imidapril and Proteinuria

The principal means for reducing proteinuria in patients with chronic kidney disease are strong blockade of the renin-angiotensin system and strict regulation of blood pressure (BP). This study compared the efficacy of the maximum permissible doses of two common angiotensin receptor blockers (ARBs), namely valsartan (maximum dose=160 mg per day) and olmesartan (maximum dose=40 mg per day). We also investigated whether a high-dose ARB or the combination of an angiotensin-converting enzyme inhibitor with a high-dose ARB would be more renal protective. We recruited 87 poorly controlled hypertensive patients. In the first study, 50 patients without proteinuria were switched from valsartan (160 mg per day) to olmesartan (40 mg per day) for 4 months. In the second study, 37 patients with proteinuria were randomized to either switch from valsartan 160 mg per day to 40 mg per day olmesartan (n=19; Olm-G) or addition of 2.5-10 mg per day imidapril (stepped up by 2.5 mg per month) to valsartan at 160 mg per day (n=18; Imi-G). After 4 months, the BP level decreased (first study) from 157/88 mm Hg to 145/82 mm Hg (P<0.001) and (second study) from 149/86 mm Hg to 135/77 mm Hg and 145/82 mm Hg for Olm-G and Imi-G, respectively. Furthermore, in the second study, urinary protein/creatinine excretion was reduced from 2.0±1.8 g g⁻¹ to 0.8±0.8 g g⁻¹ (P=0.0242) in Olm-G and from 1.4±1.3 g g⁻¹ to 0.9±1.0 g g⁻¹ (P=0.0398) in Imi-G. The significance persisted after adjustment for BP or other risk factors. Our results suggested that the maximum dose of olmesartan was more effective than that of valsartan and comparable with the combination of valsartan and imidapril for reducing BP and proteinuria in poorly controlled hypertensive patients.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chronic Disease; Drug Therapy, Combination; Female; Hawaii; Humans; Hypertension; Imidazoles; Imidazolidines; Kidney; Kidney Diseases; Male; Middle Aged; Proteinuria; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

MRL-Fas(lpr) mice spontaneously develop a systemic autoimmune disease resembling human systemic lupus erythematosus. The glomerulonephritis in MRL-Fas(lpr) mice is mediated by autoantibodies and autoreactive lymphocytes. To investigate the effect of combination therapy by angiotensin-converting enzyme inhibitor (ACEI) and hydroxymethylglutaryl-coenzyme A reductase inhibitor (statin) for lupus nephritis, we treated MRL-Fas(lpr) mice with imidapril, pravastatin or both agents. Compared with other groups, the mice treated by combination therapy survived longer and showed a significant reduction in proteinuria, renal pathology, including glomerular IgG deposit, and serum anti-DNA Ab. Furthermore, monocyte chemoattractant protein-1 (MCP-1) in the kidney was reduced significantly in the combination therapy group, compared with that in the control group. We conclude that combination therapy with ACEI and statin for MRL-Fas(lpr) mice significantly alleviates autoimmune renal disorder and prolongs survival. These results suggest that combination therapy by ACEI and statin may represent a new approach to the treatment of patients with lupus.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies, Antinuclear; Blood Pressure; Cytokines; Drug Therapy, Combination; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Imidazolidines; Immunoglobulin G; Kidney; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice; Mice, Inbred C3H; Mice, Inbred MRL lpr; Pravastatin; Proteinuria; Random Allocation; Specific Pathogen-Free Organisms

The objective of the present study was to compare the effects of imidapril hydrochloride, an angiotensin converting enzyme inhibitor, and dilazep hydrochloride, an antiplatelet agent, on urinary protein excretion and renal function in patients with chronic glomerulonephritis. Imidapril (2.5 or 5 mg/day) or dilazep (300 or 450 mg/day) was administered for 3 years. Blood pressure, proteinuria, and renal function were measured before and during the treatment. In the group administered imidapril (n = 11), urinary protein decreased by approximately 50% (2.16 +/- 1.57 versus 0.90 +/- 0.53 g/g Cr, P < 0.01) and blood pressure by 14/10 mmHg (139.6 +/- 17.4/93.6 +/- 8.7 mmHg versus 122.7 +/- 10.5/81.8 +/- 9.9 mmHg, P < 0.01) and both remained at low levels during the three years of treatment. No correlation was observed between the extent of blood pressure reduction and changes in urinary protein. Serum creatinine concentrations did not change significantly (1.3 +/- 0.3 versus 1.3 +/- 0.3 mg/dL, NS). In the dilazep group (n = 12), there were no significant changes in blood pressure, urinary protein, or serum creatinine. These findings demonstrate that imidapril reduces proteinuria and contributes to preserve renal function, suggesting its usefulness in the treatment of patients with chronic glomerulonephritis.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Chronic Disease; Dilazep; Drug Therapy, Combination; Female; Glomerulonephritis; Humans; Hypertension, Renal; Imidazolidines; Kidney; Male; Middle Aged; Proteinuria

Chronic inhibition of nitric oxide synthase (NOS) is known to cause renal parenchymal injury with systemic hypertension. To elucidate the pathogenetic mechanism in renal damage induced by NOS inhibition, N(omega)-nitro-L-arginine methyl ester (L-NAME) was given orally for 12 wk in Wistar rats, and the roles of tissue renin-angiotensin system and transforming growth factor-beta1 (TGF-beta1) were investigated. BP and urinary protein excretion increased significantly in L-NAME rats compared with control rats, and glomerulosclerosis and interstitial fibrosis developed. In L-NAME rats, the cortical tissue levels of angiotensin-converting enzyme activity and angiotensin II were significantly higher than those in control rats. The cortical mRNA expressions of both TGF-beta1 and fibronectin were significantly elevated in L-NAME rats. Immunohistochemically, increased expressions of both fibronectin and alpha-smooth muscle actin were also revealed in L-NAME rats. In L-NAME rats, these histologic injuries and the increased expression of TGF-beta1 were equally ameliorated by either angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist, but not by hydralazine. In conclusion, the locally activated renin-angiotensin system in connection with the increased TGF-beta1 expression is a major pathogenetic feature of renal injury in chronically NOS-inhibited rats.

Topics: Actins; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Enzyme Inhibitors; Fibronectins; Imidazoles; Imidazolidines; Kidney; Kidney Cortex; Kidney Diseases; Male; Muscle, Smooth; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Proteinuria; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; RNA, Messenger; Time Factors; Transforming Growth Factor beta

We investigated the effect of angiotensin-converting enzyme inhibition on spontaneous nephrosis in Dahl salt-sensitive (Dahl/S) rats. Dahl/S rats fed on a normal sodium diet spontaneously developed nephrosis and mild hypertension from a young age. In young Dahl/S rats, an angiotensin-converting enzyme inhibitor, imidapril, attenuated the development of proteinuria accompanied by a decrease in blood pressure. Methylprednisolone, a potent therapeutic agent for proteinuria, did not affect the development of nephrosis. An angiotensin AT1 receptor antagonist, losartan, but not a Ca2+ channel blocker, verapamil, inhibited the development of nephrosis while both agents decreased blood pressure to a similar extent as imidapril. In mature Dahl/S rats, imidapril suppressed not only the development of proteinuria but also the glomerular lesions. It is concluded that the development of spontaneous nephrosis in Dahl/S rats is mediated by angiotensin II.

Topics: Aging; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Body Weight; Calcium Channel Blockers; Cholesterol; Glucocorticoids; Hypertension; Imidazoles; Imidazolidines; Losartan; Male; Methylprednisolone; Nephrosis; Proteinuria; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Verapamil

To elucidate the effect of imidapril, an angiotensin-converting enzyme inhibitor, on molecular events in progressive glomerulosclerosis, we administered imidapril to 5/6 nephrectomized rats and measured the glomerular expression of genes for transforming growth factor (TGF)-beta1, fibronectin and collagen IV. Glomerular TGF-beta1, fibronectin and collagen IV mRNAs in nephrectomized rats were significantly higher than those in sham-operated rats. Treatment with imidapril for 10 weeks significantly reduced the enhanced glomerular expression of TGF-beta1 and collagen IV mRNA in nephrectomized rats, and prevented the associated proteinuria and glomerulosclerosis. Thus, imidapril may arrest progressive glomerulosclerosis by inhibiting the expression of TGF-beta1 and collagen IV.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Collagen; Fibronectins; Gene Expression; Imidazoles; Imidazolidines; Kidney Glomerulus; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sclerosis; Transforming Growth Factor beta