Effects of Phytochemicals on Blood Pressure and Neuroprotection Mediated Via Brain Renin-Angiotensin System.

BACKGROUND: The renin-angiotensin system (RAS) in the brain plays a crucial role in maintaining blood pressure as well as neuroprotection. This study compared the effects of curcumin, quercetin, and saponin on blood pressure, the brain RAS, and cholinergic system using perindopril, an angiotensin converting enzyme inhibitor (ACEI), as a positive control. METHODS: Five-week-old male mice were stabilized and randomly assigned into a control group (n = 8), three phytochemical-treated groups (curcumin (n = 8), quercetin (n = 8), and saponin (n = 8)), and a positive control group (n = 8). The groups treated with the phytochemical were orally administered daily at a dose of 50 mg/kg body weight of phytochemicals. During the experiments, the weight and dietary intakes were measured regularly. After experiments, the brain tissue was homogenized and centrifuged for an additional assay. The concentrations of ACE, angiotensin II (AngII), and aldosterone levels were measured, and the mRNA expressions of renin and ACE were measured. As biomarkers of neuroprotection, the concentrations of acetylcholine(Ach) as well as the concentration and activity of acetylcholine esterase (AChE) were measured. RESULTS: After 4 weeks of treatment, the perindopril group showed the lowest blood pressure. Among the groups treated with the phytochemicals, treatment with curcumin and saponin significantly reduced blood pressure, although such effect was not as high as that of perindopril. Among phytochemicals, curcumin treatment significantly inhibited the concentration and activity of ACE, concentration of AngII, and mRNA expression of ACE. All phytochemical treatments significantly increased the concentration of ACh. The levels of AChE activity in groups exposed to curcumin or saponin (not quercetin) were significantly inhibited, Conclusion: Curcumin administration in rats reduced blood pressure by blocking the brain RAS components and protected the cholinergic system in brain by inhibiting the activity of AChE.

Inhibition of the Renin-Angiotensin System Post Myocardial Infarction Prevents Inflammation-Associated Acute Cardiac Rupture.

PURPOSE: Inhibition of the renin-angiotensin system (RAS) is beneficial in patient management after myocardial infarction (MI). However, whether RAS inhibition also provides cardiac protection in the acute phase of MI is unclear. METHODS: Male 129sv mice underwent coronary artery occlusion to induce MI, followed by treatment with losartan (L, 20 and 60 mg/kg), perindopril (P, 2 and 6 mg/kg), amlodipine (20 mg/kg as a BP-lowering agent) or vehicle as control. Drug effects on hemodynamics were examined. Effects of treatments on incidence of cardiac rupture, haematological profile, monocyte and neutrophil population in the spleen and the heart, cardiac leukocyte density, expression of inflammatory genes and activity of MMPs were studied after MI. RESULTS: Incidence of cardiac rupture within 2 weeks was significantly and similarly reduced by both losartan (L) and perindopril (P) in a dose-dependent manner [75% (27/36) in vehicle, 40-45% in low-dose (L 10/22, P 8/20) and 16-20% (L 5/32, P 4/20) in high-dose groups, all P < 0.05]. This action was independent of their BP-lowering action, as amlodipine reduced BP to a similar degree without effect on rupture (70%, 21/30). Compared to the control group, high dose losartan and perindopril decreased counts of white blood cells, neutrophils and lymphocytes (all P < 0.05), and inhibited splenic monocyte and neutrophil release into the circulation. Consequently, monocyte, neutrophil and leukocyte infiltration, inflammatory gene expressions (IL-1ß, IL-6, MMP9, MCP-1, TNF-α and TGFß1) and activity of MMP2 and MMP9 in the infarct tissue were attenuated by losartan and/or perindopril treatment (all P < 0.05). CONCLUSIONS: RAS inhibition by losartan or perindopril prevented cardiac rupture at the acute phase of MI through blockade of splenic release of monocytes and neutrophils and consequently attenuation of systemic and regional inflammatory responses.

Perindopril/amlodipine (Prestalia(®)): a review in hypertension.

Perindopril, an ACE inhibitor, and amlodipine, a dihydropyridine calcium channel blocker, are established antihypertensive agents with complementary mechanisms of action. Recently, a once-daily, orally-administered, fixed-dose combination (FDC) of perindopril arginine plus amlodipine besylate (Prestalia(®); hereafter referred to as perindopril/amlodipine FDC) was approved in the USA for the treatment of hypertension. This article reviews the efficacy and tolerability of perindopril/amlodipine FDC and briefly summarizes the agent's pharmacologic properties. As demonstrated in short-term randomized controlled trials, perindopril/amlodipine FDC was significantly more effective in reducing blood pressure (BP) than monotherapy with either of the component drugs, and it appeared to be more effective than an up-titration scheme using valsartan and valsartan/amlodipine. The FDC agent was generally well tolerated, with the most common adverse events (peripheral edema, cough, headache, and dizziness) being consistent with the well-defined tolerability profiles of the individual component drugs. Furthermore, perindopril/amlodipine FDC was associated with a numerically lower incidence of peripheral edema compared with amlodipine monotherapy. Thus, perindopril/amlodipine FDC represents a useful option for the treatment of hypertension, including as initial therapy for patients likely to require multiple drugs to achieve their BP targets.

Inhibition of AAA in a rat model by treatment with ACEI perindopril.

BACKGROUND: The purpose of the present study was to evaluate the effect of a new angiotensin converting enzyme inhibitor perindopril on the formation of experimental abdominal aortic aneurysms (AAAs) in a rat model induced by intraluminal elastase infusion and extraluminal calcium chloride (CaCl2) application. MATERIALS AND METHODS: Thirty-six male Sprague-Dawley rats were randomly distributed into three groups (n = 12 per group): model (A), sham (B), and perindopril (C). Rats in model and perindopril groups underwent intra-aortic elastase perfusion and extraluminal CaCl2 application to induce AAAs. Rats in the sham group received aortic perfusion and extraluminal application of saline. A dose of 3 mg/kg/d of perindopril was fed orally in the perindopril group. The maximum abdominal aortic diameter was measured in vivo on days 0 and 28 and by ultrasound on days 7, 14, and 21. The arterial blood pressure was measured directly using a pressure transducer after cannulation in surgery and before death. AAA tissue samples were harvested at day 28 and evaluated using normal hematoxylin and eosin stain, Verhoeff-van Gieson stain for elastin, and image analysis technique. RESULTS: Aortic diameters of rats in the model group consistently increased within 28 d, coinciding with the development of a transmural inflammatory response, thickening of intima, and destruction of the elastic media. Without alteration in blood pressure, the AAA formation rate and mean maximal diameter of aorta at day 28 were significantly lower in the perindopril group compared with the control group (1.71 ± 0.20 versus 2.70 ± 0.69 mm, P < 0.001; 0% versus 90.91%, P < 0.001) and were similar to those in the sham group (1.79 ± 0.29 mm, P = 0.175; 0%, P = 1). The thickness of intima in the perindopril group was lower than that in the model group (20.68 ± 9.96 versus 58.49 ± 32.01 µm, P = 0.001), but higher than that in the sham group (7.23 ± 2.68 µm, P = 0.005). The intensity of elastin fiber showed the opposite trend (0.8541 ± 0.0495 in sham group versus 0.7376 ± 0.1024 in perindopril group versus 0.5413 ± 0.0912 in model group, P < 0.001). CONCLUSIONS: Perindopril inhibited the aortic degeneration and AAA formation in the experimental AAA model induced by elastase and CaCl2. This effect, which was independent of its influence on hemodynamics, appeared to be induced by the suppression of the inflammatory cell influx and intimal thickening and the preservation of aortic medial elastin.

Evaluation of nutritional and biochemical parameters in spontaneously hypertensive rats following antihypertensive treatment.

INTRODUCTION: One side effect of antihypertensive drugs is their impact on nutritional status and metabolism. The purpose of this study was to assess the nutritional and biochemical parameters in spontaneously hypertensive rats following treatment with antihypertensive drugs. MATERIAL AND METHODS: The experiment was performed on 50 male spontaneously hypertensive rats (SHR), which were assigned to five groups: control (C), with perindopril (PR), with metoprolol (MT), with indapamide (ID), and with amlodipine (AM). All rats were provided ad libitum standard diet (with or without drugs) and distilled water. After 45 days, the animals were weighed and killed. Liver, kidney, heart, spleen, pancreas, and blood samples were collected. Concentrations of glucose, cholesterol, triglycerides, and albumin were assayed in serum. Morphology parameters, such as white blood cell, red blood cell, hematocrit, and lymphocyte counts were measured in the blood. Blood pressure was measured using a tail-cuff plethysmograph. RESULTS: The results obtained indicate that the hypotensive drugs under investigation had no effect on the selected nutritional parameters. Perindopril significantly decreased the relative mass of the heart and amlodipine markedly decreased the relative mass of the pancreas. A markedly higher concentration of glucose in the group with indapamid, and a significantly lower concentration of triglycerides in the group with metoprolol, were observed. Indapamide and amlodipine markedly increased the value of red blood cells and hematocrit in the blood of SHR. CONCLUSIONS: Long-term therapy with antihypertension drugs may influence tissue mass and biochemical and morphological status in the body.

The influence of selected hypotensive drugs on the bioavailability of minerals from buckwheat groats in vitro enzymatic digestion.

BACKGROUND: The mineral status in hypertensive patients may be affected by hypotensive drugs. The aim of this study was to estimate the influence of hypotensive drugs (angiotensine converting enzyme inhibitors (ACE-I), ß-blockers, Ca-antagonists, diuretics) on the potential bioavailability of magnesium, iron, zinc and copper from buckwheat groats in vitro enzymatic digestion. MATERIAL AND METHODS: The degree of release of magnesium, iron, zinc and copper from buckwheat groats was determined with and without (the control sample) an addition of hypotensive drugs. Four antihypertensive drugs in one dose (one tablet per sample) were analysed: metocard (a ß-blocker), cardilopin (a Ca-antagonist), apo-perindox (ACE-I) and indapen (a diuretic). The samples were subjected to enzymatic digestion under in vitro conditions. The content of minerals in buckwheat groats before and after enzymatic digestion was determined by flame atomic absorption spectrometry (AAS). RESULTS: It was found that cardilopin (amlodipine) and indapen (indapamide) significantly increased the release of zinc from groats. The degree of release of magnesium was higher and the release of iron was lower in samples with apo-perindox (perindopril) than in the control group. The release of copper was significantly decreased by indapen (indapamid). CONCLUSIONS: Amlodipine, perindopril and indapamide affected the release of magnesium, iron, zinc and copper from buckwheat groats in vitro enzymatic digestion.

Clinical synergy of perindopril and calcium-channel blocker in the prevention of cardiac events and mortality in patients with coronary artery disease. Post hoc analysis of the EUROPA study.

BACKGROUND: The purposes of the study were to determine the effects of addition of perindopril to long-term continuous treatment with calcium-channel blocker (CCB) on cardiac outcomes in the stable coronary artery disease (CAD) population of EUROPA and to explore the presence of synergy between perindopril and CCB in secondary prevention. METHODS: We identified participants receiving CCB at every visit during the 4.2-year follow-up and analyzed the effect of addition of perindopril (n = 1,022 perindopril/CCB vs n = 1,100 placebo/CCB). RESULTS: Addition of perindopril to CCB significantly reduced total mortality by 46% (P < .01 vs placebo) and primary end point (a composite of cardiovascular mortality, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 35% (P < .05 vs placebo). There were 41%, 54%, and 28% reductions in cardiovascular mortality, hospitalization for heart failure, and myocardial infarction, respectively. Comparison of hazard ratios suggests the presence of a clinical synergy between perindopril and CCB, with a greater effect than addition of individual effects. CONCLUSION: Addition of perindopril to CCB in stable CAD patients had a significant supplementary impact on cardiac outcomes and mortality.

ACE-inhibitor suppresses the apoptosis induced by endoplasmic reticulum stress in renal tubular in experimental diabetic rats.

AIMS: The aim of the present study was to investigate the role of the endoplasmic reticulum stress and apoptosis in experimental diabetic nephropathy. The effects of ACE inhibitor on the endoplasmic reticulum stress and apoptosis were also assessed. METHODS: Diabetes was induced in male Sprague-Dawley rats by injection with streptozotocin at 60 mg/kg i .p. Diabetic rats were then randomly assigned into control (untreated) or treatment of an ACE inhibitor, perindopril, for 24 weeks. Tubulointerstitial injury was assessed by histopathology. Tubule apoptosis was detected by TUNEL assay. Endoplasmic reticulum stress associated proteins expression of glucose-regulated protein-78 (GRP78/BiP), phospho-eukaryotic initiation factor 2 alpha (eIF2 alpha), phospho-pancreatic ER kinase (PERK) and caspase-12 was assessed by immunohistochemistry and Western blots. RESULTS: There were more TUNEL-positive nuclei in diabetic kidneys than in control kidneys. At 24 weeks, experimental diabetes was associated with a considerable increase in protein expression of GRP78, phospho-eIF2 alpha, phospho-PERK, and caspase-12 in the tubulointestitium. ACE inhibitor not only attenuated the apoptosis but also reduced the overexpression of these endoplasmic reticulum stress associated proteins in tubulointestitium of diabetic rats. CONCLUSIONS: Increased tubular apoptosis in experimental diabetic rats is attenuated by blockade of the renin-angiotensin system with an ACE inhibitor, which might be in an association with reduced endoplasmic reticulum stress.

Cardiac protective effect of Astragalus on viral myocarditis mice: comparison with Perindopril.

In clinical practice, Astragali Radix (Astragalus), the root of Astragalus membranaceus Bunge, has been widely applied to treat patients with viral diseases, including viral myocarditis in China. The present study was designed to evaluate the protective effects of Astragalus on the function of sarcoplasmic reticulum calcium ATPase (SERCA2) activity and endothelin system at acute and chronic periods of myocarditis mice induced by CVB(3) infection. Astragalus feeding (2.2 mg/kg/day) could significantly increase the survival rate, alleviate pathological alterations and serum cardiac troponin I (cTnI), as well as restore impaired SERCA activity at the acute stage. Low affinity and capacity of ETR were reversed with Astragalus after the first CVB(3) inoculation up to 7 days and after the second virus inoculation up to 150 days. In the meantime, the contents of cardiac ET-1 and ANP were reduced. Comparison the myocarditis mice treated with Perindopril (0.44 mg/kg/day), an ACE inhibitor, shows that Astragalus achieved a similar effect on survival rate, SERCA2 and ET system. These results indicated that the beneficial effects of Astragalus and Perindopril for treating viral myocarditis might be partly mediated by preserving the functions of SERCA 2 activity and ET system.

RAS blockade decreases blood pressure and proteinuria in transgenic mice overexpressing rat angiotensinogen gene in the kidney.

Angiotensinogen (ANG) is the sole substrate of the renin-angiotensin system (RAS). Clinical studies have shown that RAS activation may lead to hypertension, a major cardiovascular and renal risk factor. To delineate the underlying mechanisms of hypertension-induced nephropathy, we generated transgenic mice that overexpress rat ANG (rANG) in the kidney to establish whether intrarenal RAS activation alone can evoke hypertension and kidney damage and whether RAS blockade can reverse these effects. Transgenic mice overexpressing renal rANG were generated by employing the kidney-specific, androgen-regulated protein promoter linked to rANG cDNA. This promoter targets rANG cDNA to renal proximal tubules and responds to androgen stimulation. Transgenic mice displayed kidney-specific expression of rANG, significantly increased blood pressure (BP) and albuminuria in comparison to non-transgenic littermates. Administration of losartan (an angiotensin II (type 1)-receptor antagonist) or perindopril (an angiotensin-converting enzyme inhibitor) reversed these abnormalities in transgenic animals. Renal injury was evident on examination of the kidneys in transgenic mice, and attenuated by losartan and perindopril treatment. We conclude that the overproduction of ANG alone in the kidney induces an increase in systemic BP, proteinuria, and renal injury. RAS blockers prevent these abnormalities. These data support the role of the intrarenal RAS in the development of hypertension and renal injury.

Inhibition of angiotensin I-converting enzyme induces radioprotection by preserving murine hematopoietic short-term reconstituting cells.

Angiotensin I-converting enzyme (ACE) inhibitors can affect hematopoiesis by several mechanisms including inhibition of angiotensin II formation and increasing plasma concentrations of AcSDKP (acetyl-N-Ser-Asp-Lys-Pro), an ACE substrate and a negative regulator of hematopoiesis. We tested whether ACE inhibition could decrease the hematopoietic toxicity of lethal or sublethal irradiation protocols. In all cases, short treatment with the ACE inhibitor perindopril protected against irradiation-induced death. ACE inhibition accelerated hematopoietic recovery and led to a significant increase in platelet and red cell counts. Pretreatment with perindopril increased bone marrow cellularity and the number of hematopoietic progenitors (granulocyte macrophage colony-forming unit [CFU-GM], erythroid burst-forming unit [BFU-E], and megakaryocyte colony-forming unit [CFU-MK]) from day 7 to 28 after irradiation. Perindopril also increased the number of hematopoietic stem cells with at least a short-term reconstitutive activity in animals that recovered from irradiation. To determine the mechanism of action involved, we evaluated the effects of increasing AcSDKP plasma concentrations and of an angiotensin II type 1 (AT1) receptor antagonist (telmisartan) on radioprotection. We found that the AT1-receptor antagonism mediated similar radioprotection as the ACE inhibitor. These results suggest that ACE inhibitors and AT1-receptor antagonists could be used to decrease the hematopoietic toxicity of irradiation.

A double-blind trial of perindopril and nitrendipine in incipient diabetic nephropathy.

UNLABELLED: We conducted a randomised, double-blind multicentre trial to compare the efficacy of the inhibitor of the angiotensin-converting enzyme (ACE) perindopril (P) with nitrendipine (N) in incipient diabetic nephropathy. METHODS: Forty-six patients with insulin-treated diabetes mellitus and mild-to-moderate hypertension and stable microalbuminuria were examined. P 4 or 8 mg once daily was compared to N 20 or 40 mg once daily; an optional open combination treatment with indapamide 2.5 mg once daily was given when needed. Main outcome measures were urinary albumin excretion rate, creatinine clearance and isotopic clearance measurements after 12 months. RESULTS: Baseline characteristics (blood pressure, HbA1, renal function) were highly comparable between groups. No serious adverse events occurred during the study period. Blood pressure was controlled (<140/90 mmHg) in all patients except for one in each group who dropped out. At the end of the study, albumin excretion rate was stabilized in both groups (P: 72% of baseline, N: 108%, NS). There were no significant differences found in radiometric clearance measurements. Creatinine clearance rose in patients treated with P by 10.0 ml/min on average, while it decreased by 9.8 m/min under N treatment (group effect: p<0.05). CONCLUSIONS: In this head-to-head comparison, P and N were effective in stabilising most parameters of renal function in incipient diabetic nephropathy.

Effect of chronic treatment with perindopril on endothelium-dependent relaxation of aorta and carotid artery in SHRSP.

Endothelium-dependent relaxation of aorta and carotid artery from stroke-prone spontaneously hypertensive rats (SHRSP) and the effect of chronic treatment of SHRSP with perindopril, an angiotensin converting enzyme inhibitor, on endothelium-dependent relaxation were studied. Endothelium-dependent relaxation was induced by acetylcholine (ACh) in preparations of SHRSP and normotensive Wistar Kyoto rats (WKY) precontracted with noradrenaline. The ACh-induced relaxation in both preparations was abolished by L-nitroarginine. The ACh-induced relaxation was impaired in preparations from SHRSP and contraction was observed at high concentrations of ACh. In the presence of indomethacin, impairment of endothelium-dependent relaxation in SHRSP was minimized and the contraction was inhibited. The relaxation with sodium nitroprusside did not differ between the preparations from WKY and SHRSP. Treatment of SHRSP with perindopril (2 mg/kg/day) for 6 weeks decreased systolic blood pressure and improved the ACh-induced relaxation of aorta and carotid artery. The treatment inhibited the contraction by higher concentrations of ACh in the presence of L-nitroarginine. These results indicate that the impairment of endothelium-dependent relaxation in aorta and carotid artery of SHRSP may be caused by the reduced availability of nitric oxide. The perindopril-treatment may prevent these changes in SHRSP.