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PubMed1996

Simvastatin increases plasma NO2- and NO3- levels in patients with hypercholesterolemia.

In this study, plasma NO2- and NO3- (NOx-) levels were studied after lowering cholesterol with simvastatin in 26 outpatients with hypercholesterolemia (male, 9; female, 17; mean age, 59 +/- 12 years; cholesterol level > 220 mg/dl). Simvastatin (5 mg) was orally administered once daily, and blood samples were collected before, and after 4 and 12 weeks of treatment. Total, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) cholesterol were lowered (total, 254 +/- 44 mg/dl to 209 +/- 34 mg/dl; VLDL, 48 mg/dl [5-126 mg/dl] to 34 mg/dl [10-67 mg/dl]; LDL, 171 +/- 41 mg/dl to 133 +/- 37 mg/dl), but high-density lipoprotein (HDL) cholesterol was elevated (33 +/- 9.5 mg/dl to 39 +/- 11 mg/dl) at 12 weeks after starting simvastatin. Although the effects of simvastatin on the lipid levels nearly reached their maximum levels at 4 weeks, NOx- was elevated in a linear fashion with simvastatin (before; 8 +/- 17 mumol/l, at 12 weeks; 57 +/- 32 mumol/l). The % changes in the NOx- correlated directly with those in HDL-cholesterol at 12 weeks (P < 0.002) but not with other lipoprotein cholesterol fractions. These results suggest that simvastatin lowers cholesterol levels and elevates HDL while increasing the plasma NOx- levels.

Administration, Oral↗
PubMed2001

[Influence of FH Valencia 1 and 2 mutations of the LDL receptor gene on the response to simvastatin in subjects with molecularly defined heterozygous familial hypercholesterolemia in Spain].

BACKGROUND: To analyse whether the molecular diagnosis in FH patients is useful to predict the response to treatment with simvastatin in a south European population. SUBJECTS AND METHOD: A randomised clinical trial with no control group, with 20 mg/day of simvastatin was conducted in 27 genetically diagnosed FH subjects (11 male) from 8 FH families, randomly selected from 30 FH families with a molecular diagnosis. Clinical features and lipid parameters at baseline and after simvastatin treatment were compared between subjects classified as null mutations (FH Valencia 1 and 2; n = 11) and defective mutations (n = 16). RESULTS: FH with null mutations (FH Valencia 1 and 2) have a poor response to simvastatin treatment. The mean reduction of plasma LDLc levels in subjects with null mutations were significantly lower (32.6% [9.5] vs 42.8% [12.2]; p = 0.03) than in subjects with defective mutations. Baseline and after treatment plasma HDLc values were also significantly lower in FH group with null mutations. No statistically significant differences were found at baseline, after treatment and in the response to treatment between males and females. CONCLUSIONS: FH subjects with null alleles (FH Valencia 1 and 2) showed a poor response to simvastatin treatment. The type of LDL receptor gene mutation could predict the response to simvastatin in our south European FH population.

Adult↗
PubMed1999

Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis.

The effects of combination therapy with chenodeoxycholic acid (CDCA) and simvastatin on serum cholestanol, low-density lipoprotein (LDL) cholesterol, and lathosterol levels were investigated in seven adult patients with cerebrotendinous xanthomatosis (CTX) who were on long-term treatment with CDCA. The patients were treated with a combination of CDCA 750 mg daily and an increasing dose of simvastatin from 10 mg to 40 mg daily for a period of 6 months. We found a significant effect of this combination therapy compared with CDCA alone in terms of decreasing the serum cholestanol and LDL cholesterol levels, particularly with a daily dose of 40 mg simvastatin. The mean cholestanol level decreased from 9.27 micromol/L (baseline) to 6.69 micromol/L (40 mg simvastatin), while the mean LDL cholesterol level decreased from 5.08 mmol/L (baseline) to 3.04 mmol/L (40 mg simvastatin). No side effects were reported, and there were no effects on the clinical condition, cerebral magnetic resonance imaging (MRI), visual evoked potentials, and electroencephalographic features. We conclude that a combination of 750 mg CDCA and 40 mg simvastatin daily is effective to further reduce serum cholestanol, LDL cholesterol, and lathosterol in adult CTX patients treated with long-term CDCA. Whether this combination treatment will be effective for the long-term prevention of neurological deterioration and atherosclerosis remains to be established.

Adult↗
PubMedDate not supplied

Cost-effectiveness of simvastatin in people at different levels of vascular disease risk: economic analysis of a randomised trial in 20,536 individuals.

BACKGROUND: Statin therapy reduces the rates of heart attack, stroke, and revascularisation among a wide range of individuals. Reliable assessment of its cost-effectiveness in different circumstances is needed. METHODS: 20,536 adults (aged 40-80 years) with vascular disease or diabetes were randomly allocated 40 mg simvastatin daily (10,269) or placebo (10,267) for an average of 5 years. Comparisons were made of hospitalisation and statin costs (2001 UK prices) during the scheduled treatment period between all simvastatin-allocated versus all placebo-allocated participants. Cost-effectiveness was estimated among different categories of participant. FINDINGS: Allocation to simvastatin was associated with a highly significant 22% (95% CI 16-27; p<0.0001) proportional reduction in hospitalisation costs for all vascular events, with similar proportional reductions in every subcategory of participant studied. During an average of 5 years, estimated absolute reductions in vascular event costs per person allocated 40 mg simvastatin daily ranged from UK 847 pounds sterling (SE 137) in the highest risk quintile studied to 264 pounds sterling (48) in the lowest. Mean excess cost of statin therapy among participants allocated simvastatin was 1497 pounds sterling (8), with similar absolute increases in every subcategory. Costs of preventing a major vascular event with 40 mg simvastatin daily ranged from 4500 pounds sterling (95% CI 2300-7400) among participants with a 42% 5-year major vascular event rate to 31,100 pounds sterling (22,900-42,500) among those with a 12% rate (corresponding to 5-year major coronary event rates of 22% and 4%, respectively). INTERPRETATION: Statin therapy is cost effective for a wider range of individuals with vascular disease or diabetes than previously recognised (particularly with lower-priced generics). It would be appropriate to consider reducing the estimated level of vascular event risk at which statin therapy is recommended.

Adult↗
PubMed1999

Sex-related differences in response of plasma lipids to simvastatin: the Saitama Postmenopausal Lipid Intervention Study. S-POLIS Group.

The Saitama Postmenopausal Lipid Intervention Study was a multicenter, uncontrolled, collaborative study that investigated tolerability and sex-related differences in the response of serum lipids to simvastatin administered for 12 months in 122 postmenopausal women and 55 men with serum total cholesterol (TC) levels > or =220 mg/dL. With simvastatin treatment, TC and low-density lipoprotein cholesterol (LDL-C) levels decreased significantly at 1 month in both groups, and these decreased levels were maintained throughout treatment (P < 0.001). A significant decrease in triglyceride (TG) levels was also observed in both groups (P < 0.05). The mean percentage decreases in TC and LDL-C levels in women (20% and 28%, respectively) were significantly greater than those in men (15% and 20%, respectively) (P < 0.001). Mean percentage changes in TC and LDL-C levels in subgroups defined by stratification for baseline TC and LDL-C levels were also greater in women. There were no sex-related differences in the percentage changes in TG or high-density cholesterol levels, although the changes were influenced by baseline levels. Although the median dose of simvastatin (milligrams per kilogram of body weight) in women was significantly higher than in men (P < 0.001), the percentage changes in serum lipids were not correlated with the doses of simvastatin calibrated by body weight. Adverse reactions occurred in 8 men and 7 women, so there appeared to be no significant sex-related difference. Eleven patients had abnormal laboratory values. Simvastatin therapy for 12 months is well tolerated and effective for both women and men with hypercholesterolemia. Sex-related differences occurred in the response to simvastatin therapy of serum lipids, especially TC and LDL-C, with greater changes in lipid levels occurring in women.

Aged↗
PubMed2001

Effects of low doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol levels in patients with hypercholesterolemia.

BACKGROUND: Simvastatin 40 to 80 mg/d has been found to increase high-density lipoprotein cholesterol (HDL-C) levels significantly more than atorvastatin at equipotent doses (ie, 20-80 mg/d). Data on the effects of lower doses of the 2 drugs on HDL-C levels are conflicting. OBJECTIVE: The purpose of this study was to investigate the effects of simvastatin 20 mg/d and atorvastatin 10 mg/d on HDL-C levels in patients with hypercholesterolemia. METHODS: Patients with primary hypercholesterolemia (total cholesterol [TC] >250 mg/dL) who were not taking any lipid-lowering agents and who were following a low-fat diet were randomized to receive 1 of 2 treatments: simvastatin 20 mg/d or atorvastatin 10 mg/d. Serum TC, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and HDL-C levels were measured using standard methods after 2 months of therapy. In a secondary analysis, lipids and lipoprotein cholesterol were measured after 1 year in patients who continued treatment. RESULTS: Of the 240 patients enrolled (108 men and 132 women; age range, 23-77 years, mean [SEM] 56.7 [0.69]), 235 completed the study. After 2 months of therapy, TC, LDL-C, and serum TG levels decreased significantly versus baseline in both groups (P < 0.001), with no significant differences between treatment groups. HDL-C levels increased by 9.0% (P < 0.001 vs baseline) in the simvastatin group and by 4.3% (P < 0.02) in the atorvastatin group. The difference between the 2 groups in the percentage increase in HDL-C was statistically significant (P < 0.05). In 113 patients who continued treatment, HDL-C levels at 1 year were still significantly higher than baseline levels in the simvastatin group (6.3%, P = 0.034), but not in the atorvastatin group (2.8%, P = 0.587). CONCLUSIONS: The findings from this study suggest that the HDL-C-increasing effect of simvastatin 20 mg is significantly greater than that of atorvastatin 10 mg. Since increasing HDL-C levels is thought to lower the risk for atherosclerosis and coronary heart disease, these results warrant further investigation.

Adult↗
PubMed2001

Anti-inflammatory effects of simvastatin in subjects with hypercholesterolemia.

AIMS: Beneficial effects of statins in preventing cardiovascular events may depend, at least in part, on their anti-inflammatory action. The aim of the study was to assess the influence of simvastatin and aspirin on serum levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in hypercholesterolemic subjects. METHODS AND RESULTS: In 33 asymptomatic men with total cholesterol (TC) >6.5 mmol l(-1) and in 25 men with coronary heart disease and borderline-high cholesterol levels (between 5.2 and 6.5 mmol l(-1)) chronically treated with low-dose aspirin (75 mg/d), serum levels of CRP, TNF-alpha, IL-6, and IL-8 were determined before and after a 3-month simvastatin therapy (20-40 mg daily). In the former group, these markers of inflammation were also measured before and after a 2-week treatment with aspirin (300 mg/d), implemented prior to and in combination with simvastatin. A distinct reduction of CRP and TNF-alpha was found in both groups; IL-6 levels were decreased only in subjects with marked hypercholesterolemia. Aspirin had no effect on the anti-inflammatory action of simvastatin. CONCLUSIONS: In men with hypercholesterolemia simvastatin treatment lowers serum levels of CRP and proinflammatory cytokines. Low-dose aspirin does not add to the anti-inflammatory action of simvastatin.

Adult↗
PubMed1993

[Comparison of the efficacy between simvastatin and gemfibrozil in primary hypercholesterolemia].

The efficacy on plasma lipids, apo A1 and B of a HMG Co A Reductase inhibitor, simvastatin, and a fibrate derivative, gemfibrozil, were compared in 136 hypercholesterolemic patients. The study was randomized, double-blinded and the active drug was given after a 4 week period of placebo. Gemfibrozil (n = 69) was given at 900 mg q.p.m. during the entire study. The primary dose of simvastatin was 10 mg q.p.m. during the first 6-weeks of treatment. At the end of this period, the dose was doubled if the cholesterol level was above 2 g/l (5,16 mmol/l). The same modification was carried out 12 weeks after the beginning active drug treatment with the same criteria. The baselines of total cholesterol were 3.24 +/- 0.69 g/l (8.38 +/- 1.78 mmol/l) 3.21 +/- 0.72 g/l (8.31 +/- 1.87 mmol/l) for patients with simvastatin and those with gemfibrozil respectively. So, at the end of active treatment, 64% of patients in the simvastatin group (n = 67) received 40 mg q.p.m. After 18 weeks of treatment, 89% of patients treated with Simvastatin and 37% with gemfibrozil had more than 20% reduction in LDL cholesterol. Simvastatin was more efficient on total cholesterol, LDL-C and apo B. The increase of HDL-C is similar in both groups of patients. In contrast, the level of triglycerides was further decreased by gemfibrozil. The tolerance was good in the two groups of patients and no difference in the frequency of side effects was observed.

Adult↗
PubMed1997

Effects of ketoconazole on plasma lipids and lipoprotein(a) in familial hypercholesterolaemia, compared with simvastatin.

BACKGROUND: Ketoconazole is an imidazole derivative that is active as a broad-spectrum antifungal agent. It is also an inhibitor of cholesterol production both in vivo and in vitro. METHODS: We compared the effect of low-dose ketoconazole (200 mg/day) or simvastatin (20-40 mg/day) on lipids, lipoproteins and lipoprotein(a) [Lp(a)] in 10 patients with familial hypercholesterolaemia. RESULTS: Ketoconazole reduced serum total cholesterol and low-density lipoprotein (LDL)-cholesterol by 7.6 and 9.7%, respectively. Simvastatin was more effective, the respective changes being -34.4 and -40.6%. Serum triglycerides and high-density lipoprotein (HDL) were unchanged by ketoconazole therapy, whereas simvastatin decreased triglyceride levels by 33.8% and increased HDL-cholesterol levels by 8.7%. Median Lp(a) levels tended to increase during simvastatin and to decrease during ketoconazole therapy. However, due to the wide range of baseline concentrations of Lp(a), these changes were not significant. CONCLUSIONS: Ketoconazole has some hypocholesterolaemic potential, but the effect of simvastatin is much more pronounced. The increase in Lp(a) during simvastatin therapy has been reported earlier, whereas ketoconazole does not exhibit an effect on the level of Lp(a).

Adult↗
PubMed2000

Second-derivative UV spectrometric determination of simvastatin in its tablet dosage form.

Simvastatin, a highly effective cholesterol-lowering agent, has been widely used for the treatment of hypercholesterolemia. During the development of simvastatin solid dosage form, formulation compositions were constantly varied to define a suitable matrix. A fast and reliable method for the dissolution and release testing of simvastatin was highly desirable to support formulation screening. A second derivative UV spectroscopic method was developed for determination of simvastatin in the tablet dosage form. After carefully choosing a zero-crossing technique of second derivative UV measurement at 243 nm, the selectivity and sensitivity of simvastatin was comparable to the previously developed HPLC method. In comparison with the direct UV method, second derivative UV spectroscopy eliminates the interference from UV absorbing excipients such as ascorbic acid, which often results in a bias of 2-10%. This method is also fast and economical in comparison to the more time-consuming HPLC method regularly used for formulation screening. Finally, this method has been validated to be precise and accurate, and is demonstrated to be an excellent alternative to HPLC method for the dissolution and release testing of simvastatin in the solid dosage form.

Anticholesteremic Agents↗
PubMed2000

Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia.

OBJECTIVE: The purpose of this study was to assess if simvastatin has an anti-inflammatory activity in patients with hypercholesterolemia. BACKGROUND: Simvastatin, an inhibitor of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase, reduced cardiovascular events in patients with myocardial infarction and hypercholesterolemia. METHODS: Sixteen patients with polygenic hypercholesterolemia were randomly allocated to diet (n = 8) or diet plus 20 mg/day simvastatin (n = 8) for eight weeks. Before and at the end of treatment period, lipid profile and monocyte expression of tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1beta) were measured. RESULTS: At baseline no difference in lipid profile and monocyte expression of TNF and IL-1beta were observed between the two groups. In patients allocated to diet alone, no change in lipid profile and monocyte expression of TNF and IL-1beta was seen. In patients with diet plus simvastatin, significant decreases of total cholesterol (-27%, p<0.02), low density lipoprotein-cholesterol (-33%, p<0.02), and monocyte expression of TNF (-49%, p<0.02) and IL-1beta (-35%, p<0.02) were observed. At the end of treatment period, patients treated with simvastatin had lower cholesterol and monocyte TNF and IL-1beta than did patients assigned to diet alone. CONCLUSION: This study suggests that simvastatin possesses anti-inflammatory activity via the inhibition of pro-inflammatory cytokines TNF and IL-1beta expressed by monocytes.

Adult↗
PubMed1994

Effects of simvastatin and pravastatin on endothelium-dependent relaxation in hypercholesterolemic rabbits.

OBJECTIVES: The present study was conducted to investigate endothelium-dependent relaxation in hypercholesterolemic rabbits after treatment with two HMG-CoA reductase inhibitors: Simvastatin and Pravastatin. METHODS: Thirty male New Zealand rabbits were randomly assigned to Control, Simvastatin and Pravastatin groups and fed a diet supplemented with lipids and cholesterol (coconut oil 10% and cholesterol 1%) for 8 weeks. The drugs were administered in dosages of 10 mg/kg from the fourth to seventh weeks; at the end of the seventh week, plasma cholesterol was determined, and the Pravastatin dosage adjusted to 15 mg/kg to obtain similar levels of plasma cholesterol for the two experimental groups. At the end of the 8th week, the animals were killed and aorta removed for histologic examination and the measurement of cholesterol content, as well as for the conduction of endothelium-dependent relaxation studies. RESULTS: At the end of the study serum cholesterol was reduced by 57.1% in the Pravastatin group and 58.4% in the Simvastatin group, with the aortic cholesterol content in the former being significantly lower than that of the Simvastatin and Control groups (p < 0.05). Histologic examination also revealed a significant decrease in volume fractions of foam cells in Pravastatin-treated animals, whereas endothelium-dependent relaxation in response to ACh was significantly impaired in the Simvastatin group. No significant difference was found in relaxation induced by nitroprusside. CONCLUSIONS: In spite of the similar reduction in plasma cholesterol obtained by different doses, it seems that Pravastatin preserves the endothelium-dependent relaxation of aortic rings of hypercholesterolemic rabbits more effectively than does Simvastatin.

Acetylcholine↗
PubMedDate not supplied

Effects of simvastatin on fasting and postprandial triglyceride-rich lipoproteins in patients with type I diabetes mellitus.

To assess the effect of simvastatin on fasting and postprandial triglyceride (TG)-rich lipoproteins in subjects with type 1 diabetes and elevated LDL cholesterol levels, eight patients participated in a simvastatin versus placebo, randomized, crossover study. At the end of each drug period fasting and postprandial lipoprotein studies were undertaken. Fasting plasma total and LDL cholesterol and apolipoprotein B (apo B) were significantly lower on simvastatin compared to placebo. Postprandial studies: simvastatin versus placebo consistently decreased the area under the curve (AUC, mean+/-SEM) of TG in plasma (12.52+/-9.07 versus 18.70+/-10.48 mmol x h/L, p = 0.02). Similarly, TG AUC was lower: in the chylomicron subfraction (Sf > 400) 3.24+/-2.71 versus 5.27+/-4.61 mmol x h/L p = 0.03; and in the [chylomicron remnant + VLDL] subfraction (Sf 20-400) 3.98+/-2.51 versus 7.04+/-3.88 mmol x h/L, p = 0.01. This was due to decreased particle n umber rather than size, as shown by a decrease in the AUC of apo B in Sf 20-400 (600+/-360 versus 980+/-600 mg x h/L, p = 0.02) and the lack of change in the ratio of TG/apo B. Intestinal lipoproteins contributed to the simvastatin effect, as shown by the lower AUC of retinyl esters in both subfractions. Chylomicrons: 627.61+/-363.43 versus 948.19+/-568.34 nmol x h/L, p = 0.02 and remnants: 129.23+/-67.12 versus 208.49+/-92.11 nmol x h/L, p = 0.04. Our data suggest an additional mechanism by which simvastatin can decrease the risk of atherosclerosis in patients with type I diabetes: a decrease of the number of circulating intestinal and hepatic postprandial TG-rich lipoprotein particles.

Adult↗
PubMed1997

The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease.

BACKGROUND: Although treatment of myocardial overload effectively reduces death from progression of heart failure, it is not known whether the retardation of progressive coronary artery disease obtained with lipid lowering treatment will prevent the onset and consequences of heart failure in patients without previous symptoms of heart failure. METHODS AND RESULTS: In the Scandinavian Simvastatin Survival Study, 4444 patients with coronary heart disease without evidence of heart failure were randomized to placebo (n = 2223) or simvastatin 20-40 mg (n = 2221) and followed for more than 5 years. Among the patients who received placebo, 228 (10.3%) were diagnosed with heart failure during follow-up evaluation compared with 184 (8.3%) of patients who received simvastatin (P < .015). Mortality was 31.9% in the placebo group and 25.5% in the simvastatin group among patients who developed heart failure. These compare with 9.2 and 6.6%, respectively, among non-heart failure patients. There were 45 hospitalizations because of acute heart failure in the placebo group and 23 in the simvastatin group (NS). Patients who developed heart failure were more likely to have suffered a recurrent myocardial infarction and have a history of diabetes, peripheral artery disease, and hypertension than patients who did not develop congestive heart failure. CONCLUSION: Long-term prevention with simvastatin reduces the occurrence of heart failure in a cohort of patients with coronary heart disease without previous evidence of congestive heart failure.

Adult↗
PubMed1999

A double-blind placebo controlled trial of simvastatin for the treatment of dyslipidaemia in renal allograft recipients.

BACKGROUND: With current techniques, renal failure patients are now able to regain near-normal health following renal transplantation. However, the development of premature cardiovascular disease is a major problem. Dyslipidaemia may be an important contributor to this. The use of lipid lowering agents in renal allograft recipients has been limited by potential interaction of these agents with the now widely used immunosuppressive agent, cyclosporine. AIM: This study was designed to investigate efficacy and safety of simvastatin in subjects taking either cyclosporine or azothioprine post renal transplantation. METHODS: Fifty-one subjects (32 females, 19 males -- mean age 51 +/- 12.5 yr) who were at least 1 yr post transplant, had creatinine < or = 2.5 mmol/L and a total cholesterol > or = 6 mmol/L were enrolled in a prospective, double-blind, placebo-controlled study. After an initial 10-wk dietary period, the last 4 wk on placebo, subjects were randomised to receive either 5 mg simvastatin/d for 6 wk followed by 10 mg simvastatin/d for 6 wk, or matching placebo. After this 12-wk double-blind phase, there was an open-label phase when all subjects were treated with 10 mg simvastatin/d for a period of 36 wk. RESULTS: Compared to placebo, 5 mg simvastatin/d significantly decreased total cholesterol by 20% (p < 0.01), low-density lipoprotein cholesterol (LDL cholesterol) by 29% (p < 0.01), and Apolipoprotein B (ApoB) by 26% (p < 0.01). Increasing simvastatin to 10 mg/d did not lead to further significant changes. But high-density lipoprotein cholesterol (HDL cholesterol) increased by 9% (p < 0.01) and Apolipoprotein A1 (ApoA1) by 7% (p < 0.01) only on 10 mg simvastatin/d. During the open-label phase, subjects previously randomised to placebo achieved similar significant changes to their lipoprotein profile. The benefits achieved from simvastatin were maintained to the end of the study. There were three withdrawals from the study, all from the simvastatin/ cyclosporine group. Two subjects had musculoskeletal pain and 1 had abdominal pain. Minor adverse events were similar in both the simvastatin- and placebo-treated groups. CONCLUSION: Low-dose simvastatin is an effective and well-tolerated agent in the treatment of dyslipidaemia in renal allograft recipients.

Adolescent↗
PubMed1999

Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat islet beta-cells.

1. Hypercholesterolaemia often occurs in patients with type 2 diabetes, who therefore encounter administration of HMG-CoA reductase inhibitors. Alteration of pancreatic beta-cell function leading to an impaired insulin secretory response to glucose plays a crucial role in the pathogenesis of type 2 diabetes. Therefore, it is important to examine the effects of HMG-CoA reductase inhibitors on beta-cell function. 2. Cytosolic Ca2+ concentration ([Ca2+]i) plays a central role in the regulation of beta-cell function. The present study examined the effects of HMG-CoA reductase inhibitors on the glucose-induced [Ca2+]i signalling and insulin secretion in rat islet beta-cells. 3. Simvastatin, a lipophilic HMG-CoA reductase inhibitor, at 0.1-3 microg ml(-1) concentration-dependently inhibited the first phase increase and oscillation of [Ca2+]i induced by 8.3 mM glucose in single beta-cells. The less lipophilic inhibitor, simvastatin-acid, inhibited the first phase [Ca2+]i increase but was two orders of magnitude less potent. The hydrophilic inhibitor, pravastatin (100 microg ml(-1), was without effect on [Ca2+]i. 4. Simvastatin (0.3 microg ml(-1)), more potently than simvastatin-acid (30 microg ml(-1)), inhibited glucose-induced insulin secretion from islets, whereas pravastatin (100 microg ml(-1)) had no effect. 5. Whole-cell patch clamp recordings demonstrated a reversible inhibition of the beta-cell L-type Ca2+ channels by simvastatin, but not by pravastatin. Simvastatin also inhibited the [Ca2+]i increases by L-arginine and KCl, agents that act via opening of L-type Ca2+ channels. 6. In conclusion, lipophilic HMG-CoA reductase inhibitors can inhibit glucose-induced [Ca2+]i signalling and insulin secretion by blocking L-type Ca2+ channels in beta-cells, and their inhibitory potencies parallel their lipophilicities. Precaution should be paid to these findings when HMG-CoA reductase inhibitors are used clinically, particularly in patients with type 2 diabetes.

Animals↗
PubMed2001

Simvastatin inhibits noradrenaline-induced hypertrophy of cultured neonatal rat cardiomyocytes.

1. Oxidative mechanisms have been implicated in neonatal cardiomyocyte hypertrophy. We and others have shown that a HMG-CoA reductase inhibitor preserves endogenous antioxidant enzyme activity and inhibits cardiac hypertrophy in vivo. We therefore have examined whether noradrenaline (NA) induces the generation of reactive oxygen species (ROS) during its induction of neonatal cardiomyocyte hypertrophy and whether simvastatin, a HMG-CoA reductase inhibitor, attenuates ROS production and thus NA-induced hypertrophy of cardiomyocytes. 2. NA increased the intracellular ROS levels in a concentration-dependent manner. This increase of ROS was significantly inhibited by simvastatin and catalase. Prazosin partially suppressed NA-induced increase of ROS and beating, while preincubation with both prazosin and propranolol completely abolished NA-evoked increase of ROS and beating. Simvastatin did not affect NA-induced increase of beating. 3. The NA-induced increase of protein content was partially suppressed by prazosin and completely abolished by preincubation with both prazosin and propranolol. Simvastatin inhibited the increase of NA-induced increase of RNA content and [(3)H]-leucine incorporation in a concentration-dependent manner. Mevalonic acid (MVA) reversed the inhibition of NA-induced RNA and protein increase by simvastatin. Catalase also inhibited the NA-induced increase of RNA and protein. 4. We conclude that the inhibitory effects of simvastatin on myocyte hypertrophy were associated with its antioxidant effects and inhibition of MVA-metabolism pathway in neonatal rat cardiomyocytes. NA-induced increases of intracellular ROS and cardiomyocyte hypertrophy requires both alpha and beta adrenoceptors activation in neonatal rat cardiomyocytes. The increases of ROS induced by NA is required for hypertrophy.

Adrenergic alpha-Agonists↗
PubMed2005

High doses of simvastatin upregulate dopamine D1 and D2 receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase.

This study aims to investigate whether or not long-term statin treatment causes upregulation of D1 and D2 receptor gene expression with concomitant increase in endothelial nitric oxide synthase (eNOS) expression in Sprague-Dawley rats. Serum triglyceride levels were dose dependently reduced in the simvastatin-treated rats reaching statistical significance at the highest dose (49% reduction), while pravastatin caused similar effects (52%) at the same dose. Cholesterol levels remained unchanged in both groups at all doses. Simvastatin, 10 or 30 mg kg(-1) day(-1), increased D1 and D2 receptor expressions in the prefrontal cortex. Similar upregulation was observed neither with simvastatin in the striatum nor with pravastatin in both brain regions. Simvastatin (10 mg kg(-1) day(-1)) also increased eNOS expression in the prefrontal cortex but not neuronal NOS or inducible NOS. D1 receptor activation by chloro-APB (5 microM) increased cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin-treated rats by 88 and 285%, respectively. This effect was markedly attenuated by the selective D1 antagonist SCH-23390 (25 microM). D2 receptor activation by quinpirole (5 microM) had no effect on the basal cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin-treated rats, while the same concentration of quinpirole completely abolished the D1 receptor-mediated increase. These results suggest that lipophilic statins can alter dopaminergic functions in the prefrontal cortex possibly via a central mechanism. The possibility of a nitric oxide mechanism involving eNOS requires further investigation.

Animals↗