Advantages of automation in plasma sample preparation prior to HPLC/MS/MS quantification: application to the determination of cilazapril and cilazaprilat in a bioequivalence study.

An HPLC/MS/MS method characterized by complete automation and high throughput was developed for the determination of cilazapril and its active metabolite cilazaprilat in human plasma. All sample preparation and analysis steps were performed by using 2.2 mL 96 deep-well plates, while robotic liquid handling workstations were utilized for all liquid transfer steps, including liquid-liquid extraction. The whole procedure was very fast compared to a manual procedure with vials and no automation. The method also had a very short chromatographic run time of 1.5 min. Sample analysis was performed by RP-HPLC/MS/MS with positive electrospray ionization using multiple reaction monitoring. The calibration curve was linear in the range of 0.500-300 and 0.250-150 ng/mL for cilazapril and cilazaprilat, respectively. The proposed method was fully validated and proved to be selective, accurate, precise, reproducible, and suitable for the determination of cilazapril and cilazaprilat in human plasma. Therefore, it was applied to a bioequivalence study after per os administration of 2.5 mg tablet formulations of cilazapril.

Effects of Cilazapril on atrial electrical, structural and functional remodeling in atrial fibrillation dogs.

BACKGROUND AND PURPOSE: The effects of angiotensin-converting enzyme inhibitor on long-term atrial electrophysiologic and structural remodeling are still unclear. The purpose of this study is to investigate the effects of Cilazapril on atrial electrical, structural, and functional remodeling in atrial fibrillation (AF) dogs induced by chronic rapid atrial pacing. METHODS: Twenty dogs were randomly divided into sham-operated group (n = 6), control group (n = 7), and Cilazapril 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 and Cilazapril group were paced at 400 beats per minute for 6 weeks. The dogs in Cilazapril group received Cilazapril (0.5 mg x kg(-1) x d(-1)) 1 week before rapid atrial pacing until pacing stop. Before and after 6-week rapid atrial pacing, atrial effective refractory period (AERP) at 8 sites, AERP dispersion, intraatrium conduction time, inducibility, and duration of AF were measured. Transthoracic and transesophageal echocardiographic examinations included left atrium (LA) maximal volume, LA minimal volume, LA ejection fraction, left atrial appendage (LAA) maximal volume, LAA minimal volume, LAA ejection fraction, LAA maximal forward flow velocity, and LAA minimal backward flow velocity were performed. Atrial collagen volume fraction was analyzed by Masson staining. RESULTS: After 6-week rapid atrial pacing, although there was no significant difference in AERP shortening and AERP rate adaptation reduction between the control group and the Cilazapril group, the inducibility and duration of AF were found to be dramatically lower in the Cilazapril group than those in the control group (AF inducibility, 65.7% vs 95.7%, P < .05; AF duration, 531.5 +/- 301.2 vs 1432.2 +/- 526.5 s, P < .01). The post-tachycardia intraatrium conduction times after 6 weeks with Cilazapril were significantly shorter than those in the control group. Cliazapril could partially prevent AERP dispersion increase induced by chronic rapid atrial pacing. Compared with the control group, the LA and LAA volumes were significantly smaller; LA ejection fraction, LAA ejection fraction, LAA maximal forward flow velocity, and LAA minimal backward flow velocity were dramatically higher in the Cilazapril group. The Cilazapril group had a significantly lower percentage of interstitial fibrosis than the control group. CONCLUSIONS: Cilazapril can suppress structural and functional remodeling and prevent the induction and promotion of AF in chronic rapid atrial pacing dogs.

Blockade of renin-angiotensin system reduces QT dispersion and improves intracellular Ca/Mg status in hemodialysis patients.

BACKGROUND: Electrolyte impairments are common in hemodialysis (HD) patients. Consequently, QT dispersion (QTd) is prolonged, correlating with high intracellular magnesium. In patients with cardiac disorders, renin-angiotensin system (RAS) inhibition reduces QTd. AIM: To compare the effects of ACE inhibition or AT-1 blockade on QTd duration and intracellular magnesium (Mg)/calcium (Ca) in peripheral blood mononuclear cells (PBMC) from chronic HD patients. METHODS: 24 HD patients received cilazapril for 8 weeks and, following a 2-week withdrawal, were switched to valsartan for additional 8 weeks. QTd measurements and PBMC isolation were performed at the beginning and the end of each period. Total intracellular Ca and Mg were assessed by atomic spectrometer, and cytosolic free Ca2+ by fluorocytometer. RESULTS: Both treatments significantly decreased QTd, demonstrating similar reduction magnitudes. In both groups, PBMC exhibited basally low cytosolic Ca2+ and undisturbed high transmembrane Ca2+ influx following phytohemagglutinin stimulation. Total intracellular Ca was increased, while Mg was reduced, following either treatment. The total intracellular Ca/Mg ratio inversely correlated with QTd duration. CONCLUSIONS: (1) RAS inhibition reduces prolonged QTd in HD patients. (2) In PBMC from ordinarily Ca-depleted HD patients, RAS suppression brings about elevation of total intracellular Ca. (3) RAS blockade decreases high intracellular Mg in PBMC from HD patients. Consequently, the Ca/Mg ratio increases, inversely correlating with QTd reduction.

Effect of high dose angiotensin-converting enzyme inhibition on restenosis: final results of the MARCATOR Study, a multicenter, double-blind, placebo-controlled trial of cilazapril. The Multicenter American Research Trial With Cilazapril After Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MARCATOR) Study Group.

OBJECTIVES: We conducted a randomized, double-blind, placebo-controlled trial to assess the effect of low and high dose angiotensin-converting enzyme inhibition with cilazapril on angiographic restenosis prevention after percutaneous transluminal coronary angioplasty. BACKGROUND: Angiotensin-converting enzyme inhibitors possess antiproliferative effects in animal models of vascular injury. However, a recent clinical trial using low dose cilazapril, a long-acting angiotensin-converting enzyme inhibitor, failed to prevent restenosis. METHODS: Patients received either cilazapril (1 or 2.5 mg in the evening after successful coronary angioplasty, then 1, 5 or 10 mg twice daily for 6 months) or matched placebo. All patients received aspirin for 6 months. Coronary angiograms before and after angioplasty and at 6-month follow-up were quantitatively analyzed. In addition, the clinical, procedural and angiographic factors associated with restenosis were determined with the use of stepwise logistic analysis. RESULTS: A total of 1,436 patients with a successful coronary angioplasty were recruited. As assessed by an intention-to-treat analysis, the mean difference in minimal coronary lumen diameter (mean +/- 1 SD) between the postangioplasty and follow-up angiogram at 6 months (primary end point) was -0.35 +/- 0.51 for the placebo group and -0.37 +/- 0.52, -0.45 +/- 0.52 and -0.412 +/- 0.53, respectively, for the 1-, 5- and 10-mg twice daily cilazapril groups (p = NS). Clinical events during follow-up did not differ among the four study groups. Multivariate analysis revealed only six variables as independent predictors of the loss of minimal lumen diameter: duration of angina < 6 months, history of myocardial infarction, minimal lumen diameter before and after angioplasty as well as a proximal lesion location and reference diameters. Traditional risk factors for atherosclerosis did not relate to restenosis. CONCLUSIONS: Long-term angiotensin-converting enzyme inhibition with cilazapril in high as well as low dosages does not prevent restenosis and does not favorably influence the overall clinical and angiographic outcome after coronary angioplasty. Few factors are predictive of restenosis.

Effects of cilazapril on vascular structure and function in essential hypertension.

Hypertension is associated with an altered design of resistance vessels and decreased endothelium-dependent vasodilator response to acetylcholine. A role of angiotensin II in both defects is suggested by animal experiments in which angiotensin-converting enzyme inhibition reverted structural and functional changes. We investigated the effects of 20 weeks of therapy with the angiotensin-converting enzyme inhibitor cilazapril (5 mg twice daily) on the endothelium-dependent response to brachial artery infusions of acetylcholine and the endothelium-independent vascular relaxation after sodium nitroprusside in 22 subjects with mild to moderate essential hypertension. In addition, we measured minimal forearm vascular resistance (ratio of mean arterial pressure and forearm blood flow after heating, ischemia, and ischemic exercise) as an indirect estimate of vascular structure. Cilazapril decreased blood pressure (151 +/- 14/99 +/- 7 mm Hg during placebo to 138 +/- 17/89 +/- 8 mm Hg after cilazapril treatment, P<.01) and baseline (42.2 +/- 12.6 to 37.1 +/- 10.6 U, P<.05) and minimal (3.0 +/- 1.1 to 2.4 +/- 0.7 U, 15.9 +/- 20.2%; P<.05) forearm vascular resistances. The change in minimal forearm vascular resistance was unrelated to age, duration of hypertension, or changes in blood pressure. Sodium nitroprusside increased forearm blood flow from 2.6 +/- 1.0 to 11.4 +/- 5.9 mL/min per 100 mL and acetylcholine to 21.5 +/- 17.8. Both responses did not change after cilazapril. The data provide indirect evidence that cilazapril therapy may improve vascular structure in human hypertension. The lack of relationship between vascular and blood pressure changes would be compatible with experimental evidence supporting a role for angiotensin II in the development and regression of vascular changes, but this needs further study. Therapy with cilazapril for 20 weeks, like other antihypertensive therapy, does not seem to influence endothelial vasodilator function in humans to a significant degree.

Altered cerebrovascular response to a potassium channel opener in hypertensive rats.

We examined whether the effect of Y-26763, an ATP-sensitive potassium channel opener, on cerebral blood flow is altered in stroke-prone spontaneously hypertensive rats (SHRSP) and, if altered, whether long-term antihypertensive treatment with cilazapril, an angiotensin-converting enzyme inhibitor, is capable of preventing the change. Cerebral blood flow during intracarotid infusion of Y-26763 was measured in anesthetized SHRSP and normotensive Wistar-Kyoto rats (WKY) as control. Y-26763 increased cerebral blood flow in a dose-dependent manner in WKY, and glibenclamide, a selective inhibitor of ATP-sensitive potassium channels, inhibited the Y-26763-induced increase in cerebral blood flow. In contrast, the response to Y-26763 in SHRSP was significantly impaired compared with that in WKY. Antihypertensive treatment with cilazapril lowered blood pressure toward normal and prevented the impaired response in cerebral blood flow to Y-26763 in SHRSP. These findings suggest that (1) ATP-sensitive potassium channels contribute to the regulation of cerebral blood flow in rats, (2) the response to an ATP-sensitive potassium channel opener is markedly diminished in hypertensive rats, and (3) the altered response to an ATP-sensitive potassium channel opener during chronic hypertension can be prevented by long-term antihypertensive treatment.

Comparative effects of three different potent renin inhibitors in primates.

The goal of the present study was to compare the effects of three potent reference renin inhibitors (remikiren, CGP 38560A, and enalkiren) in sodium-depleted normotensive squirrel monkeys. In these monkeys, arterial pressure was measured in the conscious state with a telemetry system. Oral and intravenous maximal effective doses of the three renin inhibitors were compared in parallel groups of monkeys. In additional experiments, remikiren was given on top of either CGP 38560A or enalkiren in the same animals. Finally, the three drugs were compared with the angiotensin converting enzyme inhibitor cilazapril. The effects of the three drugs on the plasma components of the renin-angiotensin system (plasma renin activity, immunoreactive renin, and immunoreactive angiotensin II concentrations) were also measured. Our results show that remikiren was as effective as cilazapril and markedly more effective than CGP 38560A or enalkiren in reducing arterial pressure in our monkey model. Interestingly, these differences in arterial pressure could not be explained by differences of in vitro potency or different biochemical changes of the plasma components of the renin-angiotensin system, because the inhibitors all reduced immunoreactive angiotensin II to similarly low levels. One possible explanation is that, in our model, remikiren in contrast to CGP 38560A and enalkiren is able to inhibit renin in a functionally important extraplasmatic compartment.

Outcome survey in unselected hypertensive patients with type 2 diabetes mellitus: effects of ACE inhibition.

Although the benefit of angiotensin converting enzyme (ACE) inhibitors in diabetic nephropathy is well documented in double-blind randomized, controlled clinical trials, it is uncertain whether the benefit extends to unselected patients with diabetes mellitus and arterial hypertension in general practice. In 2504 unselected patients with type 2 diabetes mellitus (mean age 63+/-10 years) blood pressure, cardiovascular, renal, and metabolic parameters were assessed at baseline and during a treatment period of 1 year with the ACE inhibitor cilazapril by primary care physicians. The average dose of cilazapril was 2.5 mg/day. Outcome measures were blood pressure, serum creatinine, proteinuria (dip stick), HbA1c levels, evaluation of edema, and exertional dyspnea. In the study cohort, systolic blood pressure decreased by 24+/-17 mm Hg and diastolic blood pressure by 12+/-11 mm Hg. An increase in serum creatinine (> 0.2 mg/dL) occurred more frequently in patients with than in those without renal involvement (19% v 7%; P < .05). Serum creatinine decreased more frequently in patients with renal involvement than in those without (26%+/-4% v 12%+/-3.8%; P < .05). Overall renal function in patients with diabetic nephropathy (n = 318) improved (2.1+/-1.6 mg/dL v 1.7+/-1.4 mg/dL; P < .05). The frequency of proteinuria was lower after 1 year than at baseline (62%+/-9% v 82%+/-8%; P < .05). Metabolic control of diabetes mellitus improved in parallel (median HbA1c 8.0% v 7.0%; P < .01). Scores for edema formation and exertional dyspnea improved as well (P < .01). In this outcome survey of unselected patients with type 2 diabetes mellitus and arterial hypertension, the ACE inhibitor cilazapril effectively lowered blood pressure, which was associated with an improvement in glucose metabolism, cardiac function, and renal function.

Cilazapril reverses endothelium-dependent vasodilator response to acetylcholine in mesenteric artery from spontaneously hypertensive rats.

This study was designed to evaluate the effect of chronic treatment with cilazapril on vascular reactivity of aorta and mesenteric artery from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Cilazapril (5 mg/kg), an angiotensin converting enzyme inhibitor, was injected intraperitoneally twice a day for 4 weeks. Results demonstrated that acetylcholine (ACh)-induced relaxation in aorta and mesenteric artery from SHR was significantly less than that from WKY, cilazapril-treated WKY, and SHR. The impairment of ACh-induced relaxation in SHR was significantly reversed after cilazapril treatment and there were no significant differences among WKY, cilazapril-treated WKY, and SHR. Meanwhile, both N omega-nitro-L-arginine (LNNA; 10(-4) mol/L) and methylene blue (MB; 10(-5) mol/L) completely blocked the vasodilator response to ACh in aorta but only partly inhibited in mesenteric artery from WKY, cilazapril-treated WKY, and SHR. These LNNA- and MB-resistant vasodilator responses to ACh in mesenteric artery were only slightly inhibited by TEA (10(-3) mol/L) but not by indomethacin (5 x 10(-6) mol/L). These findings suggest that there may be an unidentified endothelium-dependent relaxing factor(s) (EDRF), which exists in the endothelium and may participate in the modulation of blood pressure in SHR. Results further demonstrate that the antihypertensive effect of cilazapril may be partly mediated by the reversing function of endothelium to release EDRF and LNNA-resistant, unidentified relaxing factor(s).

Effect of cilazapril with or without low dose thiazide on LDL peroxidation in [correction of peroxidationin] hypertensive patients.

BACKGROUND: This study aims to address the question, "Does equivalent blood pressure (BP) reduction by cilazapril alone or in combination with low dose of both cilazapril and hydrochlorothiazide have an equal effect on lowering oxidation of plasma LDL?" METHODS: Fifteen patients with untreated arterial hypertension were enrolled. Patients received 5 mg/d cilazapril (C5) for 6 weeks and were treated with a combination of 2.5 mg/d cilazapril and 12.5 mg/d hydrochlorothiazide (C2.5,HCTz) for an additional 2 months to achieve the same BP reduction as in the initial period. Treatment with a combination of 5 mg/d cilazapril and 12.5 mg/d hydrochlorothiazide (C5,HCTz) was administered for an additional 6 weeks. RESULTS: Treatment with C5 or in combination with C2.5,HCTz lowered systolic BP by the same magnitude (P <.05). Treatment with C5,HCTz decreased systolic BP an additional 7% and diastolic BP by 6% (P <.05). The LDL of 15 hypertensive patients demonstrated a 16.7% shorter lag time to initiation of peroxidation and 8.5% higher malonyldialdehyde levels at point of maximal peroxidation than LDL from 10 healthy controls (P <.05). Treatment with C5 decreased LDL tendency to peroxidation (lag time was prolonged by 43%, P <.05; malonyldialdehyde levels decreased by 8.3%). The combined treatment of C2.5,HCTz achieved the same BP reduction, but did not increase LDL resistance to peroxidation. Treatment with C5,HCTz achieved the same reduction in malonyldialdehyde levels in LDL than C5 therapy, but prolonged lag time by 17% (P <.05). CONCLUSIONS: The decreased tendency of LDL to peroxidation in hypertensive patients treated by cilazapril is due to the inherent effect of cilazapril, and not to a reduction in BP.

Combination treatment with a calcium channel blocker and an angiotensin blocker in a rat systolic heart failure model with hypertension.

The mechanism and treatment of hypertensive systolic heart failure are not well defined. We compared the effect of an angiotensin-converting enzyme inhibitor (cilazapril, 10 mg/kg), an angiotensin receptor blocker (candesartan, 3 mg/kg), a calcium channel blocker (benidipine, 1, 3 or 6 mg/kg), and the same calcium channel blocker combined with renin-angiotensin blockers on systolic heart failure in Dahl salt-sensitive (DS) rats. DS rats were fed an 8% Na diet from 6 weeks of age and then subjected to the above drug treatments. Benidipine (1 mg/kg), cilazapril, and candesartan had compatible hypotensive effects and similar beneficial effects on cardiac hypertrophy, gene expression, and survival rate. The combination of benidipine with cilazapril or candesartan was found to have no additional beneficial effects on the above parameters, with the exception of a reduction in atrial natriuretic polypeptide gene expression. On the other hand, candesartan normalized serum creatinine, but serum creatinine was unaffected by either benidipine at 1 or 3 mg/kg or cilazapril. Further, the combined use of benidipine and either candesartan or cilazapril resulted in an additional reduction of urinary albumin excretion in DS rats. Thus systolic heart failure in DS rats is mainly mediated by hypertension, while renal dysfunction of DS rats is due to both hypertension and the AT1 receptor itself. These findings suggest that the combination of a calcium channel blocker with an AT1 receptor blocker or ACE inhibitor may be more effective in treating the renal dysfunction associated with systolic heart failure than monotherapy with either agent alone. However, further studies will be needed before reaching any definitive conclusion on the efficacy of this combination therapy in patients with heart failure.

Effect of renin-angiotensin inhibition on glomerular injuries in DOCA-salt hypertensive rats.

To determine whether growth factors in the glomerulus are induced in the renin suppressed hypertensive model, we examined the mRNA expressions of platelet-derived growth factor (PDGF) B-chain, transforming growth factor (TGF)-beta 1 and angiotensin II type 1 (AT1) receptors in the glomeruli of deoxycorticosterone acetate (DOCA)-salt-treated hypertensive rats (DOCA-treated rats). We also examined the effects of treatment with cilazapril, an angiotensin I-converting enzyme inhibitor (ACEI), and L-158,809, an AT1 receptor antagonist, on these expressions in DOCA-treated rats. We administered oral 10 mg/kg of cilazapril (CILAZA group) and 1 mg/kg of L-158,809 (L158 group) to DOCA-treated rats daily. Systolic blood pressure in the two groups was not decreased compared with that in DOCA-treated rats given saline. The mRNA expressions were examined using reverse transcriptase polymerase chain reaction (RT-PCR) methods. The mRNA expressions of these genes were higher in DOCA-treated rats than in age-matched control rats. After treatment with these agents for 4 weeks, the mRNA expressions of growth factors were suppressed in both the CILAZA and L158 groups. Mesangial expansion and cell proliferation observed in DOCA-treated rats were suppressed in both the CILAZA and L158 groups. Decreases in the size of the glomerulus were observed only in the CILAZA group. These findings suggested that suppression of growth factors and glomerular proliferative changes of these agents are mediated by blocking tissue renin-angiotensin system (RAS) in the renin-suppressed model.

Changes in left ventricular mass during treatment with minoxidil and cilazapril in hypertensive patients with left ventricular hypertrophy.

Attainment of the regression of hypertension-associated left ventricular hypertrophy (LVH) seems to be a desirable goal of blood pressure (BP)-reducing therapy. Since antihypertensive drugs of differing types may exhibit markedly different abilities to modulate LVH, we examined the effects of the angiotensin-converting enzyme inhibitor cilazapril, and the potassium channel activator minoxidil, alone or in combination with each other, on the left ventricular mass (LVM) in patients with severe essential hypertension who had LVH detected by echocardiography. All patients received the same base therapy of bopindolol and guanfacine. After a run-in period, they were treated with: (1) cilazapril (n = 10); (2) minoxidil, combined with a diuretic (n = 10); or (3) both cilazapril and monoxidil (n = 6) for 12 months. The LVM index (LVMI; LVM per body surface area) was estimated every 3 months by means of echocardiography. Each kind of therapy decreased the arterial pressures to a similar degree. The 1-year treatment with the cilazapril-based regimen resulted in a significantly diminished LVMI (from a mean +/- s.d. of 173 +/- 38 to 152 +/- 22 g/m2; P < 0.05). On the other hand, the minoxidil-based therapy led to a significant increase in LVMI (from 148 +/- 19 to 170 +/- 35 g/m2; P < 0.05). There were no significant LVMI changes in patients receiving the combined, cilazapril + minoxidil-based treatment (172 +/- 34 vs the pretreatment 183 +/- 54 g/m2). The results confirm that long-term treatment with cilazapril is effective both in reducing BP and in reducing LVM. In spite of yielding a satisfactory reduction of BP, minoxidil therapy, even in combination with a diuretic and a beta-blocker, may lead to an aggravation of pre-existing LVH; this effect of minoxidil could be prevented by the simultaneous administration of cilazapril.

Effects of cilazapril on the retinal vessels in spontaneously hypertensive rats: corrosion cast and scanning electron microscopic study.

The effects of the long-term oral angiotensin-converting enzyme inhibitor, cilazapril, on retinal circulation in stroke-prone spontaneously hypertensive (SHR-SP) rats were assessed by scanning electron microscopy (SEM), corrosion casts and transmission electron microscopy (TEM). Two groups of 20 male SHR-SP rats were compared. One group was treated with 10 mg/kg/day of cilazapril from 4 to 40 weeks of age, and the other group received no treatment. A third group of male Wistar-Kyoto (WKY) rats served as age-matched controls. At regular intervals the rats were weighed, and their systolic blood pressure was measured. Cilazapril normalized systolic arterial pressure to 121+/-2.7 mm Hg (SD) in the treated SHR-SP rats. There was no significant difference in body weight between the two groups of SHR-SP. In the 40-week-old SHR-SP rats without treatment corrosion cast and SEM revealed hypertensive retinal vascular changes. In the 40-week-old SHR-SP rats treated with cilazapril, these changes were markedly decreased to the level seen in WKY rats. The differences in caliber of retinal capillaries between the treated SHR-SP and untreated SHR-SP rats were statistically significant (p<.0001). TEM in the cilazapril-treated SHR-SP rats revealed intact basement membranes (0.29+/-0.057 microm) of the endothelial cells and pericytes, but in the untreated SHR-SP rats the basement membrane was thickened (0.51+/-0.123 microm) (p<.0001) and the pericytes damaged. Our results show that the long-term administration of cilazapril decreased systolic arterial pressure to a nearly normal level and prevented hypertensive retinal vascular changes, probably by improving endothelial function. The effects of cilazapril on the retinal vasculature are described for the first time. SEM of corrosion casts is a valuable technique for showing the effects of some drugs on the vasculature easily, precisely and three-dimensionally.

Disparate results of ACE inhibitor dosage on exercise capacity in heart failure: a reappraisal of vasodilator therapy and study design.

Despite manifest benefits of angiotensin converting enzyme (ACE) inhibitors on the prognosis of patients with heart failure, there is a lack of consistency in the results of trials investigating the effects of ACE inhibitors on exercise capacity. The inconsistencies cannot be readily explained by variations in effects on known neurohumoral or conventional haemodynamic factors. Drawing on insights from physiology of pump-load interactions, in a normal circulation there is an optimal extent of systemic vasodilation at which the delivery of hydraulic energy from the cardiac pump is maximal (the 'impedance matchpoint'). In heart failure, the vasoconstrictive effects shift the operating point towards mismatch at higher resistances, and optimal vasodilatory therapy would reshift the operating point to the matchpoint. Excessive dosage, however, would cause overvasodilatation leading to a reduction in cardiac power output and consequently compromising exercise ability. High levels of ACE inhibitors may not therefore improve exercise ability. Another potential reason for the observed inconsistencies is that the often used parallel-group study design (ideal for mortality studies) may not be suitable for investigating drug effects on exercise capacity because dropouts from such studies would introduce occult selection biases, thereby confounding treatment effects. In conclusion, this reappraisal of the conflicting observations reported on ACE inhibitor effects on exercise capacity has highlighted a proposition that there is an optimal dosage of ACE inhibitors which will most enhance exercise capacity, and this will require further well designed cross-over studies to elucidate.

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.

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.

[Comparative and double-blind study of the efficacy and safety of cilazapril compared to nifedipine retard in the treatment of mild and moderate arterial hypertension]. / Estudo comparativo duplo-cego da eficácia e segurança do cilazapril comparadas à nifedipina "retard" no tratamento da hipertensão arterial leve e moderada.

PURPOSE: To evaluate the antihypertensive efficacy and safety of cilazapril compared to nifedipine retard in mild to moderate hypertension. METHODS: forty randomized out-patients with mild moderate hypertension, diastolic pressure (DP) between 95 and 115 mmHg, with placebo for 15 days were randomized and allocated for treatment, double-blind, once daily with cilazapril 2.5 mg (n = 20) or nifedipine retard 20 mg (20 = n) for four weeks. The non-responders (DP > 90mmHg) had the dosage increased twice, b.i.d., while responders were maintained up to 10 weeks. Clinical visits were performed before, at baseline and every two weeks and the laboratory test was performed after placebo run-in, 4th and 10th weeks of treatment. RESULTS: The blood pressure (BP) were similar between groups at the end of the placebo (cilazapril 151 +/- 14/103 +/- 5 - nifedipine 157 +/- 17/108 +/- 7mmHg, p > 0.05). DP decreased already at second weeks (cilazapril 95 +/- 9 - nifedipine 96 +/- 11mmHg, p < 0.05, compared to week 0) in both groups at the end of study with no difference inter groups. BP normalization was obtained in 58% of the patients with cilazapril and in 61% in the nifedipine group. Adverse biochemical effects were not observed in any group. Six (16%) patients of the cilazapril and 15 (39%) of nifedipine related collateral events, although no difference were observed between groups. CONCLUSION: Cilazapril 2.5 to 25mg normalized BP in 58% of mild and moderate hypertension patients, and this efficacy was similar to sustained-release nifedipine 20 to 40mg. Cilazapril had no adverse effects on the biochemical parameters with low incidence of collateral effects.

[Refractory hypotension sustained during general anesthesia due to chronic treatment with angiotensin-converting enzyme inhibitors]. / Hipotensión refractaria y sostenida durante una anestesia general asociada al tratamiento crónico con inhibidores de la enzima conversiva de la angiotensina.

Perioperative management of angiotensin-converting enzyme inhibitors (ACEI) is controversial because of associated hypertensive episodes during induction and maintenance of anesthesia. A 71-year-old woman with a non-functioning thyroid node was scheduled for thyroid lobectomy. Her medical history included high blood pressure and she was being chronically treated with ACEI, which were taken until the morning of surgery. After induction of anesthesia, arterial hypotension refractory to crystalloid therapy developed and worsened in spite of administration of a gelatin-type colloid (Gelafundina). The patient did not respond to ephedrine or dopamine and required stabilization with adrenalin in continuous perfusion for 12 hours. Later evolution was satisfactory and recovery took place without sequelae. We discuss the anesthetic implications of chronic ACEI treatment and possible hemodynamic repercussions of associated administration with gelatin-type solutions or human albumin.