Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker on oxidative stress and metabolism of elements in kidney of STZ-induced diabetic rats.

In diabetes, increased oxidative stress and impaired trace element metabolism play an important role in the pathogenesis of diabetic nephropathy. The objective of this research was to examine the outcomes of blocking the renin-angiotensin system, using either the angiotensin-converting enzyme inhibitor (ACEI), perindopril, or the angiotensin II type 1 (AT1) receptor blocker, irbesartan, on oxidative stress and trace element levels such as Zn, Mg, Cu, and Fe in the kidneys of diabetic rats that had been induced with streptozotocin. Thirty-two Wistar albino male rats were equally divided into four groups. The first group was used as a control. The second group of rats developed diabetes after receiving a single intraperitoneal dose of STZ. The third and fourth groups of rats had STZ-induced diabetes and received daily dosages of irbesartan (15 mg/kg b.w/day) and perindopril (6 mg/kg b.w/day) treatment, respectively. Biochemical analysis of the kidneys showed a distinct increase in oxidative stress, indicated by heightened levels of malondialdehyde (MDA) and decreased superoxide dismutase (SOD) activities, as well as reduced glutathione (GSH) levels in the kidneys of diabetic rats. In the kidneys of diabetic rats, the mean levels of Fe and Cu were found to be significantly higher than those of the control group. Additionally, the mean levels of Zn and Mg were significantly lower in the diabetic rats compared to the control rats. Both perindopril and irbesartan decreased significantly MDA content and increased SOD activities and GSH levels in the kidneys of rats with diabetes. The Zn and Mg concentrations in the kidneys of diabetic rats treated with perindopril and irbesartan were markedly higher than in untreated STZ-diabetic rats, while the Cu and Fe concentrations were significantly lower. The urinary excretion of rats treated with perindopril and irbesartan showed a pronounced increase in Cu levels, along with a significant reduction in Zn and Mg levels. Although diabetic rats demonstrated degenerative morphological alterations in their kidneys, both therapies also improved diabetes-induced histopathological modifications in the kidneys. Finally, the present results suggest that manipulating the levels of Zn, Mg, Cu, and Fe - either through ACE inhibition or by blocking AT1 receptors - could be advantageous in reducing lipid peroxidation and increasing antioxidant concentration in the kidneys of diabetic rats.

Targeting inflammation and redox aberrations by perindopril attenuates methotrexate-induced intestinal injury in rats: Role of TLR4/NF-κB and c-Fos/c-Jun pro-inflammatory pathways and PPAR-γ/SIRT1 cytoprotective signals.

AIMS: The use of methotrexate (MTX), a classical immunosuppressant and anti-cancer agent, is associated with multiple organ toxicities, including the intestinal injury. Components of the renin-angiotensin system are expressed in the intestinal epithelium and mucosal immune cells where they provoke pro-inflammatory and pro-oxidant action. The present study was conducted to investigate the potential ability of perindopril (PER), an angiotensin-converting enzyme inhibitor (ACEI), to attenuate MTX-induced intestinal injury with emphasis on the role of the pro-inflammatory TLR4/NF-κB and c-Fos/c-Jun pathways alongside PPAR-γ and SIRT1 cytoprotective signals. MATERIALS AND METHODS: The intestinal injury was induced by a single-dose injection of 20 mg/kg of MTX i.p at the end of the 5th day. PER was administrated once daily in a dose of 1 mg/kg, i.p, for five days before MTX and five days later. RESULTS: Herein, perindopril attenuated the intestinal injury as seen by lowering the histopathological aberrations and preserving the goblet cells in villi/crypts. These beneficial actions were associated with downregulating the expression of the pro-inflammatory angiotensin II, TNF-α, IL-1ß, and IL-6 cytokines, alongside upregulating the anti-inflammatory angiotensin (1-7) and IL-10. At the molecular level, perindopril downregulated the TLR4/NF-κB and c-Fos/c-Jun pathways in inflamed intestine of rats. Moreover, it attenuated the pro-oxidant events by lowering intestinal MDA and boosting GSH, SOD, and GST antioxidants together with PPAR-γ and SIRT1 cytoprotective signals. The aforementioned findings were also highlighted using molecular docking and network pharmacology analysis. CONCLUSIONS: Perindopril demonstrated notable mitigation of MTX-induced intestinal injury through suppression of TLR4/NF-κB and c-Fos/c-Jun pathways alongside the augmentation of PPAR-γ/SIRT1 cytoprotective signals.

The Effect of Angiotensin-Converting Enzyme Gene Polymorphisms on the Clinical Efficacy of Perindopril Prescribed for Acute Myocardial Infarction in Chinese Han Patients.

Objective: Perindopril is an angiotensin-converting enzyme (ACE) inhibitor that is commonly used in the treatment of Chinese Han patients with acute myocardial infarction (AMI). However, there have been few studies on whether polymorphisms of the ACE gene affect the efficacy of perindopril or the prognosis of AMI patients. The purpose of this study was to analyze the relationship among the ACE rs121912703 (C>T), rs767880620 (C>A), and rs397514689 (C>T) gene polymorphisms and the prognosis of AMI patients and the clinical efficacy of perindopril in the treatment of AMI. Methods: The ACE genotypes at the rs121912703, rs767880620, and rs397514689 loci in 225 AMI patients treated with perindopril were determined by polymerase chain reaction/Sanger sequencing. Differences in cardiac structure, functional indicators, hemodynamic parameters, and related laboratory indicators were detected before and after treatment. Results: After administration of perindopril, improved ventricular remodeling in AMI patients with wild-type ACE was better than in patients with the ACE rs121912703, rs767880620, and rs397514689 minor variant alleles. The patients harboring wild-type ACE had lower systolic blood pressure and diastolic blood pressure than the patients harboring the minor variant alleles (p < 0.01). The contents of serum ACE and Ang II (angiotensin II) in AMI patients carrying the wild-type ACE alleles were lower than those of patients harboring any of the minor variant alleles (p < 0.01). The 3-year survival time of AMI patients carrying the wild-type ACE alleles was markedly greater compared with AMI patients carrying the mutant genes (p < 0.01). Conclusion: Mutations at the ACE rs121912703, rs767880620, and rs397514689 loci affect the efficacy of perindopril on ventricular remodeling and hemodynamics in Chinese Han AMI patients. The 3-year survival of AMI patients harboring the variant alleles is less than that of the patients harboring the wild-type gene.

Ultrasound-Stimulated Microbubbles Enhance Radiosensitization of Nasopharyngeal Carcinoma.

BACKGROUND/AIMS: Recent studies indicate that therapies targeting the vasculature can significantly sensitize tumors to radiation. Ultrasound-stimulated microbubbles (USMBs) are regarded as a promising radiosensitizer. In this study, we investigated the effect of USMBs on the sensitivity of nasopharyngeal carcinoma (NPC) to radiation. METHODS: Human NPC (CNE-2) cells and human umbilical vein endothelial cells (HUVECs) were exposed to radiation (0, 2, and 8 Gy) alone or in combination with USMBs. Cell viability and apoptosis were measured with the MTT assay and flow cytometry, respectively. The angiogenic activity of HUVECs was detected using matrigel tubule formation. The in vitro effects induced by these treatments were confirmed in vivo with xenograft models of CNE-2 cells in nude mice by examining vascular integrity using color Doppler flow imaging and cell survival using immunohistochemistry. Additionally, the in vivo and in vitro expressions of angiotensin II (ANG II) and its receptor (AT1R) were detected by immunohistochemistry and western blotting, respectively. With CNE-2 cells and HUVECs transfected with control, ANG II, or AT1R, perindopril (an inhibitor of angiotensin-converting enzyme) and candesartan (an inhibitor of AT1R) were used to verify the role of ANG II and AT1R in the radiosensitivity of tumor and endothelial cells by USMBs, by determining cell viability and apoptosis and angiogenic activity. RESULTS: In the NPC xenografts, USMBs slightly reduced blood flow and CD34 expression, increased tumor cell death and ANG II and AT1R expression, and significantly enhanced the effects of radiation. With CNE-2 cells and HUVECs, the USMBs further enhanced the inhibition of tumor cell viability and endothelial tubule formation and further enhanced the increase in ANG II and AT1R due to radiation. Furthermore, perindopril and candesartan significantly enhanced the inhibitory effect of radiation and USMBs on tumor cell growth and angiogenesis in vitro. CONCLUSIONS: We have demonstrated for the first time that USMB exposure can significantly enhance the destructive effect on NPC of radiation, and this effect might be further increased by ANG II and AT1R inhibition. Our findings suggest that USMBs can be used as a promising sensitizer of radiotherapy to treat NPC, and the clinical effect might be increased by ANG II and AT1R inhibition.

Adherence with perindopril therapy: a pilot study using therapeutic drug monitoring of perindoprilat and an evaluation of the clearance estimation.

Background Although measurement of drug serum levels is an objective direct method for testing compliance, it can be distorted by "white-coat compliance" or by variations in drug elimination. Objective The aim of this prospective study was to evaluate the prevalence of noncompliance with perindopril therapy in adult out-patients using pharmacokinetic simulations. The additional aim was to compare the predictive performance of two glomerular filtration rate markers-creatinine and cystatin C. Setting Department of Cardiology, Tomas Bata Regional Hospital in Zlín, Czech Republic. Method Perindoprilat pharmacokinetic models individualized according to patient characteristics were compared with measured perindoprilat serum concentrations to document compliance. Linear regression was used to evaluate the relations between perindoprilat clearance and glomerular filtration rate estimated using creatinine and cystatin C. Main outcome measure Assessment of non-compliance with medication using drug concentration measurements reinforced with therapeutic drug monitoring. Results Non-detectable perindoprilat levels were observed in 26.1% of patients. Another 21.7% were classified as non-compliant based on therapeutic drug monitoring pharmacokinetic simulations. Volume of distribution, clearance and half-life median value (interquarti°range) for perindoprilat were 408.3 (360.4-456.8) L, 10.1 (4.9-17.0) L h-1 and 24.7 (19.4-62.7) h, respectively. Linear regression models showed tight relationship between cystatin C and perindoprilat clearance. Conclusions Assessment of adherence with medication reinforced with therapeutic drug monitoring and pharmacokinetic simulations is proposed as an optimal method reducing disadvantages of simple drug concentration measurements. Cystatin C proves to be better surrogate marker for perindoprilat elimination than creatinine.

[Endothelial and metabolic effects of perindopril in patients with essential hypertension].

OBJECTIVE: To elucidate endothelial and metabolic effects of perindopril and their interaction in patients with uncomplicated essential hypertension. METHODS: The study involved 30 patients treated with perindopril (5-10 mg/day) for 3 months. The following parameters were registered at baseline and at the end of the study: body mass index, waist circumference, blood lipids and glucose, flow-mediated vasodilation (FMVD) of brachial artery assessed by ultrasound. RESULTS: Treatment with perindopril was associated with significant improvement of FMVD (6.7 ± 4.1% versus 8.7 ± 5.4% at the end of the study, p<0.05) as well as decrease of blood triglycerides (-18%, p<0.05) and glucose (-9%, p<0.01) with no significant changes of other metabolic parameters. Correlation analysis showed no relationship between changes of FMVD and blood pressure during the study (r= -0.14, p=0.42 r= -0.13, p=0.46 for systolic and diastolic blood pressure, respectively) whereas inverse association was observed with changes of blood glucose (r= -0.50, p<0.01). CONCLUSIONS: Thus our data confirm the ability of perindopril to restore impaired endothelial function in patients with essential hypertension independently of blood pressure reduction and make possible to propose its positive metabolic effect relative to changes associated with insulin resistance. It seems that endothelial effect of perindopril may in part be related to diminished adverse influence of metabolic changes on vascular wall.

Perindopril and ramipril phosphonate analogues as a new class of angiotensin converting enzyme inhibitors.

A series of phosphonate analogues related to perindopril and ramipril were prepared and tested to estimate their ability to inhibit angiotensin converting enzyme. These new synthesized compounds were active ACE inhibitors with a promising activity.

Effect of a centrally active angiotensin converting enzyme inhibitor, perindopril, on cognitive performance in chronic cerebral hypo-perfusion rats.

We have previously demonstrated that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, ameliorated the cognitive deficits in Alzheimer's disease model animals, independently of its anti-hypertensive effect. In this study, we again investigated the effects of perindopril on cognitive function in a vascular dementia model animal, comparing it with other ACE inhibitors. We also determined ACE activity in the brain and extracellular acetylcholine (ACh) concentration in the perirhinal cortex in order to elucidate the mechanism(s) responsible for the effects of these ACE inhibitors on cognitive function. Perindopril was suggested to be more centrally active than imidapril and enalapril, in consideration of the relative distribution of their active metabolites in the brain. This property was at least partially attributed to the lipophilicity of the compound. While the 3 day treatment with perindopril, imidapril or enalapril lowered blood pressure to the same level in spontaneous hypertensive rats, only perindopril reversed the decline in the recognition index in chronic cerebral hypo-perfusion rats, regarded as an animal model of vascular dementia, during an object recognition task. Using the same dosing regimen, perindopril inhibited the brain ACE activities of rats more than imidapril or enalapril. Moreover, a single treatment with perindopril enhanced the extracellular level of ACh in the perirhinal cortex of normal rats. Therefore, we confirmed that only centrally active ACE inhibitors, such as perindopril, can inhibit the ACE in the brain, augmenting cholinergic neurotransmission and thereby ameliorating cognitive impairment in the animal model of vascular dementia.

Hydrophilic interaction liquid chromatography/positive ion electrospray ionization mass spectrometry method for the quantification of perindopril and its main metabolite in human plasma.

A validated method based on liquid chromatography/positive ion electrospray-mass spectrometry (LC-ESI/MS) is described for the quantification of perindopril and its active metabolite, perindoprilat, in human plasma. The assay was based on 500-microL plasma samples, following solid-phase extraction using Oasis HLB cartridges. All analytes and the internal standard (trandolapril) were separated by hydrophilic interaction liquid chromatography using a SeQuant Zic-HILIC analytical column (150.0 x 2.1 mm i.d., particle size 3.5 microm, 200 A) with isocratic elution. The mobile phase consisted of 10% 5.0 mM ammonium acetate water solution in a binary mixture of acetonitrile/methanol (60:40, v/v) and pumped at a flow rate of 0.10 mL min(-1). Quantitation of the analytes was performed with selected ion monitoring (SIM) in positive ionization mode using electrospray ionization interface. The assay was found to be linear in the concentration range of 5.0-500.0 ng mL(-1) for perindopril and perindoprilat. Intermediate precision were found less than 3.5% over the tested concentration ranges. A run time of less than 6.0 min for each sample made it possible to analyze a large number of human plasma samples per day. The method is the first reported application of HILIC in the analysis of angiotensin-converting enzyme inhibitors and can be used to quantify perindopril and perindoprilat in human plasma covering a variety of pharmacokinetic or bioequivalence studies.

Insight into the mode of action of ACE inhibition in coronary artery disease: the ultimate 'EUROPA' story.

ACE inhibition is now recognized as superior to placebo on outcomes in stable coronary artery disease (CAD), including total and cardiovascular mortality, fatal and nonfatal myocardial infarction, heart failure, revascularization and stroke. This review examines clinical evidence for the mode of action of ACE inhibitors in CAD, which is dominated by the results of a single trial, EUROPA, and its substudies. The generally accepted mode of action for ACE inhibitors in CAD is blood pressure reduction. However, the EUROPA data demonstrate that endothelial protection, with the effect of arresting or reducing the processes of atherosclerosis is also important. Chronic overexpression of tissue ACE in CAD disrupts the angiotensin II/bradykinin balance with a net result of endothelial dysfunction. ACE inhibitors reduce production of angiotensin II, which prevents vasoconstriction, reduces adhesion molecules and growth factors, decreases oxidative stress and prevents apoptosis. A concomitant decrease in the degradation of bradykinin as a result of ACE inhibition raises levels of this kinin, leading to vasodilation and an antiapoptotic action, as well as opposition of the negative actions of angiotensin II. We now have clinical trial evidence of these processes in CAD patients participating in the EUROPA study by measurement of markers of endothelial function, including nitric oxide synthase (eNOS), the rate of apoptosis and levels of von Willebrand factor (vWf). Serum from CAD patients was found to significantly downregulate eNOS protein expression and activity versus that of healthy controls (p < 0.01), most probably as a result of upregulation of tissue ACE. One year of treatment with perindopril upregulated eNOS protein expression and activity (19% and 27% vs placebo; p < 0.05). Similarly, vWf was elevated at baseline and significantly reduced after 1 year of treatment with perindopril (p < 0.001). Increased endothelial apoptosis by serum of CAD patients was accompanied by excess angiotensin II and tumour necrosis factor-alpha and a reduction in bradykinin; all of these parameters were reversed by treatment. We therefore have clinical results showing that perindopril normalizes the angiotensin II/bradykinin balance, reduces inflammation and prevents endothelial apoptosis. Accumulating preclinical evidence for the absence of a class effect for ACE inhibitors includes differences in terms of effect on eNOS and rate of endothelial apoptosis. These differences appear to be related to tissue affinity, penetration of atherosclerotic plaque and affinity for the target enzyme. Consideration of these features is important when administering ACE inhibition as secondary prevention in CAD patients. In this context, current European guidelines for stable angina pectoris recommend prescription of agents and doses with proven efficacy in secondary prevention.

Effect of slow-release indapamide and perindopril compared with amlodipine on 24-hour blood pressure and left ventricular mass in hypertensive patients of African ancestry.

BACKGROUND: In the treatment of hypertension in subjects of African origins, although hydrochlorothiazide (HCTZ) is not as effective as calcium channel blockers, indapamide is superior to HCTZ. In the present study we therefore compared the effects of slow release (SR) indapamide with the calcium channel blocker amlodipine, when used as initial therapy, on blood pressure (BP) and left ventricular mass (LVM) during 6 months of treatment in this group. METHODS: Patients with a mean daytime ambulatory diastolic BP > or =90 mm Hg and < or =110 mm Hg (n = 125, aged 53 +/- 11 years, 68% women) were randomized to receive open-label 1.5 mg of indapamide SR or 5 mg of amlodipine. If daytime ambulatory diastolic BP at 1 month was >/=90 mm Hg, 4 mg of perindopril was added to indapamide SR or the dose of amlodipine was increased to 10 mg. RESULTS: After 1 month of therapy, there was an equivalent decline in systolic and diastolic BP in both groups (P <.0001). In the indapamide-treated group (n = 62) the daytime BP decreased from 153 +/- 12/101 +/- 6 mm Hg to 138 +/- 15/92 +/- 10 mm Hg and for amlodipine (n = 58), it decreased from 152 +/- 13/99 +/- 5 mm Hg to 138 +/- 12/91 +/- 8 mm Hg. At 6 months daytime ambulatory BP decreased to 130 +/- 15/86 +/- 8 mm Hg and to 129 +/- 11/85 +/- 5 mm Hg for the indapamide SR (n = 42) and amlodipine (n = 44) treatment groups, respectively. Both groups showed equivalent regression of LVM index and relative wall thickness. CONCLUSIONS: These data suggest that in hypertensive patients of African ancestry initiating therapy with 1.5 mg of indapamide SR and then adding 4 mg of perindopril is equally as effective as amlodipine therapy at reducing BP, and modifying target organ damage.