Enalapril enhances the anticonvulsant activity of lamotrigine in the test of maximal electroshock.

BACKGROUND: The aim of this study was to find out whether angiotensin-converting enzyme (ACE) inhibitors, enalapril and cilazapril, affect the anticonvulsant action of some second-generation antiepileptics, lamotrigine (LTG), topiramate (TPM) and oxcarbazepine (OXC). METHODS: The effects of ACE inhibitors on antiepileptic drugs were examined in the mouse model of maximal electroshock. RESULTS: Enalapril (30 mg/kg ip) potentiated the anticonvulsant action of LTG, decreasing its ED50 value from 5.3 to 3.6 mg/kg (p < 0.01). The anticonvulsant activity of TPM or OXC was not modified by enalapril. Cilazapril did not affect the protective activity of the studied antiepileptics. The interaction between enalapril and LTG could be pharmacodynamic in nature because enalapril did not change plasma and total brain concentrations of LTG. CONCLUSIONS: This study shows that there are no negative interactions between the studied antiepileptic drugs and enalapril or cilazapril. Enalapril even enhanced the anticonvulsant activity of LTG in the MES test in mice that is thought to be a predictive model of human generalized tonic-clonic seizures.

Cilazapril increases plasma ghrelin concentration in obese patients with arterial hypertension.

INTRODUCTION: Ghrelin is a polypeptide hormone secreted mainly by the stomach cells, stimulating food intake and growth hormone release. Decreased plasma ghrelin concentration was found in obese subjects. Clinical and experimental data suggest that ghrelin also exerts a blood pressure lowering property. The influence of antihypertensive medication on plasma ghrelin concentration has not been studied, yet. MATERIAL AND METHODS: Plasma ghrelin concentration was estimated in 52 hypertensive obese (HA + O), 14 normotensive obese (O), and 15 lean healthy subjects in the fasting state, and after ingestion of a standard meal. HA + O patients were randomly allocated into 4 groups treated alternatively with: cilazapril, bisoprolol, amlodipine, or indapamide. After 6 weeks of antihypertensive monotherapy, the assessments were repeated. RESULTS: Similar fasting [HA + O - 780 (676-960) pg/ml; O - 751 (619-899) pg/ml] and postprandial plasma ghrelin concentrations were found in hypertensive and normotensive obese subjects. Plasma ghrelin concentrations in lean healthy subjects were significantly higher (987 (765-1366) pg/ml) in comparison to O and HA + O. Treatment with cilazapril was followed by a 28.0% increase of plasma ghrelin concentration (p = 0.04), while with bisoprolol, a 18.9% decrease (p = 0.01). No significant changes of ghrelinaemia were observed in HA + O treated with amlodipine or indapamide. No significant correlation between blood pressure and plasma ghrelin concentration before the therapy and their changes after 6 weeks of medication were found. CONCLUSIONS: 1. Our data do not support the major role of ghrelin in blood pressure regulation in obesity. 2. An increase of plasma ghrelin concentration after treatment with cilazapril was observed. (Pol J Endocrinol 2010; 61 (1): 21-27).

Blockade of the RAS increases plasma adiponectin in subjects with metabolic syndrome and enhances differentiation and adiponectin expression of human preadipocytes.

AIMS: This observational study aimed to investigate the effects of renin-angiotensin system (RAS) blockers on plasma adiponectin in subjects with metabolic syndrome (Mets) and differentiation, adiponectin expression of human omental (OM) and subcutaneous (SC) preadipocytes. METHODS: Fifty-three patients with Mets were treated with angiotensin converting enzyme inhibition (ACEI), angiotensin II receptor blocker (ARB) or nothing, lipid profile and adiponetin were measured. OM and SC preadipocytes were obtained from sixteen normal non-menopausal women undergoing elective abdominal surgery and subsequently differentiated in the presence of ACE, ARB or thiazolidinedione (TZD). Differentiation was assessed using a number of biochemical and function parameters. RESULTS: Plasma adiponectin was increased dramatically as a result of ACEI and ARB treatment. Most of the metabolic and differentiating parameters were improved significantly by RAS blockers or TZD. Compared with TZD, RAS blockers have stronger effects on omental preadipocytes in differentiation and insulin sensitivity. The improvement of adiponectin mRNA expression was significantly greater in ARB-treated omental preadipocytes compared with TZD-treated ones. CONCLUSION: These results suggest that adiponectin may serve as potential therapeutic targets of ACEI and ARB for treating the Mets and its related complications. It also suggests a potential benefit of RAS blockers on Mets with characteristic visceral obesity.

Effect of unilateral ureteral obstruction and anti-angiotensin II treatment on renal tubule and interstitial cell apoptosis in rats.

AIM: To investigate the effects of angiotensin-converting enzyme inhibitor (cilazapril) and angiotensin II type I receptor antagonist (losartan) on tubular and interstitial cell apoptosis and caspase-3 activity in rats with obstructive nephropathy after unilateral ureteral obstruction. METHODS: Rats with unilateral obstructive nephropathy and sham-operated rats were treated with cilazapril, losartan, or the vehicle (water). Tubular and interstitial cell apoptosis was detected morphologically on hematoxylin and eosin-stained renal specimens and by the terminal deoxynucleotidyl transferase-mediated nick end-labeling. Caspase-3 activity in whole-kidney tissue homogenates was measured colorimetrically. RESULTS: After unilateral ureter ligation, there was a significant increase in the number of apoptotic tubular and interstitial cells in the obstructed kidney (P=0.049 and P=0.036, respectively, vs sham-operated rats, 10 days after ligation). In rats with unilateral obstructive nephropathy, neither cilazapril nor losartan had an effect on tubular cell apoptosis. However, cilazapril caused a significant increase in the number of renal apoptotic interstitial cells (P=0.019). Caspase-3 activity was not significantly different in rats with unilateral obstructive nephropathy than in sham-operated rats. CONCLUSION: Rats with unilateral obstructive nephropathy had increased apoptosis of tubular and interstitial cells in comparison with sham-operated rats. Neither cilazapril nor losartan had an effect on tubular cell apoptosis, and cilazapril even increased interstitial cell apoptosis.

Short-term effects of cilazapril and atenolol on P-wave dispersion in patients with hypertension.

INTRODUCTION: P-wave dispersion (PWD) has been shown to be a non-invasive electrocardiographic predictor for development of atrial fibrillation (AF). Thus, it may be possible to decrease AF risk through improvement in PWD. Our objective was to compare the effects of cilazapril and atenolol on P-wave duration and dispersion in patients with hypertension. METHODS: A total of 38 newly diagnosed hypertensive patients were enrolled in the study. The patients were randomly assigned to receive treatment with either cilazapril (5 mg) or atenolol (50 mg). Doppler echocardiographic examination, P-wave durations and PWD were measured before and 1 mo after treatment RESULTS: Both drugs reduced blood pressure significantly (P<0.001). Posttreatment heart rate was significantly lower in the atenolol group (P=0.01). The change in maximum P-wave duration was not significant. However, both agents decreased PWD (P=0.001 and P<0.001) and increased the minimum P-wave duration (P=0.004 and P=0.02). CONCLUSION: Both cilazapril and atenolol treatments resulted in improvement in PWD.

Impact of cilazapril on fibrinolytic system in hypertensive patients.

Impaired fibrinolysis is associated with thromboembolic complications in hypertensive patients. Cardiovascular morbidity/mortality rates have been reported high even after lowering the elevated blood pressure with antihypertensive drugs. We investigated the effects of clinically used dosages of cilazapril on the fibrinolytic system in hypertensive patients. The present study was performed among 30 hypertensive patients (22 women, eight men), who received 2.5-5.0 mg cilazapril daily for 1 month. Before and after the cilazapril treatment, patients' venous blood was drawn for fibrinolytic tests. The fibrinolytic activity was examined utilizing the euglobulin clot lysis time and fibrin plate methods. Using the fibrin plate method, as compared with the pretreatment group, we observed a 57% increased activity in the hypertensive patients receiving cilazapril (P < 0.001). When assessed by the euglobulin clot lysis time method, the activity due to cilazapril treatment was found to be relatively low, although highly significant (approximately 20%, P < 0.001). Changes in fibrinolytic activity were observed in 23 (77%) hypertensive patients after cilazapril treatment; however, their blood pressure remained normal. The remaining seven patients' (23%) blood pressures and fibrinolytic activity did not change significantly after cilazapril treatment. In conclusion, we suggest that the observed differential fibrinolytic activity between the pre and post cilazapril treatment values is due to the plasminogen activators released from the vascular endothelium, which may have been stimulated by cilazapril. It appears that cilazapril is not only an angiotensin-converting enzyme inhibitor but also a stimulator for fibrinolytic activity, which may be an added component in reducing thromboembolic complications in hypertensive patients.

Hyperbaric oxygen treatment augments the efficacy of cilazapril and simvastatin regimens in an experimental nephrotic syndrome model.

BACKGROUND: Oxidative stress plays a role in the mechanism of chronic kidney disease (CKD), and antioxidant regimes are regarded as promising treatment modalities. We compared the effects of cilazapril, simvastatin, and hyperbaric oxygen (HBO) treatment on proteinuria and on oxidative stress in adriamycine (ADR)-induced proteinuria. METHODS: Seventy male Sprague-Dawley rats were housed, and 60 were injected with ADR to induce nephrosis. After the stabilization of proteinuria, rats were treated for 6 weeks with simvastatin (n = 10, 4 mg/kg/day), cilazapril (n = 10, 10 mg/kg/day), HBO (n = 10, 2.8 athmosphere absolute, 90 min/daily), HBO + cilazapril (n = 10), HBO + simvastatin (n = 10), and vehicle (n = 10). After euthanization at 12 weeks, protein carbonyl (PCO), superoxide dismutase (SOD), and glutathion peroxidase (GPx) levels were analyzed from tissues. The histological alterations in the kidneys were determined by semiquantitative scoring. RESULTS: Protein carbonyl (PCO) levels were higher (p < 0.001), and the GPx and SOD levels were lower (p < 0.001 for all) in the nephrotic rats. Proteinuria was correlated to PCO (r = 0.483), GPx (r = -0.686), or SOD (r = -0.620) (p < 0.001 for all). Superoxide dismutase (SOD) (beta = -0.381, p = 0.02) and GPx (beta = -0.509, p < 0.001) were independently related to proteinuria levels. Both cilazapril and simvastatin significantly improved GPx, SOD, PCO, and proteinuria. When HBO was combined with either drug, the above markers further improved (p < 0.001). Both regimens caused distinct histological features, while the combination of HBO made much significant histological improvement. CONCLUSION: Both cilazapril and simvastatin regimens improve oxidative stress and proteinuria, while the effects significantly increase with the combination of HBO treatment. HBO seems to be a candidate antioxidant strategy in glomerular diseases.

Dual blockade of the renin-angiotensin-aldosterone system with high-dose angiotensin-converting enzyme inhibitor for nephroprotection: an open, controlled, randomized study.

OBJECTIVE: Despite the proven effectiveness of combination therapy with an angiotensin I-converting enzyme inhibitor (ACEI) and angiotensin II-receptor blockers (ARBs) for the prevention and treatment of kidney disease, it has not proved possible to inhibit the progress of chronic nephropathies completely. To improve renal outcome one may consider using increased dosages of ACEI above those usually recommended for hypertension. MATERIAL AND METHODS: A randomized, open, controlled study was conducted to evaluate the influence of two combination therapies on proteinuria, markers of tubular injury and renal fibrosis. A total of 18 patients with a creatinine level of 109+/-36 micromol/l and proteinuria of 0.97+/-0.76 g/24 h were enrolled in the study. In the 8-week run-in period, an ACEI (cilazapril 5 mg once-daily) and an ARB (telmisartan 80 mg once-daily) were administered to achieve the target blood pressure of < or = 130/80 mmHg. Next, the patients were randomly assigned to either an increased dose of cilazapril (10 mg) or the previous dose (5 mg) in two active-treatment periods, each lasting 8 weeks. RESULTS: A significant increase in renin activity was observed after administration of cilazapril 10 mg (6.46+/-1.12 vs 4.67+/-0.7 ng/ml/h; p=0.028). Proteinuria, urine excretion of N-acetyl-beta-D-glucosaminidase, and alpha1-microglobulin and amino-terminal propeptide of type III procollagen were unchanged. CONCLUSION: An increased dosage of cilazapril (twice the maximum recommended dose) in addition to combination therapy with telmisartan was associated with increased blockade of the renin-angiotensin-aldosterone system, with no additional effect on proteinuria, markers of tubular injury or renal fibrosis.

The effects of cilazapril and valsartan on the mRNA and protein expressions of atrial calpains and atrial structural remodeling in atrial fibrillation dogs.

Owing to relative inefficacy and side effects of currently available antiarrhythmic drugs, current interest has shifted to treatments that target atrial fibrillation (AF) substrate. It has been suggested that calpain-induced atrial structural remodelling is under the control of renin-angiotensin system during AF. The purpose of this study is to investigate the effects of cilazapril and valsartan on the mRNA and protein expression of atrial calpains and atrial structural remodelling in AF dogs induced by chronic rapid atrial pacing. Twenty-seven dogs were randomly divided into sham-operated group (n = 6), control group (n = 7), cilazapril group (n = 7) and valsartan group (n = 7). One thin silicon plaque containing 4 pairs of electrodes was sutured to each atrium. A pacemaker was implanted in a subcutaneous pocket and attached to a screw-in epicardial lead in the right atrial appendage. The dogs in control group, cilazapril group and valsartan group were paced at 400 beats per minutes for 6 weeks. The dogs in cilazapril and valsartan groups received cilazapril (1mg x kg(-1)x d(-1)) or valsartan (30mg x kg(-1) x d(-1)) 1 week before rapid atrial pacing until pacing stop respectively. Transthoracic and transoesophageal echocardiographic examinations were performed in order to detect the changes of left atrium volume and contractile function. The inducibility and duration of AF were measured in all the groups. The expressions of atrial calpain I and calpain II mRNA were semi-quantified by reverse transcription-polymerase chain reaction. The protein levels of calpain I and calpain II in atrial myocardium were measured by Western-blot method. Pathohistological and ultrastructural changes in atrial tissue were tested by light and electron microscopy. Compared with the sham-operated control group, dramatic smaller left atrium and left atrial appendage volumes and significant higher atrial contractile function were observed in the cilazapril and valsartan groups. After 6-week atrial tachy-pacing, the mRNA and protein expressions of calpain I increased dramatically in the control group than that in the sham group, tissue calpain protein expression in all groups significantly correlated with the myolysis (r = 0.89, P < 0.01). Cilazapril and valsartan could significantly inhibit the gene and protein expressions of calpain I. No differences were found in the expression of calpain II mRNA and protein between the groups. Compared with atrial myocytes obtained from sham dogs, atrial myocytes from the control group dogs showed a reduced number of sarcomeres, a significant higher myolytic area of atria (24.3% vs. 3.1%, P < 0.01), increased vacuolization and dissolution. Cilazapril and valsartan could effectively prevent the pathohistological and ultrastructural changes induced by chronic rapid atrial pacing, dramatically decrease the area of myolysis (P < 0.05) and significantly reduce the inducibility and duration of AF. The expression of calpain I mRNA and protein increased remarkably in AF dogs. Cilazapril and valsartan can inhibit calpain I up-regulation, suppress atrial structural remodeling, and prevent the induction and promotion of AF in chronic rapid atrial pacing dogs.

[Effect of Cilazapril on endothelial cell function and fibrinolysis system in the canine atrial fibrillation models].

OBJECTIVE: To investigate the effect of cilazapril on endothelial cell function and fibrinolysis system in the canine atrial fibrillation (AF) models. METHODS: All 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. RESULTS: NO 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. CONCLUSION: Cilazapril 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 II type 1 receptor antagonist and angiotensin-converting enzyme inhibitor altered the activation of Cu/Zn-containing superoxide dismutase in the heart of stroke-prone spontaneously hypertensive rats.

Although angiotensin II type 1 (AT1) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors are known to reduce both reactive oxygen species (ROS) generated by activated NAD(P)H oxidase and vascular remodeling in hypertension, the effects of AT1 receptor antagonists or ACE inhibitors on ROS-scavenging enzymes remain unclear. We hypothesized that AT1 receptor antagonists or ACE inhibitors may modulate vascular remodeling via superoxide dismutase (SOD) in hypertension. Male stroke-prone spontaneously hypertensive rats (SHRSP) were treated for 6 weeks with a vehicle, an AT1 receptor antagonist (E4177; 30 mg/kg/day), or an ACE inhibitor (cilazapril; 10 mg/kg/day). We evaluated protein expression using immunoblots, determined SOD activities with a spectrophotometric assay, and measured NAD(P)H oxidase activity by a luminescence assay. The two drugs showed equipotent effects on blood pressure, left ventricular hypertrophy and fibrosis, and endothelial NO synthase in the SHRSP hearts. The wall-to-lumen ratio of the intramyocardial arteries and the NAD(P)H oxidase essential subunit p22(phox) and its activity were significantly reduced, whereas Cu/Zu-containing SOD (Cu/ZnSOD) expression and activity were significantly increased in the SHRSP hearts. Furthermore, E4177 reduced vascular remodeling more than did cilazapril not only by reducing p22(phox) expression and NAD(P)H oxidase activity but also by upregulating the Cu/ ZnSOD expression and its activity in the SHRSP hearts. Thus, both the AT1 receptor antagonist and the ACE inhibitor inhibited vascular remodeling and reduced ROS in SHRSP via not only a reduction in NAD(P)H oxidase but also an upregulation of Cu/ZnSOD.

Combined therapy of cilazapril and losartan has no additive effects in ameliorating adriamycin-induced glomerulopathy.

AIMS: Effects of the blockade of renin-angiotensin system (RAS), by angiotensin-converting enzyme inhibitor (ACEi), type 1 angiotensin II receptor blocker (ARB), or a combination of both, were evaluated in Adriamycin (ADR)-induced glomerulopathy. METHODS: Male Sprague-Dawley rats (180-250 g) were induced of glomerulopathy by treatment with ADR (2 mg/kg, i.v.). Six weeks later, they were treated with cilazapril (1 mg/kg/day) and/or losartan (10 mg/kg/day) for an additional 6 weeks. RESULTS: The urinary excretion of protein progressively increased following the treatment with ADR, which was prevented by ACEi, ARB, and a combination of both. Similarly, the glomerulopathy assessed by glomerulosclerosis index was also ameliorated by ACEi or ARB. However, combined therapy of both ACEi and ARB was without an additional effect (Control 1.4 +/- 0.4%, ADR 10.7 +/- 2.7%**, ACEi 0.8 +/- 0.4%, ARB 2.6 +/- 1.0%, ACEi+ARB 1.7 +/- 1.5%, ** p < 0.01 vs. Control). The expression of transforming growth factor-beta(1) was increased following the treatment with ADR (1.4 +/- 0.07-fold, p < 0.05 vs. Control), however, the degree of which was similarly blunted by either ACEi, ARB, or the combination of both. The expression of type 1 angiotensin II receptor mRNA increased following the treatment with ADR, the degree of which was further upregulated by ACEi and decreased by ARB to the control level (ADR 1.3 +/- 0.06-fold*, ACEi 1.8 +/- 0.05-fold***, ARB 1.0 +/- 0.04-fold, * p < 0.05 and *** p < 0.001 vs. Control). The combined therapy of ACEi and ARB still showed an upregulation of type 1 angiotensin II receptor mRNA, however, of which degree was mitigated compared with that induced by ACEi alone (ACEi+ARB 1.5 +/- 0.04-fold, ** p < 0.01 vs. Control). On the contrary, the expression of type 2 angiotensin II receptor mRNA was downregulated following the treatment with ADR, which was similarly restored to the control level by ACEi, ARB, and a combination of both (ADR 0.5 +/- 0.08-fold**, ACEi 1.0 +/- 0.06-fold, ARB 1.0 +/- 0.05-fold, ACEi+ARB 1.0 +/- 0.05-fold, ** p < 0.01 vs. Control). CONCLUSION: It is suggested that combined therapy of ACEi and ARB with relatively high or maximal doses of each drug has no additive or synergistic benefits on the progression of ADR-induced glomerulopathy. Effects of RAS blockade may in part be related to differential regulation of type 1 and type 2 angiotensin II receptors.

Role of endothelium-derived hyperpolarizing factor in ACE inhibitor-induced renal vasodilation in vivo.

Although the angiotensin-converting enzyme (ACE) inhibitor-induced bradykinin enhances nitric oxide (NO) release, bradykinin may also stimulate the production of an additional vasodilator, endothelium-derived hyperpolarizing factor (EDHF). This study examined the role of EDHF in mediating the NO-independent action of ACE inhibitors in canine renal microcirculation in vivo. We used intravital CCD camera videomicroscopy that allowed direct visualization of renal microcirculation in superficial and juxtamedullary nephrons in an in vivo, in situ, and relatively intact setting. In the presence of E4177 (an angiotensin receptor blocker), cilazaprilat (30 microg/kg) had no effect on diameter of superficial afferent arterioles (Aff), but it increased renal contents of bradykinin and nitrate plus nitrite, and it elicited dilation of juxtamedullary Aff (from 24.0+/-0.2 to 28.2+/-0.8 microm), juxtamedullary efferent arterioles (Eff) (from 24.2+/-0.2 to 28.0+/-0.8 microm), and superficial Eff (from 18.2+/-0.2 to 19.7+/-0.2 microm). These changes in diameters were prevented by N(alpha)-adamantaneacetyl-d-Arg-[Hyp(3),Thi(5,8),D-Phe(7)]bradykinin, a bradykinin receptor antagonist. The pretreatment with nitro-l-arginine methylester (l-NAME) plus E4177 eliminated the dilator response of juxtamedullary/superficial Eff and the increase in renal nitrate plus nitrite levels induced by cilazaprilat. In contrast, in the presence of E4177+l-NAME, cilazaprilat still caused 8%+/-3% dilation of juxtamedullary Aff, which was completely eliminated by proadifen, a cytochrome-P450 and K(Ca) channel blocker. Collectively, the ACE inhibitor exerts multiple vasodilator mechanisms, including the inhibition of angiotensin II formation; blockade of angiotensin II activity appears to be a dominant mechanism in superficial Aff, whereas the bradykinin-induced NO acts on superficial Eff and juxtamedullary Aff/Eff. Furthermore, a putative EDHF is an additional mechanism for the ACE inhibitor-induced vasodilation of juxtamedullary Aff in vivo.

Sustained plasma fibrinogen elevation in subtotal nephrectomized rats: effect of cilazapril, an angiotensin-converting enzyme inhibitor.

The present study was undertaken to examine whether plasma fibrinogen persistently elevates in subtotal nephrectomized rats, an animal model with inflammatory renal changes. Eight weeks after the induction of 5/6 nephrectomy in male Wistar rats, plasma fibrinogen concentration was determined for the next 12 weeks in the animals received vehicle or an angiotensin-converting enzyme inhibitor, cilazapril (1 or 10 mg/kg per day) orally. In the vehicle-treated nephrectomized rats, plasma fibrinogen concentration significantly (P<0.001) increased (from 127.3 +/- 4.6 [S.E.M.] to 182.3 +/- 5.2 mg/dL) compared with that in the control rats (from 118.0 +/- 2.0 to 153.5 +/- 5.4 mg/dL). Cilazapril attenuated the increases in plasma fibrinogen concentration in a dose-dependent manner. Serum concentration of monocyte chemoattractant protein-1, a key macrophage chemoattractant and activator, increased in the vehicle-treated nephrectomized rats, which was also reduced by cilazapril. These results suggest that plasma fibrinogen elevates persistently in the nephrectomized rats. Local inflammation may be involved in the hepatic fibrinogen synthesis in this model.

[Effects of cilazapril on the expression of vascular endothelial growth factor and intercellular adhesion molecule-1 in diabetic rat glomeruli].

OBJECTIVE: To assess the effect of cilazapril, an angiotensin-converting enzyme inhibitor (ACEI), on the protection against diabetic nephropathy and on the expression of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) in diabetic rat glomeruli. METHODS: The rat model of diabetes mellitus (DM) was produced by injection of streptozocin (STZ). After the treatment with cilazapril [1 mg/(kg.d)] for 2 weeks and 8 weeks, glomerular hypertrophy, renal function and 24 h urinary protein count were measured, and the expression of VEGF and ICAM-1 were investigated by immunohistochemical technique and Mias-2000 pathology computer image analyzer in diabetic rat glomeruli. RESULTS: At 2 weeks, kidney weight/body weight (KW/BW), creatinin clearance rate (CCr) and 24 hours urine protein count increased significantly in DM model group, compared with control (P < 0.05, P < 0.01). Meanwhile, by immunohistochemistry, increased levels of glomerular VEGF and ICAM-1 were shown and their peaks were seen at 8 weeks (P < 0.01). Cilazapril could reduce KW/BW, CCr and 24 hours urine protein count and significantly suppress the overexpression of VEGF and ICAM-1 in cilazapril treatment group after 8 weeks, compared with the DM model group(P < 0.05). CONCLUSION: Cilazapril can suppress the overproduction of two cytokines, VEGF and ICAM-1, thus preventing the progression of diabetic nephropathy.

The effects of handgrip stress test on hemodynamic parameters before and after cilazapril treatment in patients with heart failure.

OBJECTIVE: To assess the effect of cilazapril treatment on several hemodynamic parameters during handgrip maneuvers in patients with congestive heart failure. Cilazapril, an ACE inhibitor with high affinity, has been shown to be highly effective against a variety of vascular disorders. The effectiveness of isometric handgrip exercise on changes of cardiovascular hemodynamic parameters before and after cilazapril treatment in patients with congestive heart failure is unknown. METHODS: The study population included 30 patients (16 male, 14 female) with mean age of 65+/-18 years. The effects of handgrip maneuver on hemodynamic parameters were studied by right heart catheterization and Doppler echocardiography. RESULTS: Heart rate (HR) and mean arterial pressures (MAP) increased significantly after handgrip maneuver (from 95+/-6 beats/min to 101+/-12 beats/min; from 109+/-15 mm Hg to 118+/-19 mm Hg, p<0.05 respectively). Pulmonary capillary wedge pressure (PCWP), pulmonary artery systolic (s) and diastolic (d) pressures (PAP), cardiac index (CI), right ventricular systolic and diastolic pressures (RVPs and RVPd), left ventricular ejection fraction (LVEF), right ventricular ejection fraction (RVEF) did not change after handgrip maneuvers (p>0.05). On the other hand, PAPs and PAPd, RVPs and RVPd, MAP and HR (p<0.05) decreased significantly during handgrip maneuvers after cilazapril treatment. However PCWP and CI, LVEF, RVEF did not change after treatment (p>0.05). CONCLUSION: Cardiovascular response to handgrip maneuver may be a marker of failure to respond to compensatory mechanisms. Cilazapril treatment was associated with significant improvement in hemodynamic parameters during handgrip stress test, the mechanisms of which are increased sympathetic and renin-angiotensin system activation, and altered vascular tonus.

In vivo visualization of subendocardial arteriolar response in renovascular hypertensive hearts.

Time-sequential responses to endothelium-dependent and -independent vasodilators and angiotensin-converting enzyme (ACE) inhibitors were studied in the subendocardial arterioles (Endo) of canine renovascular hypertension (HT) compared with subepicardial arterioles (Epi; both <120 microm) by charge-coupled device intravital microscope. Vascular responses to acetylcholine, papaverine, and cilazaprilat were compared between normotensive (NT) and HT dogs [4 wk and 12 wk of HT (4wHT and 12wHT)]. The acetylcholine-induced vasodilation of Endo in both 4wHT and 12wHT was smaller than that of NT (both P < 0.01 vs. 4wHT and 12wHT), and that of Epi was smaller than that of NT only in 12wHT (P < 0.05). The papaverine-induced vasodilation of Endo, but not Epi, was impaired only in 12wHT (both P < 0.01 vs. NT and 4wHT). Vasodilation by cilazaprilat remained unchanged at 4wHT and 12wHT in both Epi and Endo. In conclusion, at the early stage, the endothelium-dependent response of Endo was impaired, whereas at the later stage, the endothelium-dependent and -independent responses of Endo and the endothelium-dependent response of Epi were impaired. However, the vasodilatory responses to the ACE inhibitor were maintained in both Endo and Epi of HT.

The acute effects of cilazapril on pulmonary function tests and arterial blood gas changes in patients with pulmonary hypertension.

The aim of the present study was to evaluate pulmonary function tests and arterial oxygen transport in patients with pulmonary hypertension due to congestive heart failure before and after cilazapril treatment. Thirty patients (16 men and 14 women, mean age, 65 +/- 18 years) with congestive heart failure and 30 healthy volunteers (20 men and 10 women, mean age 59 +/- 12 years, p > 0.05) were included in the study. All patients underwent evaluation of pulmonary function by spirometry and arterial blood gas analysis. Arterial oxygen saturation and arterial oxygen transport changed significantly after treatment (81 +/- 7 to 87 +/- 8 and 317 +/- 74 to 392 +/- 8, respectively). Forced expiration volume in 1 second, vital capacity and total lung capacity were increased after cilazapril treatment (2.55 +/- 0.7 to 2.61 +/- 0.8, 3.2 +/- 0.9 to 3.3 +/- 1.0 and 3.6 +/- 0.9 to 4.1 +/- 1.1, respectively, p < 0.05). In conclusion, short-term cilazapril administration improved pulmonary function and arterial oxygen transport because it increased cardiac output, produced pulmonary vasodilatation, improved the pulmonary hemodynamics and removed interstitial fluid.