Protective Effect Of Amlodipine Research Articles

Amlodipine alleviates cisplatin-induced nephrotoxicity in rats through gamma-glutamyl transpeptidase (GGT) enzyme inhibition, associated with regulation of Nrf2/HO-1, MAPK/NF-κB, and Bax/Bcl-2 signaling

BackgroundThe therapeutic utility of the effective chemotherapeutic agent cisplatin is hampered by its nephrotoxic effect. We aimed from the current study to examine the possible protective effects of amlodipine through gamma-glutamyl transpeptidase (GGT) enzyme inhibition against cisplatin nephrotoxicity. MethodsAmlodipine (5 mg/kg, po) was administered to rats for 14 successive days. On the 10th day, nephrotoxicity was induced by a single dose of cisplatin (6.5 mg/kg, ip). On the last day, blood samples were collected for estimation of kidney function, while kidney samples were used for determination of GGT activity, oxidative stress, inflammatory, and apoptotic markers, along with histopathological evaluation. ResultsAmlodipine alleviated renal injury that was manifested by significantly diminished serum creatinine and blood urea nitrogen levels, compared to cisplatin group. Amlodipine inhibited GGT enzyme, which participates in the metabolism of extracellular glutathione (GSH) and platinum-GSH-conjugates to a reactive toxic thiol. Besides, amlodipine diminished mRNA expression of NADPH oxidase in the kidney, while enhanced the anti-oxidant defense by activating Nrf2/HO-1 signaling. Additionally, it showed marked anti-inflammatory response by reducing expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB), with subsequent down-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Moreover, amlodipine reduced Bax/Bcl-2 ratio and elevated hepatocyte growth factor (HGF), thus favoring renal cell survival. ConclusionsEffective GGT inhibition by amlodipine associated with enhancement of anti-oxidant defense and suppression of inflammatory signaling and apoptosis support our suggestion that amlodipine could replace toxic GGT inhibitors in protection against cisplatin nephrotoxicity.

Ischemia–reperfusion induced injury of rat ovary and the possible protective effect of amlodipine: Histological, immunohistochemial and biochemical study

Introduction: Ovarian torsion constitutes a gynecologic surgical emergency. However, early diagnosis of torsion may help to detorsion of the affected ovary and to preserve the fertility. Conservative therapy may lead to local and systemic deteriorating effects on the viability of the detorsioned ovary.Aim: The present study was done to evaluate the possible protective effect of amlodipine on ischemia and ischemia reperfusion (I/R) induced ovarian injury in a rat model using histological, immuno-histolochemical, biochemical and morphometric studies.Material and Methods: Forty adult female albino rats were used. They were equally divided into five groups. Group 1: Sham operation (control). Group 2: (ischemia) 3 hours duration of ischemia. Group 3: (ischemia/reperfusion) same as group 2 followed by 3 hours of reperfusion. Group 4: (ischemia and amlodipine) 5 mg amlodipine given orally one hour before ischemia then 3 hours of ischemia. Group 5: (ischemia, re-perfusion and amlodipine) 2 hours of ischemia then 5 mg amlodipine given orally then 3 hours of reperfusion. Then ovarian removal was performed and subjected to histological, immuno-histolochemical , biochemical and morphometric studies.Results: In ischemia and (I/R) groups, the ovaries revealed exfoliation and desquamation of granulosa cells into the follicular cavity of degenerated follicles, with karyolysis and karyorrhexis of the oocyte nucleus, Congested dilated vessels, hyaline degeneration and vacuolation in the interstitial region, Massive cellular infiltrate, hemosiderin deposits and massive hemorrhage of the ovarian stroma. There was positive immunoreactivity for PECAM-I and CD68 and negative for estrogen receptor immunostain. Both superoxide dismutase (SOD) and glutathione (GSH) concentrations were significantly decreased while malondialdehyde MDA (LPO) concentration was significantly increased in ischemia and I/R groups as compared with the other groups. Amlodipine addition improves both histological findings and biochemical valuesConclusion: Amlodipine attenuates ischemia and (I/R) induced ovarian tissue injury

Protective effect of amlodipine on diazinon-induced changes on oxidative/antioxidant balance in rat hippocampus.

Oxidative stress (OS) is a main mechanism in organophosphorus poisoning. The effects of calcium channel blockers have been confirmed in decreasing of oxidative stress. In the current study, the effects of amlodipine (AM), as a calcium channel blocker, were evaluated on oxidative damages induced by diazinon (DZN) in hippocampus tissue of Wistar rats. Forty-two rats were divided into six groups and treated intraperitoneally for two weeks. Group 1 served as control received vehicle, group 2 was treated with 9 mg/kg of AM, group 3 (positive control) received DZN (32 mg/kg), Groups 4, 5, and 6 were treated with 3, 6, and 9 mg/kg of AM adjunct with DZN (32 mg/kg), respectively. After 14 days, all the animals were sacrificed under anesthesia and hippocampus tissue and blood samples were collected for biochemical analysis and histopathology experiments. The results showed that DZN caused significant increase in lipid peroxidation (P < 0.001), nitric oxide (P < 0.001) and lactate dehydrogenase (P < 0.001) levels, depletion of total antioxidant capacity (P < 0.01), and structural changes in hippocampus tissues. Following AM administration, a significant improvement was observed in oxidative biomarkers in hippocampus tissues. Additionally, our biochemical findings were related well with histopathological examinations. In conclusion, the data of this study indicated that AM administration may prevent oxidative damages via improving of energy production and preventing of free radical formation in DZN-exposed animals.

Protective Effect of Amlodipine on Rat Bone Tissue after Orchidectomy

Aim: Our study aimed to investigate the effect of amlodipine on bone metabolism in orchidectomized rats. Methods: Eight-week-old rats were divided into three groups. The sham-operated control group (SHAM) and the control group after orchidectomy (ORX) received the standard laboratory diet (SLD). The experimental group after orchidectomy (ORX+AML) received SLD enriched with amlodipine for 12 weeks. Bone marker concentrations in serum of PINP, OPG and IGF-1, and the levels of CTX-I, BAP and BMP-2 in a bone homogenate were measured using enzyme-linked immunosorbent assay. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry. The femurs were used for biomechanical testing. Results: Bone markers (CTX-I, BAP, BMP-2) in ORX were higher versus SHAM. In ORX+AML there was a decrease in PINP, CTX-I, BAP, BMP-2 and OPG versus ORX. IGF-1 was decreased in ORX versus SHAM. In ORX+AML it was increased versus ORX. In ORX, a decrease was demonstrated versus SHAM in BMD of the whole body, in the lumbar vertebrae and in both femurs. In ORX+AML there was an increase in BMD of the whole body versus ORX. Three-point bending test revealed a decrease in maximal load values in ORX versus SHAM. After amlodipine administration there was an increase in the left femur versus ORX. Conclusions: Amlodipine is capable of mitigating the negative effects of orchidectomy and could be a good prevention of osteoporosis.

Amlodipine and atorvastatin exert protective and additive effects via antiapoptotic and antiautophagic mechanisms after transient middle cerebral artery occlusion in Zucker metabolic syndrome rats

We examined the neuroprotective effects amlodipine and/or atorvastatin in metabolic syndrome (MetS) Zucker fatty rats against transient (90 min) middle cerebral artery occlusion (MCAO). The rats were pretreated with vehicle, amlodipine, atorvastatin, or amlodipine plus atorvastatin for 28 days, and 24 hr after transient MCAO the infarct size was assessed via hematoxylin and eosin staining, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) and microtubule-associated protein 1 light chain 3 (LC3) expression were examined by immunohistochemistry to evaluate apoptosis and autophagy, respectively. Compared with the vehicle group, rats treated with amlodipine or atorvastatin alone showed a significant decrease in infarct volume (P < 0.01), which was further decreased in the amlodipine plus atorvastatin group (P < 0.001). Compared with the vehicle group, the numbers of TUNEL- and LC3-positive cells were markedly reduced by amlodipine or atorvastatin alone (P < 0.01) and further decreased by amlodipine plus atorvastatin (P < 0.001). The number of apoptotic TUNEL/autophagic LC3 double-positive cells was also significantly decreased with amlodipine or atorvastatin alone compared with vehicle (P < 0.01) and was further decreased by amlodipine plus atorvastatin (P < 0.001). These data suggest additive neuroprotective effects of combination amlodipine and atorvastatin treatment after acute ischemic stroke in MetS model Zucker rats. These effects are mediated, at least in part, via antiapoptotic and antiautophagic mechanisms. Further studies are now needed to expand these preliminary results to understand fully the mechanisms involved in the protective effects of amlodipine and atorvastatin against ischemic stroke.

The effects of amlodipine on the biochemical and histopathological changes in the rabbit ileum subjected to ischemia-reperfusion.

The aim of this study was to determine the potential, protective effects of amlodipine in an experimental, ischemia-reperfusion (I/R) model in the rabbit small intestine. The rabbits were divided into four groups: sham-operated, amlodipine (10 mg/kg) + sham-operated, I/R, and I/R + amlodipine (10 mg/kg) groups. An intestinal I/R model was applied to the rabbits. The superior mesenteric artery was occluded for 1 h with an atraumatic vascular clamp and then was reperfused for 2 h. Animals in the amlodipine and I/R + amlodipine groups received the amlodipine by oral gavage. At the end of the 2-h-reperfusion period, the animals were sacrificed. Pretreatment with amlodipine significantly increased SOD activity and GSH levels to values close to those found in the serum from the I/R group. Rabbits in the I/R group showed high levels of serum MDA. Amlodipine pretreatment significantly reduced the serum MDA levels compared to the I/R group, although the MDA levels in the I/R + amlodipine group were still higher than in the sham-operated group. The I/R damage was ameliorated by amlodipine pretreatment, as evidenced by histopathological analysis. The present study is the first to report an attenuation of I/R-induced intestinal injury by the systemic administration of amlodipine.

Amlodipine Treatment Prevents Angiotensin II-induced Human Umbilical Vein Endothelial Cell Apoptosis

Amlodipine, a long-acting dihydropyridine calcium channel blocker, is able to improve angiotensin II-mediated vascular endothelial dysfunction. However, the underlying mechanism remains not fully understood. In the present study we attempted to determine whether the protective effect of amlodipine against Ang II-induced endothelial impairment was mediated through blockage of endothelial cell apoptosis. We pretreated human umbilical venous endothelial cells with increasing doses of amlodipine (10(-8)-10(-6) M) followed by the addition of Ang II. Cell apoptosis was assessed by acridine orange/ethidium bromide staining and by annexin-V/propidium iodide double-labeled cytometry. The involvement of the apoptosis regulators, Bcl-2, Bax, and lectin-like oxidized low-density lipoprotein receptor-1, was determined. Pretreatment with amlodipine resulted in a dose-dependent suppression of Ang II-induced HUVEC apoptosis. Moreover, the Bcl-2/Bax ratio was found to be increased in cells pretreated with amlodipine, indicating an enhanced anti-apoptosis potential. Additionally, the induction of LOX-1 by Ang II was remarkably counteracted by the pre-exposure to amlodipine. Our data demonstrate that amlodipine ameliorates Ang II-induced endothelial apoptosis, which is likely associated with the elevation of Bcl-2/Bax ratio and reduction of the LOX-1 expression.

Protective effect of amlodipine against osteoporosis in stroke-prone spontaneously hypertensive rats

Hypertensive patients have an increasing risk of osteoporosis. A recent case-controlled study has demonstrated that anti-hypertensive therapy reduced a risk of fracture in these patients. In this study, we investigated whether amlodipine protects against the reduction in bone density in stroke-prone spontaneously hypertensive rats (SHR-sp). Oral dosing of amlodipine (0.5 and 3.0 mg/kg/day) was started when SHR-sp were 3 months old, and continued for 3 months. At the end of the experiment, bone density of femur and serum concentrations of calcium, parathyroid hormone (PTH) and C-telopeptide of type I collagen (CTx), reflecting osteoclast activity, were measured. The bone density dose-dependently increased by the treatment with amlodipine. In addition, amlodipine reduced serum concentrations of calcium, PTH and CTx. This study showed that amlodipine prevents the reduction in bone density during the repeated dosing in SHR-sp. Amlodipine might exert its effect through a direct inhibition of osteoclast function and/or suppression of PTH secretion and subsequent inhibition of osteoclast activity.

Protective effects of amlodipine on ischemia-reperfusion injury of rat ovary: biochemical and histopathologic evaluation

To evaluate the effects of amlodipine as an antioxidant and analyze the histopathologic changes in experimental ischemic and ischemic-reperfusion (I/R) injury in rat ovaries. Experimental study. Experimental surgery laboratory. Forty-two rats with experimentally induced ovarian torsion. Group 1: sham operation; group 2: bilateral ovarian ischemia; group 3: 3-hour period of ischemia plus 3 hours of reperfusion; groups 4 and 5: amlodipine administration at 3 and 5 mg/kg respectively before one half hour of ischemia, and then bilateral ovarian ischemia. The ovaries were removed at the third hour of ischemia. Groups 6 and 7: 3-hour period of bilateral ovarian ischemia. Two and a half hours after the induction of ischemia, the rats received amlodipine. At the end of a 3-hour period of ischemia, 3 hours of reperfusion was continued; then the ovaries were removed. Ovarian tissue superoxide dismutase and nitric oxide activity; histopathologic examination of all ovarian rat tissue. Ischemia and I/R increased the inducible nitric oxide synthase activity while decreasing the superoxide dismutase activity significantly in comparison with the sham group. Both doses of amlodipine before ischemia and I/R reversed the trend in nitric oxide synthase activities and reversed the trend in the rat's ovary. Conservative treatment with amlodipine is effective in reducing tissue damage induced by ischemia, I/R, or both in ovaries.

Protective effects of amlodipine and lacidipine on ovariectomy-induced bone loss in rats

Bone is a dynamic organ system that is directly related to calcium and phosphor metabolism. Imbalance in these two parameters upon aging or menopause leads to osteoporosis. Recently, it was also shown by researchers that high blood pressure in elderly women is statistically associated with decreased bone mineral content at the femoral neck, which may increase the susceptibility to fractures. The aim of our study was to investigate the effects of different doses of amlodipine and lacidipine on ovariectomized rat femurs' calcium and phosphor content. Bone calcium and phosphor concentration was measured by a Wavelength Dispersive Spectrometer. Calcium contents of the rat femurs were significantly lower in the ovariectomized group than in the sham group eight weeks after the operation. Amlodipine treatment at doses of 1 and 3 mg/kg significantly increased the calcium ( P < 0.01) and phosphor concentrations ( P < 0.01) in the femurs of ovariectomized rats, compared to those of control (ovariectomized) group. Both doses of lacidipine (1 and 3 mg/kg) also effectively increased calcium concentrations ( P < 0.01) significantly in ovariectomized rats. On the other hand amlodipine treatment at doses of 1 and 3 mg/kg significantly increased the calcium ( P < 0.01) and phosphor concentrations ( P < 0.01) in the femurs of ovariectomized rats compared with those of the sham group. In conclusion, amlodipine and lacidipine improved the bone loss in an ovariectomy induced osteopenic rat model. Our findings suggest that potent calcium channel blockers such as amlodipine and lacidipine have a beneficial effect on bone metabolism, and an antihypertensive effect.

The protective action of amlodipine on cardiac negative inotropism caused by prolonged incubation in vitro

The mechanism of the antihypertensive action of the 1,4-dihydropyridine Ca 2+ antagonist amlodipine was studied in isolated ventricular strips and aortic rings from Wistar rats after oral treatment with amlodipine 15 mg kg/day for one week. The contractions evoked by electrical stimulation of isolated strips from right ventricles pretreated with amlodipine (5 nM) were unaffected during the first hour after mounting, but they decreased in magnitude after prolonged incubation (4 hr). However, the decrease in response of these preparations after prolonged incubation was less than that observed in strips prepared from untreated rats. A negative inotropic effect of amlodipine was observed at concentrations higher than 300 nM. In the presence of lower concentrations of amlodipine (5nM – 30nM) after prolonged incubation, the contractions of ventricular strips were significantly more sustained than in the absence of amlodipine. Likewise, the decrease in contractility evoked by increasing the stimulation frequency from 1 to 3 Hz was reduced in amlodipine treated rats. The recovery of contractility was improved when stimulation frequency was returned to 1 Hz. On the other hand, when rat ventricular strips pretreated with amlodipine (5 nM) were exposed to isoprenaline (3 μM), the contractions evoked by isoprenaline were enhanced. The isoprenaline effect was not altered with 300 nM amlodipine, but with 3 μM became weak and was significantly lower than in strips treated with isoprenaline alone. In addition, treatment with amlodipine produced a marked decrease in the contractions evoked by 100 mM KCl solution in isolated aortic rings when compared to untreated rats. This inhibition was produced in a time-dependent manner with an IC 50 equal to 30 and 3 nM after 2 and 45 min of contraction, respectively. Ex vivo results show that amlodipine treatment decreased aortic contractility without producing a negative inotropic effect although there was an occupation of cardiac Ca 2+ channels. These results suggest that a protective effect of amlodipine on cardiac negative inotropism is produced by prolonged incubation in vitro.

Cardioprotective Effects of Amlodipine in Animal Models of Ischemia and Reperfusion

The protective effect of amlodipine was studied in isolated blood-perfused cat hearts made globally ischemic for 60 min followed by reperfusion for 60 min. Ischemia-induced alterations of left ventricular developed pressure and compliance were monitored. Amlodipine produced significant decreases in myocardial oxygen consumption (6.2 +/- 0.4 to 4.4 +/- 0.4 ml of oxygen/min/100 g) and coronary vascular resistance, as assessed by changes in perfusion pressure (120 +/- 1 to 100 +/- 4 mm Hg). When administered before the onset of global ischemia, amlodipine decreased the development of ischemic contracture as reflected by a progressive increase in resting left ventricular diastolic pressure. The return of contractile function, 60 min after reperfusion, was improved significantly in amlodipine-treated hearts compared to controls and there was better maintenance of the tissue concentration of Na+, Ca2+, and K+. In a canine model of regional myocardial ischemia (6 h) followed by reperfusion, amlodipine at 150 microg/kg, administered 15 min before reperfusion (90 min), reduced infarct size expressed as a percentage of the area at risk (34.5 +/- 3.8% vs. 45.9 +/- 2.8%, p = 0.027). We conclude that amlodipine reduces myocardial ischemic injury by mechanism(s) that may involve a reduction in myocardial oxygen demand as well as by positively influencing transmembrane Ca2+ fluxes during ischemia and reperfusion.

Cardioprotective effects of amlodipine in the ischemic-repefused heart

Amlodipine is a a dihydropyridine derivative belonging to the group of pharmacologic calcium entry blocking agents and is characterized as having a slow onset and relatively long duration of action with minimal effects on cardiac electrophysiology and myocardial contractility. The protective effect of amlodipine was studied in isolated blood-perfused feline hearts made globally ischemic for 60 minutes followed by reperfusion for 60 minutes. Ischemic-lnduced alterations of left ventricular developed pressure and compliance were monitored. In 11 control and 7 drug-treated hearts, amloipine produced significant decreases in myocardial oxygen consumption (6.2 ± 0.4 to 4.4 ± 0.4 ml oxygen/min/100 g) and coronary vascular resistance, as assessed by changes in perfusion pressure (120 ± 1 to 100 ± 4 mm Hg). Amlodipine administered before the onset of global ischemia decreased the development of ischemic contracture as reflected by a progressive increase in resting left ventricular diastolic pressure. The return of contractile function, 60 minutes after reperfusion, improved significantly in the amlodipine-treated group compared with controls, and there was better maintenance of the tissue concentration of Na +, Ca 2+ and K +. A canine model of regional myocardial ischemia (90 minutes) followed by 6 hours of reperfusion was used to assess the cardioprotective effects of amlodyrine, 150 μg/kg, administered 15 minutes before reperfusion. Infarct size, expressed as a percentage of the area at risk, was smaller in the amlodipine-treated group (n = 10) than in the control group (n = 10) (34.5 ± 3.8% vs 45.9 ± 2.8%, p = 0.027). Risk region size did not differ between groups and both groups were comparable with respect to the hemodynamic parameters of heart rate, blood pressure and rate-pressure product. Amlodipine prevented the gradual reduction in coronary blood flow observed in the control group. It is concluded that amlodipine reduces myocardial ischemic injury by mechanism(s) that may involve a reduction in myocardial oxygen demand as well as by positively influencing transmembrane Ca 2+ fluxes during ischemia and reperfusion.