Antihypertensive drug treatment in white-coat hypertension: data from the Plaque HYpertension Lipid-Lowering Italian Study.

AIM: Little evidence is available on whether antihypertensive treatment lowers cardiovascular risk in white-coat hypertension (WCH). Protection might be indirectly inferred, however, from the blood pressure (BP) effects of treatment as in trials BP reduction is linearly related to outcome reduction. We analyzed the effect of antihypertensive treatment on office and ambulatory BP in WCH using data from the Plaque HYpertension Lipid-Lowering Italian Study (PHYLLIS). METHODS: : Office and ambulatory blood pressure were measured in 470 hypertensive patients randomized to fosinopril or hydrochlorothiazide alone or combined with a statin before treatment and at 6 month or yearly intervals during 2.6 years of follow-up. Patients were divided into two groups according to whether before randomization to treatment office and 24-h mean BP were elevated (sustained hypertension) or office BP was elevated but 24-h BP values were normal (WCH). RESULTS: : In both sustained hypertension and WCH antihypertensive treatment was associated with an early marked office BP reduction, which persisted virtually unchanged throughout the treatment period. In contrast, 24-h (and day and night) BP showed a marked and persistent treatment-related fall in sustained hypertension but no change in WCH. The results were similar when data were separately analyzed in patients under fosinopril or diuretic, with or without statin treatment. CONCLUSION: : In WCH, antihypertensive treatment can effectively and durably reduce office BP. This reduction is accompanied by the inability to lower ambulatory BP from the normal values characterizing this condition at baseline. This appears to be unrelated to the type of treatment employed.

Zerumbone, a humulane sesquiterpene from Syringa pinnatifolia, attenuates cardiac fibrosis by inhibiting of the TGF-ß1/Smad signaling pathway after myocardial infarction in mice.

BACKGROUND: Zerumbone (ZER) is a humulane sesquiterpene isolated from Syringa pinnatifolia Hemsl., a representative Mongolian herbal medicine that is used to treat cardiovascular diseases. Cardiac fibrosis is a common pathological process in cardiovascular disease that results from the excessive accumulation of extracellular matrix (ECM), and the transforming growth factor (TGF)-ß/Smad pathway is a canonical signaling pathway that directly induces expressions of ECM-related genes. Currently, the cardioprotective effect and underlying mechanisms of ZER on the inhibition of cardiac fibrosis are not well known. PURPOSE: To explore the cardioprotective properties and pharmacological mechanism of ZER against cardiac fibrosis via the TGF-ß1/Smad signaling pathway. METHODS: Myocardial infarction (MI) model was induced by ligation of the left anterior descending coronary artery in ICR mice. The mice were randomly divided into six groups: sham, model, low-dose ZER (ZER-L), medium-dose ZER (ZER-M), high-dose ZER (ZER-H) and fosinopril. Mice in each group were intragastrically administered treatments for 21 days, and cardiac function was evaluated by 2D echocardiography. The pathological structure of the heart was examined by hematoxylin and eosin (HE) and Masson staining. Content of collagen I and collagen III were assessed by immunofluorescence methods. The inhibitory effect of ZER on TGF-ß1 protein expression was predicted by molecular docking technology. Reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting were used to measure the levels of genes and proteins expressed in the TGF-ß1/Smad signaling pathway and MMPs. TGF-ß1-treated cardiac fibroblasts (CFs) of neonatal SD rats were adopted for in vitro studies. RESULTS: Cardiac ejection fraction (EF) and fractional shortening (FS) in the model group were markedly decreased compared with those in the sham group, indicating that the MI model was successfully established. ZER and fosinopril elevated EF and FS values, suggesting cardioprotective effects. Pathological staining and immunofluorescence analysis showed that the content of collagen I and collagen III increased in the cardiac tissue of mice in model group, while ZER treatment obviously reduced collagen levels. The molecular docking simulations predicted the hydrophobic interactions between ZER and TGF-ß1. In addition, the expression of TGF-ß1, p-Smad2/3 and MMPs in the ZER treatment group was significantly decreased compared with the model group. In vitro studies further confirmed that α-smooth muscle actin (α-SMA) and p-Smad2/3 increased markedly in cardiac fibroblasts after incubation with TGF-ß1, and treatment with ZER suppressed the expression of α-SMA and TGF-ß1 downstream proteins in cardiac fibroblasts. CONCLUSION: ZER rescues cardiac function by attenuating cardiac fibrosis, and the antifibrotic effect may be mediated by blocking the TGF-ß1/Smad pathway.

Plasma Fibroblast Growth Factor 23 as a Predictor for Fosinopril Therapeutic Efficacy in Pediatric Primary Hypertension.

Background Plasma fibroblast growth factor 23 (FGF23) has been reported to be a predictive biomarker for therapeutic effectiveness of angiotensin-converting enzyme inhibitors in heart failure. Higher plasma FGF23 levels have been shown in pediatric primary hypertension, but the predictive value of FGF23 for angiotensin-converting enzyme inhibitors' effectiveness in pediatric primary hypertension has not been documented. Methods and Results This is a prospective study. An exploratory study with 139 patients was first conducted to determine the cutoff value of FGF23 for the prediction of treatment responsiveness. After receiving fosinopril for 4 weeks, of all 139 patients, 91 responded, while 48 did not respond to the treatment, and the responders had a significantly higher baseline plasma FGF23 level than nonresponders (P<0.01). Multiple regression analysis revealed a significant impact of baseline plasma FGF23 levels on fosinopril responsiveness (P<0.05). The receiver operating characteristic curve analysis showed that the plasma FGF23 predicted the effectiveness of fosinopril treatment with an area under the curve of 0.784 (95% CI, 0.704-0.863) for a sensitivity and a specificity of 67.0% and 89.6%, respectively, for a cutoff value of 62.08 RU/mL. Subsequently, another group of 40 patients were recruited for validation. The blood pressure control rate in those (n=22) with baseline plasma FGF23 >62.08 RU/mL was significantly higher than that in children (n=18) with FGF23 ≤62.08 RU/mL (P<0.05). Conclusions Plasma FGF23 might be a valuable biomarker to guide fosinopril therapy for primary hypertension in children.

Fabry disease with early-onset ventricular dilation: A case report.

RATIONALE: The most common cardiac involvement of Fabry disease (FD) is left ventricular hypertrophy (LVH), which usually occurs in male patients over the age of 30. In rare cases, it can progress to ventricular dilation in the late stage of the disease. PATIENT CONCERNS: A 16-year-old boy presenting with recurrent extremity pain and chest distress was admitted to our hospital. Imaging examinations revealed ventricular dilation. DIAGNOSIS: α-Galactosidase A enzyme assay and GLA gene sequencing confirmed the diagnosis of FD and revealed a novel mutation c.76_77insT. INTERVENTIONS: The patient was treated using metoprolol (23.75 mg qd) and angiotensin-converting enzyme inhibitor (fosinopril sodium 5 mg qd). He refused enzyme replacement therapy for financial reasons. OUTCOMES: The echocardiography, electrocardiography, renal function, and routine blood and urine tests performed 20 months after the patients discharge from hospital showed no significant changes. The patient reported a slow and gradual decrease in the frequency and degree of pain and chest distress, starting approximately 24 months after discharge. LESSONS: Cardiac involvement of FD can progress rapidly in some cases. Screening for FD should be considered in patients with unexplained ventricular dilation, especially in those with a history of typical FD manifestations.

Destruction of the blood-retina barrier in diabetic retinopathy depends on angiotensin-converting enzyme-mediated TGF-ß1/Smad signaling pathway activation.

Diabetes mellitus (DM) is a systemic, chronic metabolic disease that is related to heredity and autoimmunity and is often accompanied by complications of retinopathy. However, the causative mechanism involved in the pathological process remains unclear. In this research, treatment with fosinopril or LY2109761 was found to be responsible for the improvement of the pathological processes, serum biochemical indexes and retinopathy in rats with streptozotocin-induced diabetes. In addition, the upregulation of angiotensin-converting enzyme (ACE) in the serum and the increased expression of TGF-ß1 in the pathological outer nuclear layer (ONL) and inner nuclear layer (INL) of the retina were also reduced. In vitro experiments demonstrated that ACE enhanced cell damage and TGF-ß1/Smad signaling pathway activation in retinal capillary endothelial cells (RCECs) under high glucose conditions. In addition, the activity of ACE was also considered to be related to the increasing levels of activated TGF-ß1 in both rat retinal Müller cells (RMCs) and RCECs, but ACE activity had no effect on the high glucose-mediated upregulation of total TGF-ß1 in RMCs. Coculture experiments with RCECs and RMCs showed that the barrier that was established under normal conditions was significantly impaired when exposed to high glucose combined with ACE, and damage of barrier can be prevented by adding fosinopril or LY2109761. Finally, a similar auxiliary effect of ACE was also observed in the activated TGF-ß1-mediated barrier damage in blood-retinal barrier model in vitro. In summary, ACE-mediated TGF-ß1/Smad signaling pathway activation was found to be involved in the destruction of the blood-retina barrier during diabetic retinopathy in a model of streptozotocin-induced diabetes, and these data may provide evidence to guide the treatment of the complications of diabetes mellitus.

Early Renin-angiotensin System Blockade Improved Short-term and Longterm Renal Outcomes in Systemic Lupus Erythematosus Patients with Antiphospholipid-associated Nephropathy.

OBJECTIVE: To investigate the renal protective effects of early renin-angiotensin-aldosterone system (RAAS) blockade with renin-angiotensin system inhibitors (RASI) in systemic lupus erythematosus (SLE) patients with antiphospholipid-associated nephropathy (aPLN). METHODS: Medical data of 57 SLE patients with biopsy-proven aPLN were analyzed. Early RAAS blockade was defined as administration of RASI within 3 months after kidney biopsy and continued for ≥ 12 months. RESULTS: There was no significant difference in demographic data, laboratory findings, and renal histology by the time of kidney biopsy, except that the RASI group had higher proteinuria levels vs the non-RASI group [5.2 (2.8-8.8) vs 1.9 (0.6-2.8) g/d, p = 0.005, respectively] and higher prevalence of hypertension (75% vs 29%, p = 0.001, respectively). No significant difference between the 2 groups was observed in estimated glomerular filtration rate (eGFR), mean arterial pressure, and proteinuria level at 12 months after kidney biopsy. The improvement ratio of eGFR at 12 months was significantly higher in the RASI group versus the non-RASI group [26% (-5 to 86) vs -2% (-20 to 20), p = 0.028, respectively], and the rate of change in eGFR beyond 12 months was similar between the 2 groups. During a mean followup of 80 months, 4 (23%) patients in the non-RASI group and 3 (8%) patients in the RASI group developed kidney disease progression. Early RAAS blockade significantly decreased the risk of kidney disease progression [HR = 0.11 (0.02-0.59); p = 0.010]. Proteinuria and hypertension controls were similar between the 2 groups. CONCLUSION: Early RAAS blockade improved the short-term and longterm renal outcomes in SLE patients with aPLN. The renal protective effect of RASI was independent of its antihypertensive and antiproteinuric effects.

PATHOGENETIC ADVANCES OF FOSINOPRIL SODIUM WITH HYDROCHLOROTHIAZIDE IN OBESE HYPERTENSIVE PATIENTS.

Purpose - to improve antihypertensive therapy on the basis of studying the antioxidant properties of an angiotensin-converting enzyme (ACE) inhibitor (fosinopril sodium) and a diuretic (hydrochlorothiazide), their impact on endothelial dysfunction and pro-inflammatory cytokines activity in hypertensive patients with overweight and obesity. A combination of fosinopril sodium 20 mg/day and hydrochlorothiazid 12.5 mg/day was prescribed to 54 patients with essential hypertension of 1-3 grades, 30 to 65 years old . The control group included 10 healthy subjects matched for age and sex. During the course of combined antihypertensive therapy we observed a significant decrease of i-NOS activity, reduce of TNF-α type I of its soluble receptor (sTNF-αRI), and 8-iso-PgF2α in the patients. Activity of e-NOS, superoxide dismutase and catalase, in contrast, were increased in patients with hypertension and concomitant obesity. Thus, the improvement of endothelial function, a significant decrease autoimmune activation due to lower tension of oxidative stress in the examined patients optimizes use of a combination of fosinopril sodium and hydrochlorothiazid for differentiated therapy in hypertensive patients with obesity.

Angiotensin Converting Enzyme Inhibitor Dialyzability and Outcomes in Older Patients Receiving Hemodialysis.

BACKGROUND/AIMS: Some angiotensin converting enzyme (ACE) inhibitors are efficiently removed from circulation by hemodialysis ('high dialyzability'), whereas others are not ('low dialyzability'). In patients receiving hemodialysis, this may influence the effectiveness of ACE inhibitors. METHODS: Using linked healthcare databases we identified older patients receiving chronic hemodialysis who filled new ACE inhibitor prescriptions. The low dialyzability group (n = 3,369) included fosinopril and ramipril. The high dialyzability group (n = 5,974) included enalapril, lisinopril, and perindopril. The primary outcome was all-cause mortality within 180 days of first ACE inhibitor prescription. RESULTS: There were 361 deaths among 5,974 patients (6.0%) prescribed with low dialyzability ACE inhibitors and 179 deaths among 3,369 patients (5.3%) prescribed with high dialyzability ACE inhibitors (relative risk 1.1, 95% CI 0.9-1.3, p = 0.6). CONCLUSION: In this study of older patients receiving hemodialysis, the dialyzability of ACE inhibitors was not associated with mortality or cardiovascular outcomes.

Effects of antihypertensive treatment on cardiovascular autonomic control: a prospective study.

OBJECTIVE: The aim of study was to propose an approach to the control of dynamics of autonomic dysfunction in cardiovascular system (CVS) under antihypertensive treatment (AT) in patients with arterial hypertension (AH), based on individual features of synchronization of 0.1-Hz rhythms in heart rate (HR) and photoplethysmogram (PPG) and spectral indices of heart rate variability (HRV). METHODS: We designed prospective cohort diagnostic accuracy and studied 105 AH patients (66 females) aged 47±8 years during 8 weeks. The HRV spectral indices and the index S of synchronization between the 0.1-Hz rhythms in HR and PPG during a tilt test are compared in their ability to control the AT with angiotensin-converting enzyme inhibitors (ACE-Is) (fosinopril or enalapril) and ß-blockers (atenolol or metoprolol). We apply Shapiro-Wilk, Mann-Whitney U and Wilcoxon tests. RESULTS: It is shown that the power of low-frequency (LF) band in HRV spectrum and index S can be used as criteria for initial assessment of the status of autonomic regulation in AH patients. The patients with S<25% in vertical body's position and LF>250 ms2 in horizontal body's position require ACE-Is treatment. The AH patients with LF<350 ms2 and S<30% in vertical body's position require ß-blocker treatment. The AH patients with S>25% and LF>250 ms2 in horizontal body's position do not require any ACE-Is or ß-blocker treatment. Both drug groups can be used in patients with low values of index S and low power of LF band in HRV spectrum. CONCLUSION: The control of AT can be carried out in AH patients taking into account the individual features of autonomic dysfunction in CVS. Sensitivity and specificity of our approach were 65% and 73%, respectively.

A randomized controlled trial of angiotensin-converting enzyme inhibition for skeletal muscle dysfunction in COPD.

BACKGROUND: Skeletal muscle impairment is a recognized complication of COPD, predicting mortality in severe disease. Increasing evidence implicates the renin-angiotensin system in control of muscle phenotype. We hypothesized that angiotensin-converting enzyme (ACE) inhibition would improve quadriceps function and exercise performance in COPD. METHODS: This double-blind, randomized placebo-controlled trial investigated the effect of the ACE inhibitor, fosinopril, on quadriceps function in patients with COPD with quadriceps weakness. Primary outcomes were change in quadriceps endurance and atrophy signaling at 3 months. Quadriceps maximum voluntary contraction (QMVC), mid-thigh CT scan of the cross-sectional area (MTCSA), and incremental shuttle walk distance (ISWD) were secondary outcomes. RESULTS: Eighty patients were enrolled (mean [SD], 65 [8] years, FEV1 43% [21%] predicted, 53% men). Sixty-seven patients (31 fosinopril, 36 placebo) completed the trial. The treatment group demonstrated a significant reduction in systolic BP (Δ-10.5 mm Hg; 95% CI, -19.9 to -1.1; P = .03) and serum ACE activity (Δ-20.4 IU/L; 95% CI, -31.0 to -9.8; P < .001) compared with placebo. No significant between-group differences were observed in the primary end points of quadriceps endurance half-time (Δ0.5 s; 95% CI, -13.3-14.3; P = .94) or atrogin-1 messenger RNA expression (Δ-0.03 arbitrary units; 95% CI, -0.32-0.26; P = .84). QMVC improved in both groups (fosinopril: Δ1.1 kg; 95% CI, 0.03-2.2; P = .045 vs placebo: Δ3.6 kg; 95% CI, 2.1-5.0; P < .0001) with a greater increase in the placebo arm (between-group, P = .009). No change was shown in the MTCSA (P = .09) or ISWD (P = .51). CONCLUSIONS: This randomized controlled trial found that ACE inhibition, using fosinopril for 3 months, did not improve quadriceps function or exercise performance in patients with COPD with quadriceps weakness. TRIAL REGISTRY: Current Controlled Trials; No.: ISRCTN05581879; URL: www.controlled-trials.com.

Attenuation of diabetic nephropathy by Chaihuang-Yishen granule through anti-inflammatory mechanism in streptozotocin-induced rat model of diabetics.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medical herbs have been used in China for a long time to treat different diseases. Based on traditional Chinese medicine (TCM) principle, Chaihuang-Yishen granule (CHYS) was developed and has been employed clinically to treat chronic kidney disease including diabetic nephropathy (DN). The present study was designed to investigate its mechanism of action in treatment of DN. MATERIALS AND METHODS: Diabetic rats were established by having a right uninephrectomy plus a single intraperitoneal injection of STZ. Rats were divided into four groups of sham, diabetes, diabetes with CHYS and diabetes with fosinopril. CHYS and fosinopril were given to rats by gavage for 20 weeks. Samples from blood, urine and kidney were collected for biochemical, histological, immunohistochemical and molecular analyses. RESULTS: Rats treated with CHYS showed reduced 24h urinary protein excretion, decreased serum TC and TG levels, but CHYS treatment did not affect blood glucose level. Glomerular mesangial expansion and tubulointerstitial fibrosis in diabetic rats were significantly alleviated by CHYS treatment. Moreover, CHYS administration markedly reduced mRNA levels of NF-κB p65 and TGF-ß1, as well as decreased protein levels of NF-κB p65, MCP-1, TNF-α and TGF-ß1 in the kidney of diabetic rats. CONCLUSIONS: CHYS ameliorates renal injury in diabetic rats through reduction of inflammatory cytokines and their intracellular signaling.

[CLINICAL PERSPECTIVES OF COMPLEX APPLICATION OF PERCUTANEOUS CORONARY INTERVENTION AND DRUG REVASCULARIZATION IN ACUTE CORONARY SYNDROME].

The article presents the evaluation of the influence of complex application of monopril, propranolol and heparin and percutaneous coronary intervention (PCI); monopril, propranolol with methylase in combination with PCI and PCI only on hemddynamics, cardiohemodynamics and clinical course in acute myocardial infarction (MI), as well as the monitoring of these patients. A comparison of the results of the complex medical and mechanical revascularization. The study involved 63 patients with acute coronary syndrome (ACS): anterior MI with Q wave and ST-segment with the rise in age from 30 to 70 years, the average age (56.7 +/- 1.2) years old, who were randomly divided into three groups with 21 in each. Patients in group I received heparin, propranolol with monopril and PCI; II--methylase (tenakteplaza) and propranolol, monopril and after 1 day they performed PCI; group III patients performed only PCI. With the help of echocardiography and Doppler echocardiometry values studied endsystolic (ESV) and end-diastolic (EDV) volume, ejection fraction (EF), stroke (SI) and heart (HI) index, index of local contractility disturbance of the left ventricle (LV ILCD) as well as the dynamics of systolic, (SBP) and diastolic (PBP) blood pressure, clinical features of myocardial infarction during follow-up. Injection of methylase, infusion of propranolol, receiving per os of monopril and conduct after 1 day of PCI accelerate the stabilization of central hemodynamics. ESV, EDV and ILCD reduce, systolic function of LV improves, ejection fraction increases. When there was no restenosis, myocardial infarction relapse and mortality 1 patient on 5th day was recorded acute heart failure (AHF). When treating by monopril, propranolol and heparin and conduct of PCI also stabilize central hemodynamics. ESV, EDV and ILCD reduce, EF increases and systolic function of LV improves (I group). However, in one patient on the 3rd day were recorded acute heart failure (AHF). Restenosis, recurrent myocardial infarction, and mortality were not observed. During the PCI only treatment 4 patients relapsed MI, 4 patients had restenosis, 2 patients had AHF and 2 patients died. Observations have shown that the combined application of drug therapy with PCI provides a positive predictive as opposed to using only PCI.

[The use of complex tools ezetimibe, hepadyfu fosinopril and correction of blood pressure and endothelial dysfunction in patients with nonalcoholic steatohepatitis and essential hypertension stage II].

The article investigates the impact of complex tools fosinopril, hepadyf and ezetimibe for correction of functional state of the endothelium and changes in blood pressure in patients with nonalcoholic steatohepatitis, obesity and essential hypertension stage II.

TLR4-mediated anti-atherosclerosis mechanisms of angiotensin-converting enzyme inhibitor--fosinopril.

Recently, angiotensin-converting enzyme inhibitor (ACEI) has gained increasing attention for its anti-atherosclerosis activity, but the underlying mechanism is unknown. In our study, we used rabbits fed with high-fat forage, as an atherosclerosis model to investigate the effect of fosinopril, which is an ACEI. Animals which received both high-fat forage and fosinopril, were maintained as the drug-treated group. Ultrasonography and Sudan III staining were used to determine the process of atherosclerosis. The expression of TLR4 and activity NF-κB were determined using western blot, RT-PCR and ELISA. The results showed that the atherosclerotic plaque was visible at sixteen weeks. More importantly, the atherosclerotic plaque was significantly decreased after fosinopril treatment. In the atherosclerosis model, the levels of TLR4 and NF-κB were increased, but this increased expression was inhibited in the fosinopril treated group. Our results demonstrated that TLR4 could be used as a potential biomarker for atherosclerosis and ACEI has the potential to be a new anti-atherosclerotic drug.

Comparative evaluation of fosinopril and herbal drug Dioscorea bulbifera in patients of diabetic nephropathy.

Worldwide, diabetic nephropathy is one of the leading causes of end-stage renal failure. This hospital-based single-center prospective open-label randomized case-control interventional study was performed to evaluate and compare the native drug Dioscorea bulbifera with fosinopril in the management of diabetic nephropathy. Patients with diabetic nephropathy with proteinuria >500 mg/day or albuminuria >300 mg/ day, S Cr ≤2.5 mg/dL and hypertension controlled with a single drug were included into the study and were divided into three groups according to the interventional drugs that they were given; group A (n = 46) on fosinopril (5-40 mg/day), group B (n = 45) on Dioscorea bulbifera (500 mg BD) and group C (n = 46) on neither of these drugs. All necessary laboratory investigations needed to assess the effect of both the drugs were carried out. Patients were followed-up for six months. The study included 137 patients (M:F 2.61:1) with an age range of 19-76 years. At the sixth-month follow-up, a significant decrease in the systolic blood pressure was noted in all three groups whereas the diastolic blood pressure decreased significantly only in group B. There was significantly better control of both systolic and diastolic blood pressures in group B than in the other groups. Although fasting blood sugar was poorly controlled in the initial visit in all three groups, there was a significant decrease at the sixth-month follow-up in all three groups. Moreover, the decrease was significantly more pronounced in group B than in the other two groups. Low-density lipoprotein decreased significantly only in group B. Proteinuria, serum transforming growth factor-ß, interleukin-6 (IL-6) and C-reactive protein decreased in both group A and group B, more so in the latter, but the differences between the groups were not statistically significant. Importantly, proteinuria and serum IL-6 showed an increasing trend in group C. It can be concluded that Dioscorea bulbifera was more effective than fosinopril in controlling blood pressure, glycemia, cholesterolemia and inflammatory state in diabetic nephropathy. Both agents decreased proteinuria. However, creatinine clearance significantly decreased with both the drugs, more so with Dioscera, and thus further evaluation with a larger trial is needed.

Visit-to-visit blood pressure variability is a strong predictor of cardiovascular events in hemodialysis: insights from FOSIDIAL.

Optimal blood pressure (BP) targets are still controversial in end-stage renal disease. Recent data have highlighted shortcomings of the usual BP hypothesis in other patient populations and emphasized the importance of visit-to-visit variability of BP in predicting cardiovascular events. The Fosinopril in Dialysis Study failed to demonstrate the efficacy of 2-year angiotensin-converting enzyme inhibition with fosinopril versus placebo in 397 hemodialysis patients with left ventricular hypertrophy but provided an opportunity to assess the influence of BP variability on cardiovascular events. The primary end point was the occurrence of a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina, stroke, revascularization, hospitalization for heart failure, and resuscitated cardiac arrest. The variations in BP throughout the 17 visits were assessed by within-patient overall variability of systolic, diastolic, and pulse pressures between adjacent readings, by within-patient overall variability of systolic/diastolic/pulse pressures, and the residual of the linear fit. Compared with our previous predictive model of cardiovascular events occurrence based on stroke, peripheral arterial disease, coronary artery disease, diabetes mellitus, left ventricular mass, and age (which exhibited similar coefficients herein), the percentage of explained variance improved by 30.1% (R(2)=0.141-0.183) when adding the coefficient of variation of within-patient overall variability of systolic BP. Usual BP parameters were neither cardiovascular events predictors nor correlated to BP variability. Visit-to-visit BP variability was extremely high in hemodialysis patients compared with other populations and a major determinant of cardiovascular events. Such assessments should be prioritized for testing prevention strategies in end-stage renal disease.

Angiotensin converting enzyme inhibitors mitigate collagen synthesis induced by a single dose of radiation to the whole thorax.

Our long-term goal is to use angiotensin converting enzyme (ACE) inhibitors to mitigate the increase in lung collagen synthesis that is induced by irradiation to the lung, which could result from accidental exposure or radiological terrorism. Rats (WAG/RijCmcr) were given a single dose of 13 Gy (dose rate of 1.43 Gy/min) of X-irradiation to the thorax. Three structurally-different ACE inhibitors, captopril, enalapril and fosinopril were provided in drinking water beginning 1 week after irradiation. Rats that survived acute pneumonitis (at 6-12 weeks) were evaluated monthly for synthesis of lung collagen. Other endpoints included breathing rate, wet to dry lung weight ratio, and analysis of lung structure. Treatment with captopril (145-207 mg/m(2)/day) or enalapril (19-28 mg/m(2)/day), but not fosinopril (19-28 mg/m(2)/day), decreased morbidity from acute pneumonitis. Lung collagen in the surviving irradiated rats was increased over that of controls by 7 months after irradiation. This increase in collagen synthesis was not observed in rats treated with any of the three ACE inhibitors. Analysis of the lung morphology at 7 months supports the efficacy of ACE inhibitors against radiation-induced fibrosis. The effectiveness of fosinopril against fibrosis, but not against acute pneumonitis, suggests that pulmonary fibrosis may not be a simple consequence of injury during acute pneumonitis. In summary, three structurally-different ACE inhibitors mitigate the increase in collagen synthesis 7 months following irradiation of the whole thorax and do so, even when therapy is started one week after irradiation.

Intrarenal metabolomics reveals the association of local organic toxins with the progression of diabetic kidney disease.

The pathological development of diabetic kidney disease (DKD) might involve metabolic perturbations in kidney tissue. The present study was designed to detect the systematic alterations of renal cortex metabolites thereby exploring the related mechanisms of DKD development and fosinopril treatment. Based on combined gas chromatography/time-of-flight mass spectrometry (GC-TOF MS) and liquid chromatography/time-of-flight mass spectrometry (UPLC-TOF MS) data acquiring platform, we have performed a metabolomic analysis of perfused renal cortex samples from the diabetic rats induced by streptozocin and treated with or without fosinopril, a pharmacological inhibitor of angiotensin II converting enzyme (ACEI). We identified a number of abnormal metabolites in the diabetic kidney, including groups of amino acids, carbohydrates, polyols, lyso-phospholipids, glucuronides and other unidentified metabolites. Of them, an increase in intrarenal organic toxins including uremic toxins, glucuronides and glucotocixity-associated metabolites are highly correlated with diabetic kidney injury including 24h urinary protein levels and tubulointerstitial injury index. Treatment with fosinopril significantly attenuated diabetic kidney injury, and simultaneously blocked the intrarenal accumulation of these organic toxins, especially hippurate and glucuronides. These results indicate that intrarenal accumulation of organic toxins may be significant for the development of DKD and the related mechanisms deserve to be further investigated.

Fosinopril and zofenopril, two angiotensin-converting enzyme (ACE) inhibitors, potentiate the anticonvulsant activity of antiepileptic drugs against audiogenic seizures in DBA/2 mice.

The renin-angiotensin system (RAS) exists in the brain and it may be involved in pathogenesis of neurological and psychiatric disorders including seizures. The aim of the present research was to evaluate the effects of some angiotensin-converting enzyme inhibitors (ACEi; captopril, enalapril, fosinopril and zofenopril), commonly used as antihypertensive agents, in the DBA/2 mice animal model of generalized tonic-clonic seizures. Furthermore, the co-administration of these compounds with some antiepileptic drugs (AEDs; carbamazepine, diazepam, felbamate, gabapentin, lamotrigine, phenobarbital, phenytoin, topiramate and valproate) was studied in order to identify possible positive interactions in the same model. All ACEi were able to decrease the severity of audiogenic seizures with the exception of enalapril up to the dose of 100mg/kg, the rank order of activity was as follows: fosinopril>zofenopril>captopril. The co-administration of ineffective doses of all ACE inhibitors with AEDs, generally increased the potency of the latter. Fosinopril was the most active in potentiating the activity of AEDs and the combination of ACEi with lamotrigine and valproate was the most favorable, whereas, the co-administrations with diazepam and phenobarbital seemed to be neutral. The increase in potency was generally associated with an enhancement of motor impairment, however, the therapeutic index of combined treatment of AEDs with ACEi was predominantly more favorable than control. ACEi administration did not influence plasma and brain concentrations of the AEDs studied excluding pharmacokinetic interactions and concluding that it is of pharmacodynamic nature. In conclusion, fosinopril, zofenopril, enalapril and captopril showed an additive anticonvulsant effect when co-administered with some AEDs, most notably carbamazepine, felbamate, lamotrigine, topiramate and valproate, implicating a possible therapeutic relevance of such drug combinations.