PURPOSE: Effects of renin-angiotensin system blockade on tubulointerstitial lesions were examined in adriamycin-induced nephropathy. METHODS: Male Sprague-Dawley rats were used. The three experimental groups were intravenously injected with adriamycin (2 mg/kg). After 6 weeks, rats showing heavy proteinuria were orally treated with either cilazapril 1 mg/kg/day (ACEi group, n=7) or losartan 10 mg/kg/day (ARB group, n=7) during the period of additional 6 weeks. The other group was maintained without any drugs (ADR group, n=6). The control group was without adriamycin treatment and maintained during the 12 weeks (Control, n=5). RESULTS: Systolic blood pressure was increased following the adriamycin treatment, which was normalized by treatment with cilazapril or losartan. Accordingly, cilazapril and losartan normalized the 24-h urine protein/creatinine ratio, in association with morphologic improvement of tubulointerstitial lesions. The expression of laminin beta1 was not altered in any experimental groups. CONCLUSION: These results suggest that angiotensin II plays an important role in tubulointerstitial lesions in adriamycin-induced nephropathy.
Angiotensin II ; Animals ; Blood Pressure ; Cilazapril ; Doxorubicin ; Humans ; Laminin ; Losartan ; Male ; Proteinuria ; Rats ; Rats, Sprague-Dawley ; Renin-Angiotensin System*

BACKGROUND AND OBJECTIVES: Angiotensin converting enzyme inhibitor (ACEI) is known to be effective in the prevention of left ventricular failure (LVF) after acute myocardial infarction. The aim of this study was to investigate the efficacy of an ACEI, Cilazapril, on left ventricular remodeling in patients with ischemic LVF, who underwent coronary interventions. MATERIALS AND METHODS: Cilazapril, 2.5 - 5.0 mg per day was administ-ered 12 weeks after coronary interventions in 25 patients (18 M, 7 F, 61.5+/-9 years) with impaired LV function (ejection fraction< or = 50%). Fifteen patients (9 M, 6 F, 59.4+/-7 years) without ACEI were compared by clinical examinations, blood chemistry, electrocardiogram and echocardiogram with Cilzapril group at 2, 4, 8 and 12 weeks after intervention. RESULTS: Blood pressure and heart rate were not changed after Cilazapril. LV end-diastolic volume (LVEDV) decreased from 153.1+/-38.7 to 135.6+/-25.5 ml and end-systolic volume from 84.9+/-34.7 to 72.6+/-25.1 ml after 12-week Cilazapril p=0.003, p=0.001. Ejection fraction (EF) was increased from 44.4+/-3.2 to 52.4+/-2.8% after 12 weeks of Cilazapril p=0.034. In control group, LVEDV was changed from 152.7+/-44.6 to 143.6+/-28.7 ml, which failed to show significant reduction. Side effects of Cilazapril were 3 dry cough (3/25, 12%) and 1 facial edema, 1 hypotension and 1 dizziness. CONCLUSION: Cilazapril is a beneficial adjunctive therapeutic agent in patients with ischemic left ventricular failure for the prevention of ventricular dilatation, especially after coronary intervention.
Blood Pressure ; Chemistry ; Cilazapril* ; Cough ; Dilatation ; Dizziness ; Edema ; Electrocardiography ; Heart Failure* ; Heart Rate ; Heart* ; Humans ; Hypotension ; Myocardial Infarction ; Peptidyl-Dipeptidase A ; Ventricular Remodeling*

BACKGROUND: In order to investigate the efficacy and safety of cilazapril, a recently developed angiotensin converting enzyme inhibitor, a clinical study was performed in the patients with mild to moderate essential hypertension. METHODS: The study subject consisted of 31 patients with diastolic blood pressure of 95mmHg~115mmHg (mean age : 56.0+/-8.1 years, 16 males and 15 females). Cilazapril was administered orally in a daily dose of 2.5mg~5.0mg Q.D. for 8 weeks. During cilazapril medication, anti-hypertensive efficacy, side effects and laboratory changes were monitored. RESULTS: Cilazapril decreased blood pressure from baseline value of 162.2+/-4.7/98.4+/-2.8mmHg to 144.6+/-10.0/89.7+/-5.7mmHg after 4weeks of medication (p<0.05) and 138.2+/-4.5/87.8+/-4.0mmHg after 8 weeks of medication (p<0.05). Heart rate change was not significant (72.3+/-4.7/min vs 71.7+/-3.6/min). Body weight change was not significant (66.6+/-9.8 Kg vs 66.8+/-9.9 Kg). There were no significant change in blood chemistry and hematologic examination except mild elevation of alanine transaminase and serum creatinine values but these date were within normal ranges. The side effects were dry cough (4 case, 12.9%), headache (2 case, 6.4%), indigestion (1 case, 3.2%) and dry mouth (1 case, 3.2%). One patient dropped out due to severe dry cough but others were mostly mild in nature. CONCLUSIONS: Cliazapril 2.5mg~5.0mg once daily regimen was effective and well tolerated in patients with mild to moderate essential hypertension.
Alanine Transaminase ; Blood Pressure ; Body Weight Changes ; Chemistry ; Cilazapril* ; Cough ; Creatinine ; Dyspepsia ; Headache ; Heart Rate ; Humans ; Hypertension* ; Male ; Mouth ; Peptidyl-Dipeptidase A ; Reference Values

Apolipoprotein (apo) E deficient mouse can produce reproducible fixed stenotic primary atherosclerotic lesion, which reveals failure to remodel of vascular lumen, in the ascending aorta, external carotid, common carotid, iliac, femoral and popliteal arteries. To evaluate the effect of drugs in regarding to both prevention of primary atherosclerotic lesion and vascular remodeling, a systematic analysis of distribution of atherosclerotic lesions was undertaken in chow-fed, 9-momth-old apo E deficient mice, which was administrated drugs including asprin, methotrexate, probucol, sulodexide, diltiazem, cilazapril, trimetazidine, molsidomine, pentoxiphylline and Ginexin (R) for 7 month from 3 month-old. On gross and microscopic examination, formation of primary atheroscleotic lesions could be delated and/or prevented patially by effets of these drugs. On morphometric examination, failure to remodel forming vascular stenosis could not be seen, though relatively mild atherosclerotic lesion occured at vascular tree. These data suggest that the stenotic process in advanced atherosclerotic vessels can be delayed and/or prevented by several drugs including methotrexate, probucol, sulodexide, diltiazem, cilazapril, trimetazidine, molsidomine, pentoxiphylline and Ginexin (R) in vivo state.
Animals ; Aorta ; Apolipoproteins ; Apolipoproteins E* ; Atherosclerosis ; Cilazapril ; Constriction, Pathologic ; Diltiazem ; Humans ; Infant ; Methotrexate ; Mice ; Mice, Knockout* ; Molsidomine ; Popliteal Artery ; Primary Prevention ; Probucol ; Trimetazidine

Laminin, an extracellular matrix glycoprotein, is distributed in the basement membrane of renal glomerulus. Laminin has been demonstrated to regulate the development and differentiation of glomeruli and play an important role in the filtering function of glomeruli. To address whether laminin beta 1 chain is associated with the pathogenic states of renal injury and recovery, nephropathy were induced by intravenous adriamycin injection and subsequently cured by treatment with antihypertensive drugs, cilazapril (angiotensin-converting enzyme inhibitor, ACEi) and lozartan (angiotensin receptor blockade, ARB), which have been known to be effective on renal protection. The results we obtained were as follows: 1. At 6 and 12 weeks after adriamycin injection, epithelial cells of proximal convoluted tubules exhibited intensive deposition of laminin beta 1 chain reactive gold particles. Cytoplasm of podocytes and mesangial cells in glomeruli showed an increase in the gold particle deposition as compared with that of controls. The mRNA level of laminin beta 1 chain was enhanced in the epithelial cells of proximal convoluted tubules. 2. Following cilazapril administration to adriamycin -induced nephropathy rats, laminin beta 1 chain reactive gold particle deposition was reduced in the epithelial cells of proximal convoluted tubules, podocytes, and mesangial cells. The level of laminin beta 1 chain transcripts was remarkably decreased in the epithelial cells of proximal convoluted tubules. 3. Following losartan administration to adriamycin -induced nephropathy rats, podocytes and mesangial cells were deposited with reduced number of laminin beta 1 chain reactive gold particles. The laminin beta 1 chain reactive gold particles and level of laminin beta 1 chain mRNA transcripts were remarkably reduced in the epithelial cells of proximal convoluted tubules. 4. Treatment with mixture of cilazapril and losartan to adriamycin -induced nephropathy rat resulted in a decrease in laminin beta 1 chain reactive gold particle deposition within the epithelial cells of proximal convoluted tubules, podocytes, and mesangial cells. Laminin beta 1 chain mRNA expression in the epithelial cells of proximal convoluted tubules nearly disappeared. These results consequently suggest that laminin beta 1 chain may be synthesized within the epithelial cells of proximal convoluted tubules, podocytes and mesangial cells and laminin beta 1 chain may play an important role on tissue recovery of the renal tissues injured by adriamycin.
Animals ; Antihypertensive Agents ; Basement Membrane ; Cilazapril* ; Cytoplasm ; Doxorubicin ; Epithelial Cells ; Extracellular Matrix ; Glycoproteins ; Laminin* ; Losartan* ; Mesangial Cells ; Podocytes ; Rats ; RNA, Messenger

In order to investigate the efficacy and safety of oral cilazapril, a new angiotensin converting enzyme inhibitor, on essential hypertension, a single daily dose of 2.5 to 5.0mg cilazapril was administered in 30 hypertensive patients with diastolic blood pressure in the range of 95??15mmHg while off all other anti-hypertensive agents for 10 weeks. Blood pressure and heart rate were measured every 2 weeks. The complete blood count with platelet count, blood chemistry by SMA-12 including lactic dehydrogenase and serum electrolytes, and urinalysis were performed at 4th and 10th week of therapy. The electrocardiography was performed at the beginning and the end of treatment period. Any kinds of side effects were actively questioned by the examining physicians. The following results were obtained : 1) The mean age was 49.2 years, and the ratio of male-to-female was 1 : 1.3. 2) Blood pressure started to fall significantly within 2 weeks of treatment with cliazpril 2.5mg(M+/-S.E., 15.4+/-17.4mmHg vs 138.5+/-23.3, 100.3+/-6.2 vs 89.4+/-6.6, p<0.05), and after 6 weeks of treatment with a mean dosage of 2.84mg. diastolic blood pressure of all subjects was maintained below 90mmHg throughout the rest of trial. 3) Pulse rate or body weight were not significantly changed during the entire treatment period(69.3+/-6.0/min vs 10th week : 69.0+/-7.7, 64.7+/-7.4kg vs 63.6+/-6.7, p>0.05). 4) There were no significant changes in blood chemistry including blood sugar, cholesterol and electrolytes, except mild changes of serum creativine and alkaline phosphatase values. 5) Hematologic findings, urinalysis and electrocardiographic findings remained unchanged. 6)Side effects were mostly mild in nature without potentially serious episodes(dry cough : 20%, indigestion, headache, dizziness, in order), but there was 1 cases in whom the dosage was redyced due to postural hypotension. From the above results, cilazapril with the dosage of 2.5 to 5.0mg was effectvie and well tolerated in essential hypertensive patients with diastolic blood pressure of 95 to 115mmHg, and cilazapril seems to be appropriate for monotherapy of mild to moderate hypertensive patients.
Alkaline Phosphatase ; Antihypertensive Agents ; Blood Cell Count ; Blood Glucose ; Blood Pressure ; Body Weight ; Chemistry ; Cholesterol ; Cilazapril* ; Cough ; Dizziness ; Dyspepsia ; Electrocardiography ; Electrolytes ; Headache ; Heart Rate ; Humans ; Hypertension ; Hypotension, Orthostatic ; Oxidoreductases ; Peptidyl-Dipeptidase A ; Platelet Count ; Urinalysis

Angiotensin-Converting Enzyme Inhibitors ; pharmacology ; Animals ; Atrial Fibrillation ; blood ; drug therapy ; physiopathology ; Cilazapril ; pharmacology ; Dogs ; Echocardiography ; Endothelial Cells ; drug effects ; physiology ; Fibrinolysis ; drug effects ; Nitric Oxide ; biosynthesis ; Plasminogen Activator Inhibitor 1 ; analysis ; Tissue Plasminogen Activator ; analysis

OBJECTIVETo investigate the effect of cilazapril on endothelial cell function and fibrinolysis system in the canine atrial fibrillation (AF) models.

METHODSAll canines were divided into three groups: (1) Control group, without atrial pacing; (2) Atrial pacing group, in which atrial fibrillation was established by rapid atrial pacing at 400 bpm for 6 weeks; (3) Atrial pacing together with cilazapril group, in which cilazapril was given before and after atrial pacing. Nitric oxide (NO) of atrial endocardium was measured with NO-specific microelectrode. The expression of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) protein in atrium was determined by Western Blot analysis and immunohistochemical staining. Plasma levels of von Willebrand Factor (vWF), PAI-1 and tPA were analyzed by enzyme-linked immunoadsorbent assay.

RESULTSNO production from atrial endocardium was significantly increased in atrial pacing together with cilazapril group than atrial pacing group [(42.6 +/- 9.9) nmol/L vs (23.4 +/- 5.8) nmol/L, P < 0.05], whereas the plasma levels of vWF were decreased [(75.4 +/- 12.8)% vs (125.9 +/- 20.6)%, P < 0.05]. Compared to controls, the expression of atrium tPA protein in atrial pacing together with cilazapril group was significantly upregulated (4052 +/- 857 vs 1936 +/- 421, P < 0.05) and PAI-1 protein was downregulated (2487 +/- 542 vs 3164 +/- 827, P < 0.05). Cilazapril also significantly increased tPA antigen and decreased PAI-1 antigen in plasma.

CONCLUSIONCilazapril can favorably improve endothelial function and resume the balance of fibrinolysis system in AF, which might be of beneficial to hypercoagulated state in AF.

Angiotensin-Converting Enzyme Inhibitors ; pharmacology ; Animals ; Atrial Fibrillation ; blood ; drug therapy ; physiopathology ; Cilazapril ; pharmacology ; Disease Models, Animal ; Dogs ; Endothelial Cells ; drug effects ; physiology ; Female ; Fibrinolysis ; drug effects ; Immunohistochemistry ; Male ; Plasminogen Activator Inhibitor 1 ; analysis ; Tissue Plasminogen Activator ; analysis

The present study was aimed to investigate whether the adriamycin-induced nephrosis is associated with an altered regulation of local renin-angiotensin system (RAS) in the kidney. Rats were subjected to a single injection of adriamycin (2 mg/kg body weight, IV) and kept for 6 weeks to allow the development of nephrosis. They were then divided into two groups, and supplied with and without cilazapril, an angiotensin converting enzyme (ACE) inhibitor, in drinking water (100 mg/l) for additional 6 weeks. Another group without adriamycin-treatment served as control. The mRNA expression of renin, ACE, type 1 and type 2 angiotensin II receptors (AT1R, AT2R), and transforming growth factor (TGF) -beta1 was determined in the cortex of the kidney by reverse transcription-polymerase chain reaction. Adriamycin treatment resulted in heavy proteinuria. Accordingly, the mRNA expression of renin, ACE, and AT1R was increased in the renal cortex, while that of AT2R was decreased. Co-treatment with cilazapril attenuated the degree of proteinuria. While not affecting the altered expression of renin, cilazapril decreased the expression of ACE to the control level. Cilazapril further increased the expression of AT1R, while it restored the decreased expression of AT2R. The expression of TGF-beta1 was increased by the treatment with adriamycin, which was abolished by cilazapril. An altered expression of local RAS components may be causally related with the development of adriamycin-induced nephrosis, in which AT1R is for and AT2R is against the development of nephrosis.
Animals ; Body Weight ; Cilazapril ; Doxorubicin ; Drinking Water ; Kidney ; Nephrosis* ; Peptidyl-Dipeptidase A ; Proteinuria ; Rats* ; Receptors, Angiotensin ; Renin ; Renin-Angiotensin System* ; RNA, Messenger ; Transforming Growth Factor beta1 ; Transforming Growth Factors ; Up-Regulation*