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1.  Simvastatin ameliorates radiation enteropathy development after localized, fractionated irradiation by a protein C-independent mechanism 
Background
Microvascular injury plays a key role in normal tissue radiation responses. Statins, in addition to their lipid-lowering effects, have vasculoprotective properties that may counteract some effects of radiation on normal tissues. We examined whether administration of simvastatin ameliorates intestinal radiation injury, and whether the effect depends on protein C activation.
Methods
Rats received localized, fractionated small bowel irradiation. The animals were fed either regular chow or chow containing simvastatin from 2 weeks before irradiation until termination of the experiment. Groups of rats were euthanized at 2 weeks and 26 weeks for assessment of early and delayed radiation injury by quantitative histology, morphometry, and quantitative immunohistochemistry. Dependency on protein C activation was examined in TM mutant mice with deficient ability to activate protein C.
Results
Simvastatin administration was associated with lower radiation injury scores (p<0.0001), improved mucosal preservation (p=0.0009), and reduced thickening of the intestinal wall and subserosa (p=0.008 and p=0.004), neutrophil infiltration (p=0.04), and accumulation of collagen I (p=0.0003). The effect of simvastatin was consistently more pronounced for delayed than for early injury. Surprisingly, simvastatin reduced intestinal radiation injury in TM mutant mice, indicating that the enteroprotective effect of simvastatin after localized irradiation is unrelated to protein C activation.
Conclusions
Simvastatin ameliorates the intestinal radiation response. The radioprotective effect of simvastatin after localized small bowel irradiation does not appear to be related to protein C activation. Statins should undergo clinical testing as a strategy to minimize side effects of radiation on the intestine and other normal tissues.
doi:10.1016/j.ijrobp.2007.03.036
PMCID: PMC2000701  PMID: 17674978
Endothelium; Intestine; Radiation injuries; Hydroxymethylglutaryl-CoA reductase inhibitors
2.  Simvastatin and Losartan Differentially and Synergistically Inhibit Atherosclerosis in Apolipoprotein E-/- Mice 
Korean Circulation Journal  2012;42(8):543-550.
Background and Objectives
Since statins and angiotensin receptor blockers are a frequently prescribed combination in patients with atherosclerotic cardiovascular diseases, we tested the interactive effects of simvastatin and losartan on atherosclerosis in apolipoprotein E (apoE)-/- mice.
Materials and Methods
Apolipoprotein E-/- mice were fed a high-fat, high-cholesterol (HFHC) diet for 12 weeks, with and without simvastatin (40 mg/kg) and/or losartan (20 mg/kg). The mice were divided into 5 groups and were fed as follows: regular chow (control diet, n=5), HFHC diet (n=6), HFHC diet with losartan (n=6), HFHC diet with simvastatin (n=6), and HFHC diet with both losartan and simvastatin (n=6).
Results
Losartan treatment in apoE-/- mice significantly decreased atherosclerotic lesion areas in whole aortic strips stained with Oil Red O. The plaque area measured at the aortic sinus level was reduced significantly by 17% (HFHC; 346830.9±52915.8 µm2 vs. HFHC plus losartan; 255965.3±74057.7 µm2, p<0.05) in the losartan-treated group. Simvastatin and simvastatin plus losartan treatments reduced macrophage infiltration into lesions by 33% (HFHC; 183575.6±43211.2 µm2 vs. HFHC plus simvastatin; 120556.0±39282.8 µm2, p<0.05) and 44% (HFHC; 183575.6±43211.2 µm2 vs. HFHC plus simvastatin and losartan; 103229.0±8473.3 µm2, p<0.001, respectively). In mice fed the HFHC diet alone, the smooth muscle cell layer in the aortic media was almost undetectable. In mice co-treated with losartan and simvastatin, the smooth muscle layer was more than 60% preserved (p<0.05). Given alone, losartan showed a slightly stronger effect than simvastatin; however, treatment with losartan plus simvastatin induced a greater inhibitory effect on atherosclerosis than either drug given alone. Serum lipid profiles did not differ significantly among the groups.
Conclusion
Losartan displayed anti-atherosclerotic effects in apoE-/- mice that were equivalent to or greater than the effects of simvastatin. Combined treatment with these drugs had greater effect than either drug alone.
doi:10.4070/kcj.2012.42.8.543
PMCID: PMC3438264  PMID: 22977450
Atherosclerosis; Losartan; Simvastatin; Mice, knockout; Models, animal
3.  Simvastatin Blocks Blood-Brain Barrier Disruptions Induced by Elevated Cholesterol Both In Vivo and In Vitro 
Background. Hypercholesterolemia and disruptions of the blood brain barrier (BBB) have been implicated as underlying mechanisms in the pathogenesis of Alzheimer's disease (AD). Simvastatin therapy may be of benefit in treating AD; however, its mechanism has not been yet fully understood. Objective. To explore whether simvastatin could block disruption of BBB induced by cholesterol both in vivo and in vitro. Methods. New Zealand rabbits were fed cholesterol-enriched diet with or without simvastatin. Total cholesterol of serum and brain was measured. BBB dysfunction was evaluated. To further test the results in vivo, rat brain microvascular endothelial cells (RBMECs) were stimulated with cholesterol in the presence/absence of simvastatin in vitro. BBB disruption was evaluated. Results. Simvastatin blocked cholesterol-rich diet induced leakage of Evan's blue dye. Cholesterol content in the serum was affected by simvastatin, but not brain cholesterol. Simvastatin blocked high-cholesterol medium-induced decrease in TEER and increase in transendothelial FITC-labeled BSA Passage in RBMECs. Conclusions. The present study firstly shows that simvastatin improves disturbed BBB function both in vivo and in vitro. Our data provide that simvastatin may be useful for attenuating disturbed BBB mediated by hypercholesterolemia.
doi:10.1155/2012/109324
PMCID: PMC3296225  PMID: 22506129
4.  Adverse Impact of Diet-Induced Hypercholesterolemia on Cardiovascular Tissue Homeostasis in a Rabbit Model: Time-Dependent Changes in Cardiac Parameters 
The present study evaluates a hypothesis that diet-related hypercholesterolemia increases oxidative stress-related burden to cardiovascular tissue, resulting in progressively increased mortality, along with deterioration of electrophysiological and enzymatic function in rabbit myocardium. New Zealand white rabbits were divided into four groups, defined as follows: GROUP I, cholesterol-free rabbit chow for 12 weeks; GROUP II, cholesterol-free chow, 40 weeks; GROUP III, chow supplemented with 2% cholesterol, 12 weeks; GROUP IV, chow supplemented with 2% cholesterol, 40 weeks. At the 12 and 40 weeks time points, animals in each of the aforementioned cohorts were subjected to echocardiographic measurements, followed by sacrifice. Significant deterioration in major outcome variables measured in the present study were observed only in animals maintained for 40 weeks on 2% cholesterol-supplemented chow, with much lesser adverse effects noted in animals fed high cholesterol diets for only 12 weeks. It was observed that rabbits receiving high cholesterol diets for 40 weeks exhibited significantly increased mortality, worsened ejection fraction and general deterioration of cardiac functions, along with increased atherosclerotic plaque formation and infarct size. Additionally, myocardium of GROUP IV animals was observed to contain lower levels of heme oxygenase-1 (HO-1) and cytochrome c oxidase III (COX III) protein relative to the controls.
doi:10.3390/ijms140919086
PMCID: PMC3794822  PMID: 24048247
hypercholesterolemic rabbit; cardiac parameters; echocardiography; heme-oxygenase; cytochrome oxidase; VEGF
5.  Impact of oral simvastatin therapy on acute lung injury in mice during pneumococcal pneumonia 
BMC Microbiology  2012;12:73.
Background
Recent studies suggest that the reported protective effects of statins (HMG-CoA reductase inhibitors) against community-acquired pneumonia (CAP) and sepsis in humans may be due to confounders and a healthy user-effect. To directly test whether statins are protective against Streptococcus pneumoniae, the leading cause of CAP, we examined the impact of prolonged oral simvastatin therapy at physiologically relevant doses in a mouse model of pneumococcal pneumonia. BALB/c mice were placed on rodent chow containing 0 mg/kg (control), 12 mg/kg (low simvastatin diet [LSD]; corresponds to 1.0 mg/kg/day), or 120 mg/kg (high simvastatin diet [HSD]; corresponds to 10 mg/kg/day) simvastatin for four weeks, infected intratracheally with S. pneumoniae serotype 4 strain TIGR4, and sacrificed at 24, 36, or 42 h post-infection for assessment of lung histology, cytokine production, vascular leakage and edema, bacterial burden and bloodstream dissemination. Some mice received ampicillin at 12-h intervals beginning at 48 h post-infection and were monitored for survival. Immunoblots of homogenized lung samples was used to assess ICAM-1 production.
Results
Mice receiving HSD had reduced lung consolidation characterized by less macrophage and neutrophil infiltration and a significant reduction in the chemokines MCP-1 (P = 0.03) and KC (P = 0.02) and ICAM-1 in the lungs compared to control mice. HSD mice also had significantly lower bacterial titers in the blood at 36 (P = 0.007) and 42 (P = 0.03) hours post-infection versus controls. LSD had a more modest effect against S. pneumoniae but also resulted in reduced bacterial titers in the lungs and blood of mice after 42 h and a reduced number of infiltrated neutrophils. Neither LSD nor HSD mice had reduced mortality in a pneumonia model where mice received ampicillin 48 h after challenge.
Conclusions
Prolonged oral simvastatin therapy had a strong dose-dependent effect on protection against S. pneumoniae as evidenced by reduced neutrophil infiltration, maintenance of vascular integrity, and lowered chemokine production in the lungs of mice on HSD. Statin therapy also protected through reduced bacterial burden in the lungs. Despite these protective correlates, mortality in the simvastatin-receiving cohorts was equivalent to controls. Thus, oral simvastatin at physiologically relevant doses only modestly protects against pneumococcal pneumonia.
doi:10.1186/1471-2180-12-73
PMCID: PMC3438118  PMID: 22587610
6.  Cytotoxic evaluation of doxorubicin in combination with simvastatin against human cancer cells 
Doxorubicin is a broad spectrum antibiotic used in the treatment of cancers. Its dose dependent cardiotoxicity is the most serious side effect causing withdrawal of drug from hard chemotherapeutic regimen. Statins are shown to be cytotoxic in concentrations higher than the effective doses for the treatment of hypercholesterolemia (40 mg/day). Co-administration of statins and chemotherapeutic agents suppose to be synergic although there are some controversies in the literature. In this study, cytotoxic effects of doxorubicin alone and in combination with simvastatin on Hela tumor cell line were evaluated. Different concentration of doxorubicin and simvastatin were added to the cultured cells and incubated for 72 h. Cell survival was evaluated using MTT and trypan blue exclusion assays. The results indicated that simvastatin in low concentration (0.25 μM) seems to be growth stimulator although cell viability was reduced in concentrations of ≥2 μM. Doxorubicin alone at all tested concentrations (0.1, 1 and 2 μM) was a cell growth inhibitor. It was also shown that percent cell viability was reduced in a decreasing manner with the following protocols: 1) co-administration of doxorubicin and simvastatin in different concentrations; 2) addition of simvastatin after incubation of cells with doxorubicin and 3) addition of doxorubicin after incubation of cells with simvastatin. It could be concluded that between 3 tested protocols combination of doxorubicin and simvastatin after 72 h incubation, showed the highest cytotoxicity against Hela cells.
PMCID: PMC3203264  PMID: 22049271
Doxorubicin; Simvastatin; Cytotoxicity; Hela cell; HPLC; MTT assay
7.  Simvastatin reduces atherogenesis and promotes the expression of hepatic genes associated with reverse cholesterol transport in apoE-knockout mice fed high-fat diet 
Background
Statins are first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans. However the effects of statins on atherosclerosis in mouse models are very paradoxical. In this work, we wanted to evaluate the effects of simvastatin on serum cholesterol, atherogenesis, and the expression of several factors playing important roles in reverse cholesterol transport (RCT) in apoE-/- mice fed a high-fat diet.
Results
The atherosclerotic lesion formation displayed by oil red O staining positive area was reduced significantly by 35% or 47% in either aortic root section or aortic arch en face in simvastatin administrated apoE-/- mice compared to the control. Plasma analysis by enzymatic method or ELISA showed that high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) contents were remarkably increased by treatment with simvastatin. And plasma lecithin-cholesterol acyltransferase (LCAT) activity was markedly increased by simvastatin treatment. Real-time PCR detection disclosed that the expression of several transporters involved in reverse cholesterol transport, including macrophage scavenger receptor class B type I, hepatic ATP-binding cassette (ABC) transporters ABCG5, and ABCB4 were induced by simvastatin treatment, the expression of hepatic ABCA1 and apoA-I, which play roles in the maturation of HDL-C, were also elevated in simvastatin treated groups.
Conclusions
We demonstrated the anti-atherogenesis effects of simvastatin in apoE-/- mice fed a high-fat diet. We confirmed here for the first time simvastatin increased the expression of hepatic ABCB4 and ABCG5, which involved in secretion of cholesterol and bile acids into the bile, besides upregulated ABCA1 and apoA-I. The elevated HDL-C level, increased LCAT activity and the stimulation of several transporters involved in RCT may all contribute to the anti-atherosclerotic effect of simvastatin.
doi:10.1186/1476-511X-10-8
PMCID: PMC3031258  PMID: 21241519
8.  Simvastatin preserves diastolic function in experimental hypercholesterolemia independently of its lipid lowering effect 
Atherosclerosis  2011;216(2):283-291.
Objective:
Isolated diastolic dysfunction is present in 40% of heart failure patients. It has been attributed to myocardial fibrosis and related to cardiovascular risk factor exposure. We hypothesized that simvastatin will improve these dynamics in experimental hypercholesterolemia (HC).
Methods:
Three groups of pigs were studied after 12 weeks of normal (N) diet, HC diet, or HC diet with simvastatin (80 mg/day) treatment. Cardiac function was assessed by electron beam computed tomography (EBCT) and percentage of myocardium occupied by microvessels (myocardial vascular fraction) was calculated by micro-CT. Collagen content was determined by Sirius red staining and confirmed by a quantitative, hydroxyoproline-based assay.
Results:
Compared with N, LDL serum concentration was higher in HC and HC + simvastatin (1.0 ± 0.1 vs. 7.9 ± 1.7 and 9.6 ± 1.2 mmol/L, p < 0.05 for both). Cardiac early diastolic filling was reduced in HC compared with N (102.4 ± 11.3 vs. 151.1 ± 12.1 mL/s; p < 0.05) but restored in HC + simvastatin (176.8 ± 21.3 mL/s, p < 0.05 vs. HC). Compared with N, myocardial vascular fraction was higher in HC but not in HC + simvastatin (1.98 ± 0.84 vs. 4.48 ± 0.31 and 2.95 ± 0.95%; p < 0.05 for HC vs. N). Myocardial collagen content was higher in HC than in HC + simvastatin and N (4.72 ± 1.03 vs. 1.62 ± 0.12 and 1.21 ± 0.24% area staining; p < 0.05 for HC vs. N), which was attributable mainly to an increase in collagen III (2.90 ± 0.48 vs. 1.62 ± 0.12 and 1.21 ± 0.24% area staining; p < 0.05 for HC vs. N).
Conclusions:
Simvastatin is able to prevent diastolic dysfunction in experimental HC independent of its lipid lowering effect. This beneficial effect is, at least partially, due to a decrease in myocardial fibrosis and angiogenesis.
doi:10.1016/j.atherosclerosis.2011.02.036
PMCID: PMC3786354  PMID: 21414623
Diastolic dysfunction; Hypercholesterolemia; Fibrosis; Angiogenesis
9.  Ezetimibe/simvastatin vs simvastatin in coronary heart disease patients with or without diabetes 
Background
Treatment guidelines recommend LDL-C as the primary target of therapy in patients with hypercholesterolemia. Moreover, combination therapies with lipid-lowering drugs that have different mechanisms of action are recommended when it is not possible to attain LDL-C targets with statin monotherapy. Understanding which treatment or patient-related factors are associated with attaining a target may be clinically relevant.
Methods
Data were pooled from two multicenter, randomized, double-blind studies. After stabilization on simvastatin 20 mg, patients with coronary heart disease (CHD) alone and/or type 2 diabetes mellitus (T2DM) were randomized to ezetimibe 10 mg/simvastatin 20 mg (EZ/Simva) or simvastatin 40 mg. The change from baseline in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), TC/HDL-C ratio, triglycerides, and the proportion of patients achieving LDL-C < 2.6 mmol/L (100 mg/dL) after 6 weeks of treatment were assessed, and factors significantly correlated with the probability of achieving LDL-C < 2.6 mmol/L in a population of high cardiovascular risk Italian patients were identified. A stepwise logistic regression model was conducted with LDL-C < 2.6 mmol/L at endpoint as the dependent variable and study, treatment, gender, age (≥65 years or < 65 years), as independent variables and baseline LDL-C (both as continuous and discrete variable).
Results
EZ/Simva treatment (N = 93) resulted in significantly greater reductions in LDL-C, TC, and TC/HDL-C ratio and higher attainment of LDL-C < 2.6 mmol/L vs doubling the simvastatin dose to 40 mg (N = 106). Study [including diabetic patients (OR = 2.9, p = 0.003)], EZ/Simva treatment (OR = 6.1, p < 0.001), and lower baseline LDL-C (OR = 0.9, p = 0.001) were significant positive predictors of LDL-C target achievement. When baseline LDL-C was expressed as a discrete variable, the odds of achieving LDL-C < 2.6 mmol/L was 4.8 in favor of EZ/Simva compared with Simva 40 mg (p < 0.001), regardless of baseline LDL-C level.
Conclusion
EZ/Simva is an effective therapeutic option for patients who have not achieved recommended LDL-C treatment targets with simvastatin 20 mg monotherapy.
Trial Registration
Clinical trial registration numbers: NCT00423488 and NCT00423579
doi:10.1186/1476-511X-9-80
PMCID: PMC2918617  PMID: 20663203
10.  Cyclic nucleotides and mitogen-activated protein kinases: regulation of simvastatin in platelet activation 
Background
3-Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been widely used to reduce cardiovascular risk. These statins (i.e., simvastatin) may exert other effects besides from their cholesterol-lowering actions, including inhibition of platelet activation. Platelet activation is relevant to a variety of coronary heart diseases. Although the inhibitory effect of simvastatin in platelet activation has been studied; the detailed signal transductions by which simvastatin inhibit platelet activation has not yet been completely resolved.
Methods
The aim of this study was to systematically examine the detailed mechanisms of simvastatin in preventing platelet activation. Platelet aggregation, flow cytometric analysis, immunoblotting, and electron spin resonance studies were used to assess the antiplatelet activity of simvastatin.
Results
Simvastatin (20-50 μM) exhibited more-potent activity of inhibiting platelet aggregation stimulated by collagen than other agonists (i.e., thrombin). Simvastatin inhibited collagen-stimulated platelet activation accompanied by [Ca2+]i mobilization, thromboxane A2 (TxA2) formation, and phospholipase C (PLC)γ2, protein kinase C (PKC), and mitogen-activated protein kinases (i.e., p38 MAPK, JNKs) phosphorylation in washed platelets. Simvastatin obviously increased both cyclic AMP and cyclic GMP levels. Simvastatin markedly increased NO release, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, and endothelial nitric oxide synthase (eNOS) expression. SQ22536, an inhibitor of adenylate cyclase, markedly reversed the simvastatin-mediated inhibitory effects on platelet aggregation, PLCγ2 and p38 MAPK phosphorylation, and simvastatin-mediated stimulatory effects on VASP and eNOS phosphorylation.
Conclusion
The most important findings of this study demonstrate for the first time that inhibitory effect of simvastatin in platelet activation may involve activation of the cyclic AMP-eNOS/NO-cyclic GMP pathway, resulting in inhibition of the PLCγ2-PKC-p38 MAPK-TxA2 cascade, and finally inhibition of platelet aggregation.
doi:10.1186/1423-0127-17-45
PMCID: PMC2894762  PMID: 20525309
11.  The mechanical uncoupler blebbistatin is associated with significant electrophysiological effects in the isolated rabbit heart 
Experimental Physiology  2013;98(5):1009-1027.
Blebbistatin (BS) is a recently discovered inhibitor of the myosin II isoform and has been adopted as the mechanical uncoupler of choice for optical mapping, because previous studies suggest that BS has no significant cardiac electrophysiological effects in a number of species. The aim of this study was to determine whether BS affects cardiac electrophysiology in isolated New Zealand White rabbit hearts. Langendorff-perfused hearts (n= 39) in constant-flow mode had left ventricular monophasic action potential duration (MAPD) measured at apical and basal regions during constant pacing (300 ms cycle length). Standard action potential duration restitution was obtained using the single extrastimulus method with measurement of the maximal restitution slope. Ventricular fibrillation threshold was measured as the minimal current inducing sustained ventricular fibrillation with burst pacing (30 stimuli, at 30 ms intervals). Optical action potentials were recorded using the voltage-sensitive dye di-4-ANEPPS. Measurements were taken at baseline and after 60 min perfusion with BS (5 μm). Blebbistatin significantly prolonged left ventricular apical (mean ± SEM; from 129.9 ± 2.9 to 170.7 ± 4.1 ms, P < 0.001, n= 8) and basal MAPD (from 135.0 ± 2.3 to 163.3 ± 5.6 ms, P < 0.001) and effective refractory period (from 141.3 ± 4.8 to 175.6 ± 3.7 ms, P < 0.001) whilst increasing the maximal slope of restitution (apex, from 0.79 ± 0.09 to 1.57 ± 0.16, P < 0.001; and base, from 0.71 ± 0.06 to 1.44 ± 0.24, P < 0.001) and ventricular fibrillation threshold (from 5.3 ± 1.1 to 17.0 ± 2.9 mA, P < 0.001). In other hearts, blebbistatin significantly prolonged optically recorded action potentials (from 136.5 ± 6.3 to 173.0 ± 7.9 ms, P < 0.05, n= 4). In control experiments, the increase of MAPD with blebbistatin was present whether the hearts were perfused in constant-pressure mode (n= 5) or in unloaded conditions (n= 5). These data show that blebbistatin significantly affects cardiac electrophysiology. Its use in optical mapping studies should be treated with caution.
doi:10.1113/expphysiol.2012.069369
PMCID: PMC3734628  PMID: 23291912
12.  Simvastatin Activates the PPARγ-Dependent Pathway to Prevent Left Ventricular Hypertrophy Associated with Inhibition of RhoA Signaling 
Texas Heart Institute Journal  2013;40(2):140-147.
Left ventricular hypertrophy is an independent risk factor for major adverse cardiovascular events. Statins have positive effects on this condition; however, the mechanisms are incompletely understood. In this study, we examined whether the effect of simvastatin on left ventricular hypertrophy can be mediated with the peroxisome proliferator-activated receptor (PPAR)γ-dependent pathway in rabbits with nonischemic heart failure (HF).
We induced aortic insufficiency and constriction in 48 rabbits and divided them equally into control, HF, and HF with simvastatin therapy (HF-SIM) groups. The HF-SIM group was given 10 mg/kg/d of simvastatin. We echocardiographically measured baseline and 8-week cardiac structure and function, and we used Western blot, polymerase chain reaction, and electrophoretic analytic techniques to evaluate messenger RNA expression and protein expression and activity. In comparison with the HF group, the HF-SIM rabbits had an increased ejection fraction and decreased left ventricular mass index, interventricular septal thickness, ventricular posterior-wall thickness, and collagen volume fraction. Moreover, the messenger RNA and protein expression of PPARγ in the HF-SIM rabbits were significantly higher than those in the HF rabbits; and the activity and expression of nuclear factor-κB subunit p65, RhoA, and Rho GTPase were significantly lower. Our results indicate that simvastatin therapy attenuates the PPARγ-dependent pathway in association with the inhibition of RhoA and Rho GTPase signaling to inhibit nuclear factor-κB activation, thus preventing the development of left ventricular hypertrophy and fibrosis in rabbits with nonischemic heart failure.
PMCID: PMC3649785  PMID: 23678211
Disease models, animal; heart failure/drug therapy; heart ventricles/drug effects; hypertrophy, left ventricular/physiopathology/prevention & control; NF-kappa B/metabolism; PPAR gamma/drug effects/metabolism; rhoA GTP-binding protein; simvastatin; ventricular function, left/drug effects
13.  The influence of high-dose simvastatin and diltiazem on myocardium in rabbits: a haemodynamic study 
Introduction
Simvastatin and diltiazem are often prescribed together for the treatment of hypercholesterolaemia in patients with hypertension and/or angina pectoris. However, diltiazem, a CYP3A inhibitor, is a well-recognized risk factor of skeletal muscle myopathy. It is not known whether such interaction also affects myocardial efficiency causing haemodynamic changes. The aim of the experiment was to establish the impact of simvastatin co-administered with diltiazem on the haemodynamic parameters after continuous infusion of dopamine.
Material and methods
The experiments were performed on 28 New Zealand white rabbits. The animals were divided into four groups receiving: 0.2% MC – methylcellulose (control group); diltiazem; simvastatin; simvastatin + diltiazem, for 14 days (po). The following haemodynamic parameters were estimated: cardiac output index (CI), heart rate (HR), systolic blood pressure (SBP), mean blood pressure (MBP), diastolic blood pressure (DBP) and total peripheral resistance index (TPRI). The registration of haemodynamic parameters was performed by the Doppler method and during the experiments the animals were anaesthetized with α-chloralose (75 mg/kg bw) and urethane (500 mg/kg bw).
Results
Dopamine did not cause a statistically significant increase in CI in rabbits receiving simvastatin alone. Diltiazem significantly increased CI if given simultaneously with simvastatin, which might suggest the improvement of cardiac efficiency resulting from such interaction.
Conclusions
The possibility of another mechanism of drug-drug interaction than the one based on CYP3A inhibition, and its impact on cardiac or skeletal muscle, might be considered.
doi:10.5114/aoms.2011.23401
PMCID: PMC3258750  PMID: 22312373
statins; diltiazem; haemodynamic parameters; myopathy; myocardium; rabbits
14.  Pleiotropic effects of simvastatin in physically trained ovariectomized rats 
This study tested the hypothesis that simvastatin treatment can improve cardiovascular and autonomic functions and membrane lipoperoxidation, with an increased effect when applied to physically trained ovariectomized rats. Ovariectomized rats were divided into sedentary, sedentary+simvastatin and trained+simvastatin groups (n = 8 each). Exercise training was performed on a treadmill for 8 weeks and simvastatin (5 mg/kg) was administered in the last 2 weeks. Blood pressure (BP) was recorded in conscious animals. Baroreflex sensitivity was evaluated by the tachycardic and bradycardic responses to BP changes. Cardiac vagal and sympathetic effects were determined using methylatropine and propranolol. Oxidative stress was evaluated based on heart and liver lipoperoxidation using the chemiluminescence method. The simvastatin-treated groups presented reduced body weight and mean BP (trained+simvastatin = 99 ± 2 and sedentary+simvastatin = 107 ± 2 mmHg) compared to the sedentary group (122 ± 1 mmHg). Furthermore, the trained group showed lower BP and heart rate compared to the other groups. Tachycardic and bradycardic responses were enhanced in both simvastatin-treated groups. The vagal effect was increased in the trained+simvastatin group and the sympathetic effect was decreased in the sedentary+simvastatin group. Hepatic lipoperoxidation was reduced in sedentary+simvastatin (≈21%) and trained+simvastatin groups (≈57%) compared to the sedentary group. Correlation analysis involving all animals demonstrated that cardiac lipoperoxidation was negatively related to the vagal effect (r = -0.7) and positively correlated to the sympathetic effect (r = 0.7). In conclusion, improvement in cardiovascular and autonomic functions associated with a reduction of lipoperoxidation with simvastatin treatment was increased in trained ovariectomized rats.
doi:10.1590/1414-431X20122111
PMCID: PMC3854401  PMID: 23739748
Menopause; Exercise training; Simvastatin; Autonomic function; Oxidative stress
15.  Statin Treatment Increases Lifespan and Improves Cardiac Health in Drosophila by Decreasing Specific Protein Prenylation 
PLoS ONE  2012;7(6):e39581.
Statins such as simvastatin are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and standard therapy for the prevention and treatment of cardiovascular diseases in mammals. Here we show that simvastatin significantly increased the mean and maximum lifespan of Drosophila melanogaster (Drosophila) and enhanced cardiac function in aging flies by significantly reducing heart arrhythmias and increasing the contraction proportion of the contraction/relaxation cycle. These results appeared independent of internal changes in ubiquinone or juvenile hormone levels. Rather, they appeared to involve decreased protein prenylation. Simvastatin decreased the membrane association (prenylation) of specific small Ras GTPases in mice. Both farnesyl (L744832) and type 1 geranylgeranyl transferase (GGTI-298) inhibitors increased Drosophila lifespan. These data are the most direct evidence to date that decreased protein prenylation can increase cardiac health and lifespan in any metazoan species, and may explain the pleiotropic (non-cholesterol related) health effects of statins.
doi:10.1371/journal.pone.0039581
PMCID: PMC3380867  PMID: 22737247
16.  Simvastatin Inhibits Glucose Metabolism and Legumain Activity in Human Myotubes 
PLoS ONE  2014;9(1):e85721.
Simvastatin, a HMG-CoA reductase inhibitor, is prescribed worldwide to patients with hypercholesterolemia. Although simvastatin is well tolerated, side effects like myotoxicity are reported. The mechanism for statin-induced myotoxicity is still poorly understood. Reports have suggested impaired mitochondrial dysfunction as a contributor to the observed myotoxicity. In this regard, we wanted to study the effects of simvastatin on glucose metabolism and the activity of legumain, a cysteine protease. Legumain, being the only known asparaginyl endopeptidase, has caspase-like properties and is described to be involved in apoptosis. Recent evidences indicate a regulatory role of both glucose and statins on cysteine proteases in monocytes. Satellite cells were isolated from the Musculus obliquus internus abdominis of healthy human donors, proliferated and differentiated into polynuclear myotubes. Simvastatin with or without mevalonolactone, farnesyl pyrophosphate or geranylgeranyl pyrophosphate were introduced on day 5 of differentiation. After 48 h, cells were either harvested for immunoblotting, ELISA, cell viability assay, confocal imaging or enzyme activity analysis, or placed in a fuel handling system with [14C]glucose or [3H]deoxyglucose for uptake and oxidation studies. A dose-dependent decrease in both glucose uptake and oxidation were observed in mature myotubes after exposure to simvastatin in concentrations not influencing cell viability. In addition, simvastatin caused a decrease in maturation and activity of legumain. Dysregulation of glucose metabolism and decreased legumain activity by simvastatin points out new knowledge about the effects of statins on skeletal muscle, and may contribute to the understanding of the myotoxicity observed by statins.
doi:10.1371/journal.pone.0085721
PMCID: PMC3885717  PMID: 24416446
17.  Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects 
Kidney international  2006;69(9):1535-1542.
Acute kidney injury (AKI) occurs in about half of patients in septic shock and the mortality of AKI with sepsis is extremely high. An effective therapeutic intervention is urgently required. Statins are HMG-CoA reductase inhibitors that also have pleiotropic actions. They have been reported to increase survival of septic or infectious patients. But the effect of simvastatin, a widely used statin, on sepsis-induced AKI is unknown. The effects of simvastatin and TNF-alpha neutralizing antibody were studied in a clinically relevant model of sepsis-induced AKI using cecal ligation and puncture (CLP) in elderly mice. Simvastatin siginificantly improved CLP-induced mortality and AKI. Simvastatin attenuated CLP-induced tubular damage and reversed CLP-induced reduction of intrarenal microvascular perfusion and renal tubular hypoxia at 24 hours. Simvastatin also restored towards normal CLP-induced renal vascular protein leak and serum TNF-alpha. Neither delayed simvastatin therapy nor TNF-alpha neutralizing antibody improved CLP-induced AKI. Simvastatin improved sepsis-induced AKI by direct effects on the renal vasculature, reversal of tubular hypoxia, and had a systemic anti-inflammatory effect.
doi:10.1038/sj.ki.5000300
PMCID: PMC2377392  PMID: 16557230
18.  d,l-Sotalol at Therapeutic Concentrations Facilitates the Occurrence of Long-lasting Non-stationary Reentry During Ventricular Fibrillation in Isolated Rabbit Hearts 
Background
Effects of d,l-sotalol at therapeutic concentrations (≤10 mg/L) on wavefront dynamics during ventricular fibrillation (VF) and electrophysiological heterogeneity remain unclear.
Methods and Results
By using an optical mapping system, epicardial activation patterns of VF were studied in 6 Langendorff-perfused rabbit hearts at baseline, during 10 mg/L d,l-sotalol infusion, and after washout. An additional 4 hearts, action potential duration (APD), conduction velocity, and wavelength (WL) restitutions were determined. During d,l-sotalol infusion, VF was terminated in 3 of the 6 hearts. Only one experienced a transient ventricular tachycardia (VT). d,l-Sotalol reduced the number of phase singularities (i.e., wavebreak) during VF (p<0.05). d,l-Sotalol also increased the occurrence frequency (p<0.05) and life span (p<0.05) of epicardial reentry during VF. These reentries were non-stationary in nature and did not anchor on anatomical structures. Restitution data showed that d,l-Sotalol flattened APD restitution. Furthermore, APD dispersion and spatial heterogeneity of restitutions were not enhanced by d,l-sotalol.
Conclusions
d,l-Sotalol at therapeutic concentrations decreased wavebreak and facilitated the occurrence of long-lasting non-stationary reentry during VF. However, VT rarely occurred. The related mechanisms include: (1) APD restitution flattening without enhancement of spatial heterogeneity of electrophysiological properties causes wavefront organization, and (2) WL prolongation prevents a steady anchoring of reentry.
PMCID: PMC3060151  PMID: 19008631
d,l-sotalol; reentry; ventricular fibrillation
19.  The Effect of Simvastatin on Glucose Homeostasis in Streptozotocin Induced Type 2 Diabetic Rats 
Journal of Diabetes Research  2013;2013:274986.
Objective. To investigate the effect of simvastatin on glucose homeostasis in streptozotocin induced type 2 diabetic rats. Methods. Forty male Wistar rats were randomly divided into four groups. Normal control rats were fed with standard diet, others were fed with high-fat diet. Diabetic rats were induced by a single intraperitoneal injection of STZ. The simvastatin intervention rats were fed with simvastatin during the experiment process, and the simvastatin treatment rats were fed with simvastatin after diabetes rats were induced. We measured body weight, fasting plasma glucose, cholesterol, high-density lipoprotein cholesterol, and triglyceride after an overnight fast. Results. The FPG was higher in diabetic rats when compared to normal control ones; the simvastatin intervention rats had a higher FPG compared to the diabetic rats and were more easily be induced to diabetes at the end of 4 weeks, FPG level of simvastatin treatment rats was increased compared with diabetic model rats after 12 weeks. Conclusion. These data indicate that simvastatin intervention rats may cause hyperglycemia by impairing the function of islet β cells and have an adverse effect on glucose homeostasis, especially on FPG level.
doi:10.1155/2013/274986
PMCID: PMC3647597  PMID: 23671864
20.  The Effects of Simvastatin on the Serum Concentrations of Thyroid Stimulating Hormone and Free Thyroxine in Hypothyroid Patients Treated with Levothyroxine 
Background: Statins, such as simvastatin, are the drugs of choice for the treatment of hypercholesterolemia. On the other hand hypercholesterolmia can occur in hypothyroid patients, who receive levothyroxine. There are few clinical case reports in regards to drug interaction between levothyroxine and lovastatin or simvastatin, indicating decreased levothyroxine effects. This study aimed at determining possible interaction between simvastatin and levothyroxine in hypothyroid patients by assessing serum levels of thyroid stimulating hormone (TSH) and free thyroxine (FT4), the two important laboratory indices for levothyroxine therapy.
Methods: In a cross sectional study, 41 eligible hypothyroid patients receiving levothyroxine (50-150 µg/d) were selected. Blood samples were taken before and after three months of simultaneous treatment with simvastatin (20 mg/d) and levothyroxine to determine the serum levels of TSH and FT4.
Results: There was no significant difference between the serum levels of TSH (P=0.77) or FT4 (P=0.76) before and after three months of simultaneous treatment. Also, there was no aggravation or initiation of any sign or symptom of hypothyroidism in the patients during the study period.
Conclusion: Considering that FT4 and TSH are the most reliable indicators for the levothyroxine treatment, the findings of the present study suggest that there may not be any significant interaction between simvastatin and levothyroxine.
PMCID: PMC3556755  PMID: 23359141
Simvastatin; levothyroxine; drug interaction; thyroid stimulating hormone; free thyroxine
21.  Inhibition of Akt Attenuates RPO-Induced Cardioprotection 
Previous studies have shown that red palm oil (RPO) supplementation protected rat hearts against ischaemia-reperfusion injury. Evidence from these studies suggested that Akt may be partly responsible for the observed protection. The aim of the current study was therefore to prove or refute the involvement of Akt in the RPO-induced cardioprotection by administration of a specific Akt inhibitor (A6730). Male Wistar rats were randomly divided into 2 groups: a control group receiving standard rat chow and an experimental group receiving standard rat chow plus 2 mL RPO for six weeks. Hearts were excised and mounted on the Langendorff perfusion system. Functional recovery was documented. A different set of hearts were freeze-clamped to assess total and phosphorylation status of Akt. Another set of hearts were subjected to the same perfusion conditions with addition of A6730. Hearts from this protocol were freeze-clamped and assessed for total and phospho-Akt. RPO improved functional recovery which was associated with increased phosphorylation of Akt on Ser473 and Thr308 residues. Blockade of Akt phosphorylation caused poor functional recovery. For the first time, these results prove that Akt plays an important role in the RPO-induced cardioprotection.
doi:10.1155/2012/392457
PMCID: PMC3469093  PMID: 23082275
22.  Efficacy, safety and tolerability of ongoing statin plus ezetimibe versus doubling the ongoing statin dose in hypercholesterolemic Taiwanese patients: an open-label, randomized clinical trial 
BMC Research Notes  2012;5:251.
Background
Reducing low-density lipoprotein cholesterol (LDL-C) is associated with reduced risk for major coronary events. Despite statin efficacy, a considerable proportion of statin-treated hypercholesterolemic patients fail to reach therapeutic LDL-C targets as defined by guidelines. This study compared the efficacy of ezetimibe added to ongoing statins with doubling the dose of ongoing statin in a population of Taiwanese patients with hypercholesterolemia.
Methods
This was a randomized, open-label, parallel-group comparison study of ezetimibe 10 mg added to ongoing statin compared with doubling the dose of ongoing statin. Adult Taiwanese hypercholesterolemic patients not at optimal LDL-C levels with previous statin treatment were randomized (N = 83) to ongoing statin + ezetimibe (simvastatin, atorvastatin or pravastatin + ezetimibe at doses of 20/10, 10/10 or 20/10 mg) or doubling the dose of ongoing statin (simvastatin 40 mg, atorvastatin 20 mg or pravastatin 40 mg) for 8 weeks. Percent change in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides, and specified safety parameters were assessed at 4 and 8 weeks.
Results
At 8 weeks, patients treated with statin + ezetimibe experienced significantly greater reductions compared with doubling the statin dose in LDL-C (26.2% vs 17.9%, p = 0.0026) and total cholesterol (20.8% vs 12.2%, p = 0.0003). Percentage of patients achieving treatment goal was greater for statin + ezetimibe (58.6%) vs doubling statin (41.2%), but the difference was not statistically significant (p = 0.1675). The safety and tolerability profiles were similar between treatments.
Conclusion
Ezetimibe added to ongoing statin therapy resulted in significantly greater lipid-lowering compared with doubling the dose of statin in Taiwanese patients with hypercholesterolemia. Studies to assess clinical outcome benefit are ongoing.
Trial registration
Registered at ClinicalTrials.gov: NCT00652327
doi:10.1186/1756-0500-5-251
PMCID: PMC3403927  PMID: 22621316
Ezetimibe; Simvastatin; Atorvastatin; Pravastatin
23.  Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation. 
Journal of Clinical Investigation  1995;95(6):2520-2529.
Excess vascular oxidative stress and the local formation of oxidized LDL (ox-LDL) have been implicated in the development of impaired endothelium-dependent arterial relaxation in hypercholesterolemia and atherosclerosis. Dietary antioxidants limit LDL oxidation in vitro and treatment of cholesterol-fed rabbits with dietary antioxidants preserves endothelium-derived relaxing factor (EDRF) action. To investigate the mechanism(s) responsible for these observations, we examined EDRF action, vascular oxidative stress, and antioxidant protection in male New Zealand White rabbits using four dietary treatments. Animals consumed standard chow (chow group) or chow supplemented with: (a) 0.5% cholesterol (0.5% cholesterol group); (b) 1% cholesterol (1% cholesterol group); or (c) 1% cholesterol and 1% probucol (probucol group). After 28 d of dietary treatment, segments of thoracic aorta from the 0.5 and 1% cholesterol groups demonstrated impairment of acetylcholine-mediated endothelium-dependent arterial relaxation compared to chow-fed animals (57 +/- 11% and 45 +/- 9% vs 78 +/- 3%, respectively; P < 0.05). In contrast, vessels from the probucol group demonstrated normal relaxation to acetylcholine (83 +/- 5%). Plasma cholesterol levels and the extent of atherosclerosis were similar among all cholesterol-fed groups. Probucol treatment was associated a threefold increase in LDL resistance to copper-induced oxidative modification (P < 0.05) and a reduction in tissue lipid peroxidation (as assessed by thiobarbituric acid-reactive substances; P < 0.05) compared to animals fed cholesterol alone. Most importantly, both of these changes were strongly correlated with preserved EDRF action. Moreover, cholesterol feeding was associated with a dose-dependent increase in vascular superoxide generation and lysophosphatidylcholine content, both of which were prevented by probucol treatment. From these findings, we conclude that probucol, a lipid-soluble antioxidant, preserves EDRF action in cholesterol-fed rabbits in association with limiting vascular oxidative stress and superoxide generation.
PMCID: PMC295934  PMID: 7769097
24.  Effects of 4-week administration of simvastatin in different doses on heart rate and blood pressure after metoprolol injection in normocholesterolaemic and normotensive rats 
Introduction
Statins and β1-adrenergic antagonists are well established in cardiovascular events therapy and prevention. The previous study showed that statins might impact on β-adrenergic signalling and blood pressure in a dose-dependent manner. The aim of the study was to evaluate the impact of 4-week administration of simvastatin given at different doses on the heart rate and blood pressure after injection of metoprolol in rats.
Material and methods
The experiments were performed in normocholesterolaemic and normotensive Wistar rats. Rats received simvastatin in doses of 1, 10 and 20 mg/kg body weight (bw) for 4 weeks. The control group received 0.2% methylcellulose. For the further estimation of the heart rate and blood pressure, metoprolol at 5 mg/kg bw or 0.9% NaCl was injected intraperitoneally.
Results
Simvastatin at doses of 1, 10 and 20 mg/kg bw did not influence the heart rate or blood pressure as compared to the control group. Metoprolol injection statistically significantly decreased the heart rate (439.29±14.03 min−1 vs. 374.41±13.32 min−1; p<0.05). In rats receiving simvastatin during the 4-week period after metoprolol injection, heart rate and blood pressure (mean, systolic, diastolic) were similar as compared to the group receiving metoprolol alone.
Conclusions
Simvastatin administration during a 4-week period in different doses did not influence the heart rate or blood pressure after metoprolol injection in normocholesterolaemic and normotensive rats.
doi:10.5114/aoms.2012.27275
PMCID: PMC3309431  PMID: 22457669
rats; simvastatin; metoprolol; heart rate; blood pressure
25.  Role of the Alternans of Action Potential Duration and Aconitine-Induced Arrhythmias in Isolated Rabbit Hearts 
Journal of Korean Medical Science  2011;26(12):1576-1581.
Under conditions of Na+ channel hyperactivation with aconitine, the changes in action potential duration (APD) and the restitution characteristics have not been well defined in the context of aconitine-induced arrhythmogenesis. Optical mapping of voltage using RH237 was performed with eight extracted rabbit hearts that were perfused using the Langendorff system. The characteristics of APD restitution were assessed using the steady-state pacing protocol at baseline and 0.1 µM aconitine concentration. In addition, pseudo-ECG was analyzed at baseline, and with 0.1 and 1.0 µM of aconitine infusion respectively. Triggered activity was not shown in dose of 0.1 µM aconitine but overtly presented in 1.0 µM of aconitine. The slopes of the dynamic APD restitution curves were significantly steeper with 0.1 µM of aconitine than at baseline. With aconitine administration, the cycle length of initiation of APD alternans was significantly longer than at baseline (287.5 ± 9.6 vs 247.5 ± 15.0 msec, P = 0.016). The functional reentry following regional conduction block appears with the progression of APD alternans. Ventricular fibrillation is induced reproducibly at pacing cycle length showing a 2:1 conduction block. Low-dose aconitine produces arrhythmogenesis at an increasing restitution slope with APD alternans as well as regional conduction block that proceeds to functional reentry.
doi:10.3346/jkms.2011.26.12.1576
PMCID: PMC3230017  PMID: 22147994
Aconitine; Optical mapping; APD restitution; APD alternans

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