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Arterial hypertension, which represents a common problem in patients with renal transplant, contributes to the cardiovascular morbidity and mortality of these patients. The most usual immunosuppressive drugs (cyclosporine and FK-506) collaborate on the development of hypertension. Calcium channel blockers are the most habitually used antihypertensive drugs in this population, although its long-term hemodimamycs effects could be deleterious especially in transplanted patients with chronic graft nephropathy. Losartan, a specific blocker of angiotensin II (AT1) receptors, has demonstrated a potent antihypertensive effect with a good safety and tolerance profile. The glomerular effects of losartan could be useful in transplanted patients. The present open, prospective and multicenter study evaluated the efficacy and safety of losartan in the treatment of hypertension in a group of patients with a renal transplant. Seventy-six patients with systolic blood pressure > or = 140 and/or diastolic blood pressure > or = 90 mm Hg, and/or patients on therapy with one antihypertensive drug and related side effects were included. After inclusion, therapy with losartan 50 mg/24 hr was started, discontinuing the previous antihypertensive therapy and/or therapy which caused the side effects. At four weeks, if blood pressure (BP) was not controlled, hydrochlorothiazide 25 mg or furosemide 40 mg/24 hr was added. At baseline and at weeks 2, 4, 8 and 12, the following parameters were monitored: BP, creatinine, hematocrit, hemoglobin, glucose, ions, uric acid, cholesterol, triglycerides, bilirubin, SGOT, SGPT, GGT, LDH, calcium, phosphate, alkaline phosphatase, proteinuria, and both cyclosporine and FK-506 levels in whole blood. Sixty-seven patients completed the 12-week study period. Mean blood pressure decreased from 113 +/- 10 to 102 +/- 9 mm Hg at the end of the study (P < 0.0001); 38 of the 67 patients (56.7%) who completed the study had a SBP lower than 140 mm Hg and a DBP lower than 90. These blood pressures were obtained in 30 patients on monotherapy with losartan (78.9%). Proteinuria decreased significantly at week 4 and was confirmed at week 12, especially in patients with proteinuria > or = 300 mg/24 hr. Nine patients were withdrawn during the study period for different reasons. Serum creatinine showed a slight, non-clinically significant increase at week 4, remaining stable until the end of the study. Two patients developed a mild normocytic anemia, and three others presented a mild impairment of pre-existent anemia. No interactions with cyclosporine or FK-506 were described. These results indicate that losartan is effective in reducing BP in hypertensive patients with a renal transplant. It has a good tolerance profile and does not interfere with immunosuppressive therapy.
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PMID:Efficacy and safety of losartan in the treatment of hypertension in renal transplant recipients. 983 98

In the present study we evaluated the nature of angiotensin receptors involved in the antidiuretic effect of angiotensin-(1-7) (Ang-(1-7)) in water-loaded rats. Water diuresis was induced in male Wistar rats weighing 280 to 320 g by water load (5 ml/100 g body weight by gavage). Immediately after water load the rats were treated subcutaneously with (doses are per 100 g body weight): 1) vehicle (0.05 ml 0.9% NaCl); 2) graded doses of 20, 40 or 80 pmol Ang-(1-7); 3) 200 nmol Losartan; 4) 200 nmol Losartan combined with 40 pmol Ang-(1-7); 5) 1.1 or 4.4 nmol A-779; 6) 1.1 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 7) 4.4 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 8) 95 nmol CGP 42112A, or 9) 95 nmol CGP 42112A combined with 40 pmol Ang-(1-7). The antidiuretic effect of Ang-(1-7) was associated with an increase in urinary Na+ concentration, an increase in urinary osmolality and a reduction in creatinine clearance (CCr: 0.65 +/- 0.04 ml/min vs 1.45 +/- 0.18 ml/min in vehicle-treated rats, P < 0.05). A-779 and Losartan completely blocked the effect of Ang-(1-7) on water diuresis (2.93 +/- 0.34 ml/60 min and 3.39 +/- 0.58 ml/60 min, respectively). CGP 42112A, at the dose used, did not modify the antidiuretic effect of Ang-(1-7). The blockade produced by Losartan was associated with an increase in CCr and with an increase in sodium and water excretion as compared with Ang-(1-7)-treated rats. When Ang-(1-7) was combined with A-779 there was an increase in CCr and natriuresis and a reduction in urine osmolality compared with rats treated with Ang-(1-7) alone. The observation that both A-779, which does not bind to AT1 receptors, and Losartan blocked the effect of Ang-(1-7) suggests that the kidney effects of Ang-(1-7) are mediated by a non-AT1 angiotensin receptor that is recognized by Losartan.
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PMID:Effect of selective angiotensin antagonists on the antidiuresis produced by angiotensin-(1-7) in water-loaded rats. 987 90

The benefit of angiotensin-converting enzyme (ACE) inhibitor (i) therapy in diabetic glomerulosclerosis is thought to be largely the result of attenuation of angiotensin II (AngII) effects on blood pressure, glomerular hemodynamics and hypertrophy, and tissue fibrosis. The present study was undertaken to determine whether the addition of AngII receptor antagonist therapy to ACEi therapy in diabetic nephropathy results in attenuation of AngII effects beyond that achieved by ACEi therapy alone. Seven patients were studied as inpatients on the General Clinical Research Center each for 3 consecutive weeks as follows: week 1, the patients' usual regimen which included daily oral moderate to high dose ACEi therapy; week 2, the patients' usual regimen plus oral losartan (an antagonist (a) of the angiotensin type 1 receptor, AT1) 50 mg (n = 3) or 100 mg (n = 4) daily; week 3, return to the patients' usual regimen. Diet, physical activity, and blood glucose were held as constant as possible during the three weeks of daily testing. We found that plasma renin levels increased significantly during combination therapy and then returned to baseline values with discontinuation of AT1a therapy: mean baseline renin values (week 1) 3.0 ng/ml/min +/- 1.1 SE, mean renin values during combination therapy (week 2) 7.0 ng/ml/min +/- 3.2 (p = 0.0078 by Wilcoxon rank sum test), mean renin values after discontinuation of AT1a therapy (week 3) 3.9 ng/ml/min +/- 2.0 (NS compared to baseline values). In addition, 2 patients developed transient hypotension when losartan therapy was initiated. During this short-term study, 24-hour proteinuria, serum creatinine, serum potassium, and plasma aldosterone were not changed significantly by combination therapy. We conclude that in patients with diabetic nephropathy addition of AT1a therapy to ACEi therapy attenuates AngII effects better than ACEi therapy alone. We suggest that combination therapy for the management of diabetic glomerulosclerosis merits further investigation.
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PMID:Combination ACE inhibitor and angiotensin II receptor antagonist therapy in diabetic nephropathy. 1008 42

Experimental renal ischaemic injuries are typically produced by temporary closure of the renal artery. In rats, two different methods of such temporary closure of the renal artery were compared: snaring of the artery by tourniquet, and clamping by a microsurgical bulldog clamp. The consequences of ischaemic periods 60, 90 and 120 minutes were evaluated. In different experimental series, the potential protective effect of non-peptic AT1 angiotensin II receptor antagonist losartan on postischaemic renal injury was evaluated. The seven-day survival and the degree of functional renal damage (according to the plasma levels of creatinine and urea) were analyzed 24 hours and 7 days after experimental renal ischaemia. Ischaemia, produced by the tourniquet led to a more significant renal damage than ischaemia caused by clamping of the renal artery by a microclamp (higher 7-day mortality rate, higher postischaemic plasma levels of creatinine and urea). Losartan decreased the consequences of renal ischaemia caused by the tourniquet, but did not change the outcome of renal ischaemia produced by microsurgical bulldog clamps. We found, that not only the duration of ischaemia and pharmacology, but even the surgical technique of producing renal ischaemia are important factors in experimental studies evaluating ischaemic renal damage. These findings provide evidence of the role of angiotensin II in postischaemic renal injury by a renal tourniquet. This particular mechanism is probably not involved, when renal artery is gently temporarily closed by a bulldog microclamp.
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PMID:[Experimental ischemic renal injury--effect of surgical technique and the protective effect of a nonpeptide angiotensin II antagonist (losartan)]. 1107 68

AT1 receptor antagonists control blood pressure (BP) effectively and reduce left ventricular hypertrophy in patients with essential hypertension. Because left ventricular hypertrophy is very common in renal transplant recipients, we examined the cardiovascular effects and the safety profile of the AT1 receptor antagonist losartan in hypertensive renal transplant recipients. In 20 renal transplant recipients with stable renal graft function 50 mg of losartan was added to the preexisting antihypertensive treatment (no angiotensin-converting enzyme inhibitors) at least 6 months after renal transplantation. Twenty-four-hour ambulatory BP, two-dimensional-guided M-mode echocardiography, and duplex sonography, as well as renal function, red blood cell count, cyclosporine A and FK 506 levels, erythropoetin, and angiotensin II concentration were determined at baseline and after 6 months of therapy. With 24-h ambulatory BP measurement, systolic blood pressure (SBP) was reduced by 7.5 +/- 2.4 mm Hg and diastolic blood pressure (DBP) by 4.5 +/- 1.8 mm Hg (P < .01 and P < .05, respectively). Posterior, septal, and relative wall thickness decreased by 0.95 +/- 0.2 mm, 0.91 +/- 0.2 mm and 0.04 +/- 0.01 mm, respectively (all P < .001). Left ventricular mass index decreased by 18.1 +/- 4.7 g/m2 (P < .01). Ejection fraction and midwall fractional fiber shortening as systolic parameters and the relation of passive-to-active diastolic filling of the left ventricle were unaltered. Serum creatinine and cyclosporine A concentration remained stable in all patients. Hemoglobin and hematocrit decreased by 1.0 +/- 0.3 g/dL and 3.6% +/- 0.9%, respectively (P < .002 and P < .001) without a change in serum erythropoetin level. In renal transplant recipients the AT1 receptor antagonist losartan reduces left ventricular hypertrophy without altering systolic or diastolic function. It is safe with regard to renal function and immunosuppression, but slightly decreases hemoglobin level.
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PMID:Regression of left ventricular hypertrophy by AT1 receptor blockade in renal transplant recipients. 1113 Jul 74

This study was undertaken to determine whether angiotensin receptor blockers are as renoprotective as angiotensin-converting enzyme inhibitors in an experimental model of chronic interstitial renal disease. Groups of rats received one of the following treatments for 1 week: (1) enalapril, (2) diltiazem, (3) a cocktail of hydralazine, reserpine, and hydrochlorothiazide, or (4) irbesartan (an AT1 antagonist). The animals were injected with bromoethylamine (200 mg/kg), and antihypertensive treatment continued for 1 month. All drugs were effective in lowering the mean arterial pressure. The bromoethylamine-treated rats developed albuminuria and sustained a 40-50% decrease in creatinine clearance. Enalapril and irbesartan reduced albuminuria, but only enalapril partially prevented the decline in creatinine clearance and lowered the number of ED-1-positive cells. Diltiazem and cocktail had no effect on proteinuria, creatinine clearance, or ED-1 cells. In this experimental model, the effects of enalapril and irbesartan were not identical. Both drugs reduced proteinuria, but enalapril was more effective in protecting the renal function. The fact that the AT1 antagonist protected against albuminuria but did not affect the clearance of creatinine implies that the results seen with angiotensin-converting enzyme inhibition may be in part due to an effect on angiotensin II via AT2 receptor blockade or through an effect on bradykinin.
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PMID:Differential effects of enalapril and irbesartan in experimental papillary necrosis. 1117 5

1. In the present study, we examined whether KRH-594, a new angiotensin AT1 receptor antagonist, would stop the progression of renal failure and end-organ damage and improve the survival rate in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP/Izm). 2. Oral administration of KRH-594 (3 and 10 mg/kg per day) for 11 weeks significantly reduced systolic blood pressure, urinary total protein, blood urea nitrogen, serum creatinine and urinary N-acetyl glucosaminidase and increased creatinine clearance in SHRSP/Izm. 3. In a histological study, KRH-594 (3 and 10 mg/kg per day) significantly improved the glomerulosclerosis, basophilic change and hyalin cast of tubules, proliferation of afferent arterioles and interlobular artery wall scores of the kidney and the cardiac fibrosis scores of the heart in SHRSP/Izm. KRH-594 (3 and 10 mg/kg per day) also significantly inhibited cardiac hypertrophy. 4. KRH-594 (3 and 10 mg/kg per day) prevented death in SHRSP/Izm during the examination period. 5. These results suggest that KRH-594 improves hypertensive complications, such as renal failure, cardiac hypertrophy and thickening of the artery wall, and prevents death in salt-loaded SHRSP/Izm.
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PMID:KRH-594, a new angiotensin AT1 receptor antagonist, prevents end-organ damage in stroke-prone spontaneously hypertensive/Izm rats. 1120 77

The present study investigated the effects of telmisartan, a selective AT1 receptor antagonist, on renal function in dogs. Conscious female dogs were treated with (i) vehicle (controls) and three doses of telmisartan (0.03 mg/kg, 0.1 mg/kg and 0.3 mg/kg) administered intravenously; (ii) vehicle and three doses of telmisartan (0.3 mg/kg, 1.0 mg/kg and 3.0 mg/kg) administered orally; or (iii) 1.0 mg/kg per day telmisartan orally for 12 days. Eight dogs were used for each experiment. Each of the four treatments in (i) and (ii) was administered 7 days apart. During the 6 h after intravenous administration, urine volume was significantly higher in dogs treated with telmisartan 0.1 mg/kg (8.5 +/- 1.6 ml/kg) and 0.3 mg/kg (7.0 +/- 0.9 ml/kg) than controls (2.7 +/- 0.3 ml/kg; P < 0.05), and renal sodium excretion was increased significantly with telmisartan 0.03 mg/kg (803 +/- 124 micromol/kg), 0.1 mg/kg (1039 +/- 213 micromol/kg) and 0.3 mg/kg (966 +/- 161 micromol/kg) versus controls (159 +/- 21 micromol/kg; P < 0.05). Oral telmisartan at doses of 1.0 mg/kg and 3.0 mg/kg also produced significant increases in urine volume (7.2 +/- 1.1 ml/kg and 6.6 +/- 1.2 ml/kg, respectively) and renal sodium excretion (599 +/- 146 micromol/kg and 555 +/- 131 micromol/kg, respectively) compared with controls (2.8 +/- 0.5 ml/kg and 80 +/- 33 mciromol/kg; P < 0.05) over the 6-h post-dose period. Telmisartan at all intravenous doses and at 3.0 mg/kg orally increased the urinary excretion of chloride significantly over the 6-h post-dose period compared with vehicle alone. The excretion of potassium and creatinine were unchanged by any treatment. Telmisartan 1.0 mg/kg administered orally for 12 days produced similar results. In conclusion, acute intravenous or oral as well as subchronic oral administration of telmisartan to conscious dogs promotes diuresis and natriuresis without affecting potassium or creatinine excretion.
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PMID:Effects of telmisartan on renal excretory function in conscious dogs. 1139 46

Angiotensin-converting enzyme (ACE) inhibitors and AT1-receptor antagonists (ARAs) are widely administered to reduce urinary protein loss and slow the progression of proteinuric nephropathy to end-stage renal failure. Our group recently observed that the combination of ACE inhibitors and ARAs may have an additive antiproteinuric effect, which may occur because ACE inhibitors do not completely reduce angiotensin II (Ang II) production. Ang II is also produced by chymase. Thus, combination therapy better antagonizes the effects of Ang II. The purpose of this study is to ascertain whether the additive antiproteinuric effect of ACE inhibitors plus ARAs is dose dependent and related to the drug-induced reduction in systemic blood pressure. Therefore, enalapril (E; 10 mg/d) and losartan (LOS; 50 mg/d) were randomly administered alone and then in association; initial dosages were doubled when drugs were administered alone and in association. To determine the influence of the drug-dependent effect on reducing blood pressure and the reduction in urinary proteinuria, both ambulatory and office blood pressures were recorded. E and LOS administered alone reduced proteinuria by the same extent; no further reduction was observed when E and LOS alone were administered at a doubled dose. When E and LOS were coadministered, proteinuria decreased by a greater extent compared with E and LOS alone; an additional reduction in proteinuria was observed when combined therapy doses were doubled. The reduction in proteinuria was not correlated with clinical through blood pressure; however, reductions in diastolic and mean ambulatory blood pressures significantly correlated with the decrease in proteinuria, as well as with creatinine clearance. In conclusion, this study shows that combination therapy with E and LOS has an additive dose-dependent antiproteinuric effect that is likely induced by the drug-related reduction in systemic blood pressure. In normotensive proteinuric patients, it is likely that even a small reduction in systemic blood pressure may affect intraglomerular hemodynamics by a great extent because efferent arteriole regulation is hampered more completely by the coadministration of ACE inhibitors and ARAs.
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PMID:Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. 1177 26

The effect on renal function and efficacy of the angiotensin II AT1-receptor blocker (ARB), telmisartan, were compared with those of the angiotensin-converting enzyme inhibitor, enalapril, for the treatment of mild-to-moderate hypertension (diastolic blood pressure [DBP] 95-114 mmHg) in the presence of moderate renal failure (creatinine clearance [Ccr] 30-80 ml/minute). The study was multicentre, double-blind, double-dummy and active-controlled in design, with patients randomised in a 2:1 ratio to receive telmisartanor enalapril. After a two-week placebo run-in period, the 71 eligible patients received either telmisartan, 40 mg, orenalapril, 10 mg, once-daily for four weeks. Thereafter, doses were titrated to telmisartan 80 mg or enalapril 20 mg once-daily if supine trough DBP was still > or =90 mmHg. After a further four weeks, dose titration was again performed, as required, to telmisartan, 80 mg,or enalapril, 20 mg, or frusemide was given in addition if the double dose was already being administered. Mean Ccr decreases of 4.6% for telmisartan and 2.8% forenalapril were not clinically significant. Adverse events occurred in 12 (26.7%) telmisartan-treated patients and in 12 (46.2%) patients receiving enalapril. The mean reduction in supine trough DBP from baseline to the last available value was 12.5 mmHg for telmisartan,compared with 11.9 mmHg for enalapril. A full (reduction of >or=10 mmHg) or partial (reduction of 7-9 mmHg) response occurred in 78% of telmisartanpatients and 65% of enalapril patients. In the enalapril group, 43% of patients required frusemide, compared with 29% of those in the telmisartan group. In conclusion, telmisartan lacks detrimental effect on renal function, is effective in the treatment of mild-to-moderate hypertension in patients with moderate renal failure,and is comparable to enalapril.
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PMID:Evaluation of the safety and efficacy of telmisartan and enalapril, with the potential addition of frusemide, in moderate-renal failure patients with mild-to-moderate hypertension. 1188 Nov 31


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