCTs, only hypertensive RCTs, or only normotensive RCTs. Surface under the cumulative ranking (SUCRA) probability rankings were calculated for all outcomes. Sensitivity analyses on type 2 diabetes status, age, or follow-up duration were also performed.. A total of 38 RCTs were included in the meta-analyses. The angiotensin-converting enzyme inhibitor-calcium channel blocker (ACEI-CCB) combination therapy of captopril+diltiazem was most efficacious in reducing albuminuria irrespective of blood pressure status. However, the ACEI-angiotensin receptor blocker (ACEI-ARB) combination therapy of trandolapril+candesartan was the most efficacious in reducing albuminuria for normotensive patients, while the ACEI-CCB combination therapy of fosinopril+amlodipine was the most efficacious in reducing albuminuria for hypertensive patients. The foregoing combination therapies displayed inferior safety profiles relative to ACEI monotherapy with respect to dry cough, presyncope, and edema. With respect to type 2 diabetic patients with microalbuminuria, the Chinese herbal medicine Tangshen formula followed by the ACEI ramipril were the most efficacious in reducing albuminuria.. Trandolapril+candesartan appears to be the most efficacious intervention for reducing albuminuria for normotensive patients, while fosinopril+amlodipine appears to be the most efficacious intervention for reducing albuminuria for hypertensive patients. For practitioners opting for monotherapy, our SUCRA analysis supports the use of trandolapril and fosinopril in normotensive and hypertensive adult diabetic patients with microalbuminuria, respectively.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Bayes Theorem; Benzimidazoles; Biphenyl Compounds; Diabetes Mellitus, Type 2; Follow-Up Studies; Fosinopril; Humans; Hypertension; Indoles; Kidney Diseases; Middle Aged; Patient Safety; Probability; Randomized Controlled Trials as Topic; Tetrazoles; Treatment Outcome; Young Adult

Both trandolapril and verapamil are effective and widely used antihypertensive agents. The aim of this study was to estimate the efficacy and tolerability of trandolapril/verapamil (Tr/Ve) combination for blood pressure control and renoprotection. PubMed, EMBASE and Cochrane Library were searched for relevant studies. A meta-analysis of all randomized controlled trials (RCTs) meeting the criteria was performed. Twelve RCTs were ultimately included out of 62 studies. (1) Combination versus trandolapril: a greater diastolic blood pressure (DBP) reduction (weighted mean difference (WMD): 3.71, 95% confidence interval (CI): 1.84-5.57); a greater reduction in albuminuria (WMD: 136.77, 95% CI: 12.44-261.09). There were no differences in reduction in systolic blood pressure (SBP), blood pressure response rate or proteinuria. (2) Combination versus verapamil: a greater SBP reduction (WMD: 6.14, 95% CI: 3.59-8.70); a greater DBP reduction (WMD: 2.49, 95% CI: 0.81-4.17); a greater reduction in proteinuria (standardized mean difference: 0.84, 95% CI: 0.22-1.45); a greater reduction in albuminuria (WMD: 255.00, 95% CI: 119.26-390.74). (3) Incidence of all-cause adverse events (AEs) was comparable between combination and monotherapy. The present meta-analysis indicates that Tr/Ve combination provides a superior blood pressure control and a favourable renoprotective effect without an increase of overall AEs than verapamil monotherapy. The combination also shows a slight advantage over trandolapril monotherapy by reducing DBP and albuminuria to a greater extent.

Topics: Albuminuria; Antihypertensive Agents; Drug Therapy, Combination; Female; Humans; Hypertension; Indoles; Kidney; Kidney Diseases; Male; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome; Verapamil

Angiotensin II (ANG II) is an important factor for the progression of renal diseases. ANG II has many pleiotropic effects on the kidney such as pro-inflammatory and profibrotic actions besides the well-known blood pressure-increasing effect.. Organs have local ANG II-generating systems that work independently from their classic systemic counterpart. Renal proximal tubular cells could generate and secrete ANG II into the urine in concentrations that are 10,000 times higher than those found in serum. These local systems are only incompletely blocked by currently used doses of ACE inhibitors or AT(1) antagonists. There are other enzyme systems besides ACE that contribute to the formation of ANG II. Alternative pathways generate peptides such as angiotensin 1-7 that have antagonistic effect compared with ANG II. Degradation products of ANG II such as angiotensin IV bind at separate receptors and could mediate fibrosis. The discovery of AT(1) receptor dimers and agonistic antibodies against AT(1) receptors contributes to the complexity of the system.. The complexity of the renin-angiotensin-aldosterone system (RAAS) implies that dual blockade with ACE inhibitors and AT(1) receptor antagonists makes sense for pathophysiological reasons. First clinical studies have shown that such as dual therapy reduces progression of chronic renal disease more efficiently that the respective monotherapies in certain risk populations. This shows that novel pathophysiological data could lead to innovative clinical treatment strategies.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chronic Disease; Chymases; Clinical Trials as Topic; Diabetic Nephropathies; Disease Progression; Drug Therapy, Combination; Humans; Indoles; Kidney Diseases; Kidney Tubules, Proximal; Losartan; Prospective Studies; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors; Serine Endopeptidases

Present angiotensin-converting-enzyme inhibitor treatment fails to prevent progression of non-diabetic renal disease. We aimed to assess the efficacy and safety of combined treatment of angiotensin-converting-enzyme inhibitor and angiotensin-II receptor blocker, and monotherapy of each drug at its maximum dose, in patients with non-diabetic renal disease.. 336 patients with non-diabetic renal disease were enrolled from one renal outpatient department in Japan. After screening and an 18-week run-in period, 263 patients were randomly assigned angiotensin-II receptor blocker (losartan, 100 mg daily), angiotensin-converting-enzyme inhibitor (trandolapril, 3 mg daily), or a combination of both drugs at equivalent doses. Survival analysis was done to compare the effects of each regimen on the combined primary endpoint of time to doubling of serum creatinine concentration or end-stage renal disease. Analysis was by intention to treat.. Seven patients discontinued or were otherwise lost to follow-up. Ten (11%) of 85 patients on combination treatment reached the combined primary endpoint compared with 20 (23%) of 85 on trandolapril alone (hazard ratio 0.38, 95% CI 0.18-0.63, p=0.018) and 20 (23%) of 86 on losartan alone (0.40, 0.17-0.69, p=0.016). Covariates affecting renal survival were combination treatment (hazard ratio 0.38, 95% CI 0.18-0.63, p=0.011), age (1.30, 1.03-2.29, p=0.009), baseline renal function (1.80, 1.02-2.99, p=0.021), change in daily urinary protein excretion rate (0.58, 0.24-0.88, p=0.022), use of diuretics (0.80, 0.30-0.94, p=0.043), and antiproteinuric response to trandolapril (0.81, 0.21-0.91, p=0.039). Frequency of side-effects with combination treatment was the same as with trandolapril alone.. Combination treatment safely retards progression of non-diabetic renal disease compared with monotherapy. However, since some patients reached the combined primary endpoint on combined treatment, further strategies for complete management of progressive non-diabetic renal disease need to be researched.

Topics: Adult; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Drug Therapy, Combination; Female; Humans; Indoles; Kidney Diseases; Kidney Function Tests; Losartan; Male; Middle Aged; Treatment Outcome

Guidelines recommend lower threshold and goal blood pressure (BP) for patients with proteinuria. BP reduction could be accompanied by a different fall in proteinuria depending of the antihypertensive drug. The objective was to compare proteinuria reduction when BP is lowered to the same level with different drugs.. Prospective, randomized, double-blind, controlled trial.. 12 Spanish centres.. A total of 119 patients with primary renal disease, blood pressure > 130/85 mmHg, proteinuria > 1 g/day, and creatinine clearance > or = 50 ml/min.. After a 4-week run-in placebo period, patients were randomized to: atenolol 50 mg/day; trandolapril 2 mg/day; verapamil 240 mg/day or verapamil 180 + trandolapril 2 mg/day combination; forced double-dose titration was carried out at the 4th week. Treatment duration was 6 months.. Changes in BP, 24 h proteinuria, serum albumin and calcium.. BP was significantly reduced with the four treatments [SBP/DBP (mmHg]: atenolol 12.2/9.9; trandolapril 12.9/9.3; verapamil 8.2/7.9 and verapamil + trandolapril 13.6/11.3) without differences between them. A significant fall in proteinuria was seen in the trandolapril, 40.2% [95% confidence interval (CI) 24.3-56.2%], and verapamil + trandolapril groups, 48.5% (95% CI, 31.7-64.3%) accompanied with increases in serum albumin (trandolapril: from 3.86 +/- 0.64 to 4.03 +/- 0.67 g/dl; verapamil + trandolapril: from 4.15 +/- 0.58 to 4.40 +/- 0.51 g/dl).. In patients with proteinuric primary renal disease, adequate dose titration of antihypertensive drugs may provide a substantial BP reduction. Only angiotensin-converting enzyme inhibitor (trandolapril) treatment, alone or better combined with verapamil, reduces proteinuria and increases serum albumin.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium; Calcium Channel Blockers; Creatinine; Double-Blind Method; Female; Heart Rate; Humans; Indoles; Kidney Diseases; Male; Middle Aged; Prospective Studies; Proteinuria; Serum Albumin; Spain; Verapamil

Non-dihydropyridine calcium antagonists such as verapamil are equally effective in reducing proteinuria as ACE inhibitors in hypertensive patients with diabetic nephropathy. To date it is unknown whether verapamil elucidates such an antiproteinuric capacity in non-diabetic renal disease.. We performed a double-blind, placebo-controlled, random cross-over study which compared the antiproteinuric effect of 6 weeks treatment with verapamil SR (360 mg) to that of the ACE inhibitor trandolapril (4 mg), and their fixed combination vera/tran (180 mg verapamil SR and 2 mg trandolapril) in 11 non-diabetic patients with proteinuria of 6.6 (5.1-8.8) g/day, a creatinine clearance of 87 (74-106) ml/min, and a 24-h blood pressure of 136/85 (126/76-157/96) mmHg at baseline.. Twenty-four-hour mean arterial pressure did not change during verapamil, whereas both trandolapril and vera/tran induced a significant reduction in MAP. Verapamil showed no significant effects on renal haemodynamics. Trandolapril and vera/tran did not significantly change GFR, but ERPF increased and FF decreased during both treatments (P<0.05). The antiproteinuric response of verapamil was significantly less compared to that of trandolapril and vera/tran (-12% (-17/-1) vs -51% (-56/-25) and -41% (-50/-19) respectively). The blood pressure and antiproteinuric response during verapamil tended to be greater in hypertensive patients than in normotensive patients, although this difference was not significant. Baseline blood pressure was related to the change in blood pressure during verapamil (r = -0.70; P < 0.02).. The antiproteinuric and antihypertensive response of verapamil is less than that of the ACE inhibitor trandolapril in patients with non-diabetic renal disease. In contrast to the antiproteinuric response of trandolapril, the antiproteinuric reponse of verapamil seems to be completely dependent from effective blood pressure reduction. The fixed combination of verapamil and ACE inhibition at half doses has similar effects as ACE inhibition at full dose.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Double-Blind Method; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Indoles; Kidney Diseases; Male; Middle Aged; Proteinuria; Pulse; Verapamil

Early detection of hypertensive end-organ damage and secondary diseases are key determinants of cardiovascular prognosis in patients suffering from arterial hypertension. Presently, there are no biomarkers for the detection of hypertensive target organ damage, most outstandingly including blood vessels, the heart, and the kidneys.We aimed to validate the usefulness of the urinary excretion of the serine protease kallikrein-related peptidase 9 (KLK9) as a biomarker of hypertension-induced target organ damage.Urinary, plasma, and renal tissue levels of KLK9 were measured by the Western blot in different rat models of hypertension, including angiotensin-II infusion, DOCA-salt, L-NAME administration, and spontaneous hypertension. Urinary levels were associated to cardiovascular and renal injury, assessed by histopathology. The origin of urinary KLK9 was investigated through in situ renal perfusion experiments.The urinary excretion of KLK9 is increased in different experimental models of hypertension in rats. The ACE inhibitor trandolapril significantly reduced arterial pressure and the urinary level of KLK9. Hypertension did not increase kidney, heart, liver, lung, or plasma KLK9 levels. Hypertension-induced increased urinary excretion of KLK9 results from specific alterations in its tubular reabsorption, even in the absence of overt nephropathy. KLK9 urinary excretion strongly correlates with cardiac hypertrophy and aortic wall thickening.KLK9 appears in the urine in the presence of hypertension as a result of subtle renal handling alterations. Urinary KLK9 might be potentially used as an indicator of hypertensive cardiac and vascular damage.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arterial Pressure; Biomarkers; Blood Pressure; Cardiovascular Diseases; Disease Models, Animal; Gene Expression; Hypertension; Indoles; Kallikreins; Kidney; Kidney Diseases; Male; Polymerase Chain Reaction; Rats; Rats, Wistar

Hypertension is present in nearly 80% of dialysis patients yet adequately controlled in less than half. We designed a stepped antihypertensive regimen using long-acting antihypertensives (trandolapril, atenolol and amlodipine) administered thrice a week (TIW) after each hemodialysis, and compared blood pressure (BP) control, medication cost and pill burden to each patient's prior daily antihypertensive prescriptions.. Patients were continued on their daily medications, pre-dialysis sitting BP was measured and a 44-hour interdialytic ambulatory BP monitoring (ABPM) was obtained. Then, their medications were stopped and replaced with trandolapril (2 mg TIW). Atenolol and/or amlodipine were also given TIW if the patients had any member of these classes of drugs as part of their daily regimen. Medications were titrated every 2 weeks to achieve a pre-dialysis mean arterial pressure (MAP) of <107 mm Hg. After 2 consecutive weeks with a pre-dialysis MAP of <107 mm Hg, a second 44-hour ABPM was obtained.. Ten patients completed the study. A persistent MAP of <107 was maintained in all 10 patients after conversion to TIW dosing. The systolic BP decreased from 122.2 +/- 7.1 to 116.4 +/- 11.6, and the diastolic BP decreased from 75.3 +/- 10.4 to 70.4 +/- 11.4 mm Hg. Pill burden and cost of medications were also significantly less.. This pilot study found that ACE inhibitor-based, directly observed TIW therapy to be effective in hemodialysis patients with mild to moderate hypertension. Larger trials of directly observed therapy for hypertension in dialysis patients are warranted.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atenolol; Blood Pressure; Calcium Channel Blockers; Chronic Disease; Delayed-Action Preparations; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypertension; Indoles; Kidney Diseases; Male; Middle Aged; Pilot Projects; Renal Dialysis; Severity of Illness Index; Treatment Outcome

In Dahl S rats, high salt increases activity of the tissue renin-angiotensin-aldosterone system (RAAS) in the CNS, heart and kidneys. Here, we assessed the effects of chronic angiotensin converting enzyme (ACE) inhibition on salt-induced hypertension and cardiovascular and renal hypertrophy and fibrosis, relative to the extent of ACE blockade.. From 4.5 weeks of age, Dahl S rats received either the lipophilic ACE inhibitor trandolapril (1 or 5 mg kg(-1) day(-1)) or the hydrophilic ACE inhibitor lisinopril (10 or 50 mg kg(-1) day(-1)) and a high salt diet was started 0.5 week later. Treatments ended at 9 weeks of age.. High salt diet markedly increased blood pressure (BP), decreased plasma angiotensin II and increased ACE binding densities in brain, heart, aorta and kidneys. Trandolapril and lisinopril prevented 50% of the increase in BP in light and dark period of the day. After the last doses, trandolapril decreased ACE densities by approximately 80% in brain nuclei and heart and lisinopril by approximately 60% in the brain and by approximately 70% in the heart. The two ACE inhibitors prevented right ventricular hypertrophy and attenuated left ventricular hypertrophy but did not affect renal hypertrophy caused by high salt. Both drugs prevented high salt-induced fibrosis in heart, kidney and aorta.. As the ACE inhibitors could completely prevent tissue fibrosis and partially prevent tissue hypertrophy and hypertension, the tissue RAAS may play a critical role in salt-induced fibrosis, but a lesser role in the hypertrophy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Cardiovascular Diseases; Drinking; Echocardiography; Fibrosis; Heart Rate; Hypertension; Hypertrophy; Indoles; Injections, Subcutaneous; Kidney; Kidney Diseases; Lisinopril; Male; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Sodium, Dietary; Telemetry

Patients with chronic kidney disease are at increased risk for cardiovascular morbidity and mortality. We assessed the association between albuminuria and the risks for death and cardiovascular events among patients with stable coronary disease.. We studied patients enrolled in the Prevention of Events with an ACE inhibitor (PEACE) trial, in which patients with chronic stable coronary disease and preserved systolic function were randomized to trandolapril or placebo and followed up for a median of 4.8 years. The urinary albumin to creatinine ratio (ACR) assessed in a core laboratory in 2977 patients at baseline and in 1339 patients at follow-up (mean 34 months) was related to estimated glomerular filtration rate and outcomes. The majority of patients (73%) had a baseline ACR within the normal range (<17 mug/mg for men and <25 mug/mg for women). Independent of the estimated glomerular filtration rate and other baseline covariates, a higher ACR, even within the normal range, was associated with increased risks for all-cause mortality (P<0.001) and cardiovascular death (P=0.01). The effect of trandolapril therapy on outcomes was not modified significantly by the level of albuminuria. Nevertheless, trandolapril therapy was associated with a significantly lower mean follow-up ACR (12.5 versus 14.6 mug/mg, P=0.0002), after adjustment for baseline ACR, time between collections, and other covariates. An increase in ACR over time was associated with increased risk of cardiovascular death (hazard ratio per log ACR 1.74, 95% CI 1.08 to 2.82).. Albuminuria, even in low levels within the normal range, is an independent predictor of cardiovascular and all-cause mortality.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Coronary Disease; Creatinine; Death; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Indoles; Kidney Diseases; Male; Middle Aged; Predictive Value of Tests; Randomized Controlled Trials as Topic; Risk Factors; Survival Rate

Endoglin is a membrane glycoprotein that regulates TGF-beta1 signaling. Previous studies have revealed that endoglin is upregulated in several models of experimental fibrosis, and that endoglin expression can counteract the fibrogenic effects of TGF-beta1. As treatment with angiotensin converting enzyme (ACE) inhibitors reduces renal fibrosis by mechanisms that are, in part, not dependent on angiotensin II blockade, we have assessed the hypothesis that this effect could be mediated by endoglin upregulation.. We have used the 5/6-nephrectomy renal mass reduction (RMR) model of renal fibrosis in rats treated (RMR+T) or not treated with the ACE inhibitor trandolapril (0.7 mg/kg/day). One, 3 and 5 months after RMR, mean arterial pressure and renal function were measured. In addition, renal fibrosis was evaluated quantitatively and endoglin, TGF-beta1, collagen type I and collagen type IV expression was assessed by Northern blot and immunohistochemistry.. RMR induced a progressive increase in mean arterial pressure, urinary protein excretion and glomerular and tubulointerstitial fibrosis, which is accompanied by an increased expression of TGF-beta1, endoglin and collagen types I and IV. Trandolapril treatment reduced systemic blood pressure and lessened proteinuria after RMR, as well as expression of TGF-beta1, endoglin and collagens.. The present study demonstrates an increased TGF-beta1, endoglin, collagen type I and collagen type IV expression in rats with severe hypertension and renal damage. The effect of trandolapril to decrease renal fibrosis seems to be based in a reduced TGF-beta1 expression but not in an increased expression of endoglin.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Down-Regulation; Endoglin; Fibrosis; Indoles; Intracellular Signaling Peptides and Proteins; Kidney Diseases; Male; Rats; Rats, Wistar; Signal Transduction; Time Factors; Transforming Growth Factor beta; Up-Regulation

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Indoles; Kidney Diseases; Losartan; Renal Dialysis

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Creatinine; Diuretics; Dose-Response Relationship, Drug; Humans; Indoles; Kidney Diseases; Losartan; Sodium

Inhibition of the renin-angiotensin system (RAS) prevents development of chronic allograft dysfunction in experimental animals. Whether this therapeutic approach is effective even if started when signs of allograft nephropathy are already manifested has not been investigated.. To address this issue, we studied the effect of a late treatment with the angiotensin-convertine enzyme (ACE) inhibitor trandolapril in the Fisher 344 to Lewis rat kidney transplant model. Seven months after transplant a renal biopsy was done for graft histology examination. Thereafter rats received either no treatment (allograft-none) or trandolapril until sacrifice at month 13.. All animals were alive at the end of the study with the exception of a rat in the untreated group that died of renal insufficiency at day 292. Despite the fact that the grafts had already signs of structural injury and function impairment at the time treatment was stated, trandolapril completely restored renal function to baseline pretransplant values. Trandolapril also halted the progression of glomerular damage and suppressed intragraft T-lymphocyte infiltration and reduced the expression of the chemokine monocyte chemoattractant protein-1 (MCP-1). However, trandolapril had no direct effect on T cell function, since in vivo treatment did not modify recipient T-cell alloreactivity against donor antigens.. These findings provide the basis for a novel treatment intervention with RAS blockade that, together with pharmacologic inhibition of the immune response, could interrupt progression of chronic allograft dysfunction and injury.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antibody Formation; Chemokine CCL2; Indoles; Kidney; Kidney Diseases; Kidney Transplantation; Lymphocyte Culture Test, Mixed; Rats; Rats, Inbred F344; Rats, Inbred Lew; Recovery of Function; T-Lymphocytes

Specific endothelin A (ET(A))-receptor blockade and ACE inhibition attenuate chronic transplant nephropathy (CTN) in the 'Fisher-to-Lewis' rat model. It is unknown (i) which of both pharmacological interventions attenuates CTN more effectively and (ii) whether combination therapy exerts additive nephroprotection.. We compared (i) the effects of specific ET(A)-receptor blockade with LU 302146 (30 mg/kg bw/day) and ACE inhibition with trandolapril (0.3 mg/kg bw/day) and (ii) the effect of a combination therapy of both drugs on the development of CTN. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Untreated 'Fisher-to-Lewis' allografts served as controls (TX). All animals received low-dose cyclosporin A (1.5 mg/kg body weight) for 10 days post-transplant to inhibit early acute rejection episodes. The duration of the experiment was 36 weeks. Blood pressure (BP) was measured every other week by tail plethysmography. Indices of glomerulosclerosis (GS), tubulointerstitial and vascular damage, number of glomeruli, total glomerular volume and mean glomerular volume were measured using morphometric and stereological techniques, respectively. Albuminuria, blood chemistry and haematology were measured at the end of the experiment.. LU 302146 did not affect systolic BP. In contrast, trandolapril and combination treatment significantly reduced systolic BP. Histological signs of CTN were almost completely prevented by LU 302146 and trandolapril as compared to TX, e.g. GS=0.8+/-0.08 and 0.9+/-0.20 vs 1.8+/-0.21* (arbitrary unit; *P<0.001 vs treated groups). Allograft weight was significantly lower in treated vs TX animals. Trandolapril and combination therapy, but not LU 302146 alone, abrogated glomerular hypertrophy, i.e. mean glomerular volume: TX 2.22+/-0.43, trandolapril 1.61+/-0.38**, LU 302146 2.22+/-0.11, trandolapril+LU 302146 1.78+/-0.28* (microm(3); *P<0.05 vs control and LU 302146, **P<0.01 vs control and LU 302146). Albuminuria was lower in treated compared to TX animals. Combination therapy did not confer additional benefit compared to the respective monotherapies.. We conclude that ET(A)-receptor blockade abrogates GS, tubulointerstitial and vascular damage in the 'Fisher-to-Lewis' model of CTN to a similar extent as ACE inhibition. However, only ACE inhibition inhibits glomerular hypertrophy. In contrast to ACE inhibition, the effect of ET(A)-receptor blockade is independent of BP. This finding is consistent with the notion that ET(A)-receptor mediated events play a partly BP-independent role in the genesis of CTN. Combination therapy exerts no additive nephroprotection.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Chronic Disease; Drug Therapy, Combination; Endothelin Receptor Antagonists; Indoles; Kidney; Kidney Diseases; Kidney Transplantation; Male; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptor, Endothelin A

The effects of long-term oral administration of the angiotensin-converting enzyme (ACE) inhibitor trandolapril (0.01 mg/kg [T0.01] and 1 mg/kg [T1]) on the occurrence of stroke and on mortality were investigated in young salt-loaded stroke-prone spontaneously hypertensive rats during the treatment period (5-20 weeks of age) and up to 8 weeks thereafter. During the treatment period T1, but not T0.01, limited the increase in blood pressure. However, both doses of trandolapril prevented stroke and mortality and strongly opposed (T0.01) or abolished (T1) the increases in saline intake, diuresis, and proteinuria observed in control animals. Simultaneously, trandolapril markedly prevented (T0.01) or abolished (T1) vascular fibrinoid necrosis formation in the brain, kidney, and heart. Finally, trandolapril dose-dependently reduced arterial thickening and glomerular and tubulointerstitial lesions in the kidney, as well as arterial thickening, infarction, and fibrosis in the myocardium. At 8 weeks after treatment withdrawal, the antihypertensive effect of T1 had disappeared, but stroke-related mortality and fibrinoid necrosis remained completely suppressed. Further, no additional cerebral, renal, or cardiac lesions developed, and no increase in proteinuria occurred. In the T0.01 group, 17% of the animals died, fibrinoid necrosis tended to develop, organ lesions worsened, and proteinuria strongly increased. We conclude that (1) early ACE inhibition with trandolapril affords a long-lasting protection versus stroke and mortality both during and after the treatment period; and (2) that this beneficial effect is due to the suppression of fibrinoid necrosis formation and not to the drug's antihypertensive action. In contrast, both properties appear to contribute to trandolapril's renal and cardiac protective effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cerebrovascular Disorders; Heart Diseases; Hypertension; Indoles; Kidney Diseases; Male; Rats; Rats, Inbred SHR; Time Factors