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PubMed2005

Echocardiographic quantification of atherosclerosis leads to cost-effective treatment with statins.

OBJECTIVE: Use of statins in prevention of atherosclerosis is effective but expensive. Patient selection gains wider public attention as medication costs in the US and Europe augment by 8% to 10% per year. We examined different clinical risk stratification strategies, particularly focusing on echocardiographic atherosclerosis quantification, for their impact on event reduction and cost-effectiveness in statin treatment. METHODS AND RESULTS: In a prospective, consecutive cohort of 336 patients referred to non-invasive cardiac examination, risk stratification was done by various combinations of risk factors and noninvasive atherosclerosis quantification. Atherosclerotic burden was determined through measuring "aortic elastance" by transthoracic echocardiogram, a validated non-invasive method. Cardiovascular events were recorded at a mean follow-up of one year. Echocardiographically determined atherosclerosis severity and event history, especially in combination, yielded the best selection strategies for statin treatment over a broad range of predetermined funding or required event reductions, surpassing conventional cardiovascular risk factors. From 26.8 statin-preventable events/1000 patients/year (assuming all patients treated), the best selection strategies could avoid: 24 with 66% of the cost for statin treatment (atherosclerosis and age criteria), 20.1 with <50% of the budget, 12.2 with <30% of the budget or 9.6 with <15% of the budget (using combinations of atherosclerosis and prior events), while conventional strategies without echo quantification of atherosclerosis were inferior. CONCLUSION: Non-invasive echocardiographic quantification of atherosclerosis improves efficiency and cost-effectiveness in statin treatment.

Aged↗
PubMed2006

Factors associated with healthcare utilization costs for statin therapy--a pilot study in Hong Kong.

BACKGROUND: Socio-economic status, comorbidities and adherence to statin therapy might affect the cost-effectiveness of statin therapy in hyperlipidemia. OBJECTIVE: To examine the effects size of demographic factors, clinical factors and adherence to statin therapy on the direct medical costs for Chinese patients at high risk of coronary heart disease (CHD). METHODS: This was a prospective, observational cohort study conducted in the outpatient departments of a public teaching hospital in Hong Kong. Patients at high risk of CHD who had been on statin monotherapy for < 12 months were recruited. Baseline demographic and clinical data were obtained. Statin adherence was monitored prospectively over 6 months using the Medication Event Monitoring System. Total direct medical costs per member per month (cPMPM), including cost for clinic visits, statin medication, laboratory tests on lipids and management of CHD events if any, were calculated from the perspective of a public healthcare organization. RESULTS: 83 patients completed the study. Median cPMPM in 80 patients (96% of 83 patients) without a new CHD event (USD 42) and for 3 (4%) patients who experienced CHD events (USD 444) were significantly different (p = 0.003). History of congestive heart failure (beta = 1,957, 95% CI = 1,006 - 2,909), male gender (beta = 584, 95% CI = 215 - 952), coronary atherosclerosis (beta = 1,436, 95% CI = 538 - 2,334) and diabetes mellitus (beta = 604, 95% CI = 136 - 1,07 1) were positive predictors for cPMPM. CONCLUSION: In this pilot study male gender, diabetes mellitus, congestive heart failure and coronary atherosclerosis appear to be significantly associated with higher costs for Chinese patients at high risk of CHD.

Cohort Studies↗
PubMed2004

Global analysis of RNA expression profile in human vascular cells treated with statins.

In addition to a lipid-lowering effect, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have an effect on the expression levels of many genes. In order to elucidate the range of this effect as comprehensively as possible, we investigated the changes in gene expression profiles brought about by atorvastatin or pitavastatin in cultured human umbilical vein endothelial cells (HUVEC), cultured human coronary artery smooth muscle cells (HCASMC) and cultured human hepatocarcinoma Hep G2 cells by means of DNA microarrays. Among the 6146 genes in the array, statins affected the expression levels of genes involved in coagulation, vascular constriction and cell growth in a cell-type specific manner. In HUVEC, they induced integrin beta4 and thrombomodulin profoundly, and profoundly suppressed pentraxin 3 both at 8 and 24 hours. In HCASMC, the statins induced thrombomodulin and urokinase inhibitor, and potently suppressed the cysteine-rich angiogenic inducer 61 and cyclin B. Many genes related to the cell cycle and/or growth were also regulated in HUVEC and HCASMC by the statins. These results indicate that many aspects of the pleiotropic effect can be mediated by transcriptional control by statins. Genes newly identified by this study may be useful in statin therapy.

Base Sequence↗
PubMed2006

Statins: beneficial or adverse for glucose metabolism.

Large-scale clinical trials have established that statin use for lowering blood cholesterol is beneficial in reducing atherosclerotic cardiovascular diseases in different populations. However, the general reputation of statins seems to be clouded by a potential adverse effect of a class of statins on glucose metabolism. This paper reviewed clinical data of statins regarding the effects on diabetes mellitus and glucose metabolism. At least five randomized controlled studies, primarily investigating the protective effect of statins on the risk of cardiovascular diseases, have addressed the effect of statins on glucose metabolism in Western countries. One study showed that pravastatin (40 mg/day) was protective against the development of diabetes mellitus. Two studies of atorvastatin (10 mg/day) and one study of simvastatin (40 mg/day) showed no measurable effect of these regimens on the risk of diabetes mellitus or the clinical course of diabetes mellitus. One study of atorvastatin (80 mg/day) versus pravastatin (40 mg/day) suggested a deterioration of glucose metabolism associated with a high dose of atorvastatin. In Japan, a few case reports have noted a potential adverse effect of atorvastatin on glycemic control in patients with diabetes mellitus; however, seven clinical trials have showed no such effect of atorvastatin although these studies were relatively small in size and short in follow-up. Only one of the two observational studies suggested a possible adverse effect of atorvastatin on glycemic control. Evidence is extremely limited regarding atorvastatin use and deterioration in glycemic control, and further studies are needed to draw a conclusion on this issue.

Atorvastatin↗
PubMed2006

Aspirin, statins, or both drugs for the primary prevention of coronary heart disease events in men: a cost-utility analysis.

BACKGROUND: Aspirin and statins are both effective for primary prevention of coronary heart disease (CHD), but their combined use has not been well studied. OBJECTIVE: To perform a cost-utility analysis of the effects of aspirin therapy, statin therapy, combination therapy with both drugs, and no pharmacotherapy for the primary prevention of CHD events in men. DESIGN: Markov model. DATA SOURCES: Published literature. TARGET POPULATION: Middle-aged men without a history of cardiovascular disease at 6 levels of 10-year risk for CHD (2.5%, 5%, 7.5%, 10%, 15%, and 25%). TIME HORIZON: Lifetime. PERSPECTIVE: Third-party payer. INTERVENTIONS: Low-dose aspirin, a statin, both drugs as combination therapy, or no therapy. OUTCOME MEASURE: Cost per quality-adjusted life-year gained. RESULTS OF BASE-CASE ANALYSIS: For 45-year-old men who do not smoke, are not hypertensive, and have a 10-year risk for CHD of 7.5%, aspirin was more effective and less costly than no treatment. The addition of a statin to aspirin therapy produced an incremental cost-utility ratio of 56,200 dollars per quality-adjusted life-year gained compared with aspirin alone. RESULTS OF SENSITIVITY ANALYSIS: Excess risk for hemorrhagic stroke and gastrointestinal bleeding with aspirin, risk for CHD, the cost of statins, and the disutility of taking medication had important effects on the cost-utility ratios. LIMITATIONS: Several input parameters, particularly adverse event rates and utility values, are supported by limited empirical data. Results are applicable to middle-aged men only. CONCLUSIONS: Compared with no treatment, aspirin is less costly and more effective for preventing CHD events in middle-aged men whose 10-year risk for CHD is 7.5% or higher. The addition of a statin to aspirin therapy becomes more cost-effective when the patient's 10-year CHD risk before treatment is higher than 10%.

Aspirin↗
PubMedDate not supplied

[Statins: similarities and differences in the pharmacological, clinical and laboratory aspects].

The inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (or statins) are the most powerful drugs affecting lipid and lipoprotein levels in plasma. Results obtained from large controlled trials using simvastatin, pravastatin and lovastatin for the primary or secondary prevention of coronary heart disease have demonstrated that treatment with statins is associated with a significant reduction in coronary morbidity and mortality and in total mortality. This is probably due to a more general anti-atherogenic effect of these drugs beyond their lipid-lowering activity. Meta-analysis of data from these large trials indicates that statins have an impact also on the incidence of cerebrovascular events. Currently, six statins have been approved for therapeutic use in different countries. In spite of the similarities in their chemical structure and mechanisms of action, statins may differ in many aspects such as pharmacological properties (hydrophilic vs lipophilic, elimination half-life, cytochrome P450 metabolism, etc.), effects on lipid and other biochemical variables, or pleiotropic effects on different metabolic processes related to atherosclerosis (endothelial function, platelet aggregation, immune function, etc.). In general, the safety and tolerability profile for all statins currently in use is good with a < 2% incidence of undesirable effects.

Atorvastatin↗
PubMedDate not supplied

Statin-stimulated nitric oxide release from endothelium.

BACKGROUND: There is increasing evidence that loss of endothelium-derived NO is a major factor in cardiovascular complication events, and that NO might exert antiatherosclerotic actions. The beneficial effects of HMG CoA reductase inhibitors (statins) therapy in atherosclerosis outweigh those expected from simply lowering low-density lipoprotein (LDL) cholesterol, and may be related to the direct action in the endothelium. Based on these concepts, in the studies described here, the effect of new statin derivatives on nitric oxide (NO) and superoxide (O2-) release in bovine endothelial cells was tested. MATERIAL AND METHODS: Highly sensitive electrochemical NO and O2--microsensors were placed near the surface of endothelial cells, and the concurrent kinetics of NO and O2-- release were measured in situ. RESULTS: All tested statins stimulated NO release. The peak concentration of NO after stimulation with 1 Kmol/l Lovastatin, 1 Kmol/l Atorvastatin, 1 Kmol/l Pravastatin, or 1 Kmol/l Simvastatin was about 77%, 73%, 72%, and 44% lower, respectively, as compared with the NO peak concentration after stimulation with 1 Kmol/l calcium ionophore A23187 (receptor-independent agonist). The tested statins stimulated NO release in a modest way, which resulted in diminishing O2- generation during activation of nitric oxide synthase. Moreover, the kinetics of O2- release after administration of the statins suggested that these compounds may also scavenge O2-. The NO/O2- peak concentration ratio after the NOS agonists administration was as follows: 7.51 for CaI, 6.56 for Lovastatin, 6.00 for Atorvastatin, 4.17 for Pravastatin and 6.25 for Simvastatin. CONCLUSIONS: The tested statins, i.e. Lovastatin, Atorvastatin, Pravastatin and Simvastatin demonstrate variable potency to enhance the NO/O2- concentration ratio after stimulation of NOS, resulting in an increase of NO bioavailability in endothelial cells.

Animals↗
PubMed2001

Lipid-independent effects of an estrogen-statin combination: inhibition of expression of adhesion molecules and plasminogen activator inhibitor--I in human endothelial cell cultures.

OBJECTIVE: Estrogens have been shown to elicit beneficial effects on the cardiovascular system by modulating the lipid profile as well as by direct vascular actions. Since estrogenic cardioprotection has still been not confirmed by randomized interventional trials, the combination with statins, which have been proved to act in a cardioprotective fashion, is of special interest. Statins are lipid-lowering drugs, but direct vascular effects also seem to be of importance in this case. Apart from some clinical studies investigating the effect of such combination therapy on the lipid profile, no reports of a possible influence on biochemical markers of vascular function are yet available. The aim of the present study was to investigate, for the first time, lipid-independent effects of an estrogen-statin combination on markers of vascular endothelial function. METHODS: Experiments were conducted using endothelial cell cultures from human umbilical veins. Markers of endothelial function chosen were adhesion molecules, which are involved in the early stages of atherosclerosis, and plasminogen activator inhibitor-1 (PAI-1), which is an independent risk factor for the development of cardiovascular disease. The concentrations of soluble forms of the adhesion molecules E-selectin and intercellular adhesion molecule (ICAM) as well as concentrations of PAI-1 were measured after the addition of 17 beta-estradiol, fluvastatin and equimolar combinations of the two in concentrations of 0.01, 0.1 and 1 mumol/l. RESULTS: Both drugs significantly reduced concentrations of E-selectin and ICAM, and the effect of the combination was not superior to that of the monosubstances. In addition, both substances were able to inhibit the synthesis of PAI-1. In this case the effect of the combination was significantly greater than that of the monosubstances. CONCLUSION: In summary, an estrogen-statin therapy is able to elicit lipid-independent positive modulations on the expression of cell adhesion molecules and the synthesis of PAI-1. The estrogen-statin combination showed partially additive effects and no negative, antagonistic actions. Since the combination of statins with hormone replacement therapy may attain clinical significance in preventing cardiovascular disease, it seems worthwhile to elucidate further the direct vascular effects of this combination therapy, especially in postmenopausal women with pre-existing coronary disease.

Anticholesteremic Agents↗
PubMed2001

[Safety profile of statins].

HMG-CoA reductase inhibitors (statins) are the treatment of choice for patients with hypercholesterolaemia. Several large-scale clinical trials have examined the efficacy and tolerability of statins, providing a wealth of information on their safety and adverse effect profile. Adverse hepatic effect is reflected as asymptomatic elevations in serum levels of aminotransaminases. Myopathy, occasionally leading to myoglobulinuria secondary to rhabdomyolysis, is a rare and potentially fatal complication. Cerivastatin, the last statin approved for use in humans, was voluntarily withdrawn from the market by Bayer, because fatal rhabdomyolysis was most frequently reported with cerivastatin than for other approved statins. The concomitant use of statins with drugs that inhibit CYP3A4 (cyclosporin, erythromycin, clarithromycin, itraconazole, and ketoconazole), may result in increased plasma concentrations of HMG-CoA reductase inhibitors leading occasionally to myotoxicity. Fibric acid derivatives can produce myotoxicity, and the association of both types of drugs increases the risk of this adverse event. The reason for the greater association of rhabdomyolysis with cerivastatin than with other statins is unknown. The efficiency of post marketing drug surveillance programs in different countries, was the clue for the awareness of this problem.

Anticholesteremic Agents↗
PubMed2001

[Use of statins in hospitals after myocardial infarction].

BACKGROUND: The objective of this study was to register the frequency of statin prescription during the initial hospitalization for acute myocardial infarction and therapeutic intensity at follow-up. MATERIAL AND METHODS: A retrospective study among patients aged below 70 of both sexes with acute myocardial infarction, who survived the initial hospitalization at the University Hospital of Tromsø during 1995-1998. RESULTS: 473 patients with acute myocardial infarction, 76% men, mean age 57.4 (range 33-70 yrs) were included. Statin treatment was started in 55% of the patients within discharge from the hospital. Total cholesterol (odds ratio 0.51, 0.41-0.64; 95% CI) and decreasing age (1.60, 1.21-2.10) were significant predictors for statin prescription. Statin treatment started during hospitalization increased gradually from 42% in 1995 to 91% in 1998 (p < 0.001) among patients with total cholesterol above 5.0 mmol/l at admission. 54% of the statin users achieved the treatment goal at their first outpatient control 8-12 weeks after discharge. INTERPRETATION: The proportion of statin users has increased satisfactory during 1995-98, but the therapeutic intensity is unsatisfactory compared to guidelines for cholesterol-lowering treatment of patients with acute myocardial infarction.

Adult↗
PubMed2002

[From prevention to cardiovascular rehabilitation: statins and evidence-based medicine].

The recent "Lipobay affair" prompted us to review the biomedical literature focusing on statins, in a prevention and rehabilitation perspective, and to prepare a pertinent evidence-based report. A number of randomized controlled clinical trials have assessed the efficacy and the safety of statins in cardiovascular prevention; these drugs have proved to be effective (number needed to treat values between 20 and 40) and safe (number needed to harm value for myopathy even when in association with fibrates around 833, as deduced from literature data). Fatal rhabdomyolysis is virtually not detectable in current scientific literature when statin therapy is administered in an appropriate fashion and when the patient undergoes periodical check-ups. In the individual patient, the benefits and risks related to his treatment have to be precisely tailored, evaluating his individual risk profile, the strength of the indication to statin therapy, the concomitant presence of other treatments and/or habits and the potential and actual adverse events foreseeable (to an extent) if established risk factors which predispose to myopathy are taken into consideration. The hematological lipids management strategy including a correct diet, physical exercise and statin therapy represents a key component of every evidence-based rehabilitation program too. Cardiovascular prevention and rehabilitation are major priorities at an individual as well as at a public health level. Both these strategies are based on a careful management of known risk factors, among them hypercholesterolemia, that today can be effectively and safely treated with statins.

Cardiac Rehabilitation↗
PubMed2002

[Broader indication for treatment with statins; the 'heart protection study'].

The introduction of statins has been a breakthrough in the treatment of hypercholesterolaemia. Statins are safe and effective in reducing the risk of coronary heart disease in the general population. The 'Heart protection study' has provided evidence for the benefit of statin treatment in much broader populations than is presently indicated in the Dutch national guidelines, i.e. also in high-risk persons with diabetes mellitus, and irrespective of age or cholesterol level. The use and cost of statins, which have been referred to as 'lifestyle-drugs' in the lay press, have risen enormously. Recently, the Dutch College of Healthcare Insurers issued a report in which recommendations concerning the reimbursement of the costs for cholesterol-lowering drugs are based on 'generally accepted insights into the appropriate use of these drugs'. Lifestyle and/or age are not exclusion criteria for treatment with statins. The expiration of patents of some statins and modifications to the reimbursement system in 2003 could lead to cost reductions.

Age Factors↗
PubMed2002

Rhabdomyolysis from the combination of a statin and gemfibrozil: an uncommon but serious adverse reaction.

We report a patient with renal insufficiency who developed rhabdomyolysis 1 month after initiating cerivastatin and gemfibrozil for hyperlipidemia. Myopathy caused by HMG-CoA reductase inhibitors (statins) alone is rare, but occurs more frequently when a statin is used with gemfibrozil, a medication that likely has a direct toxic effect on muscles. Predisposing factors to the development of myopathy from the combination include use of medications affecting statin metabolism, higher doses of statins, renal insufficiency, diuretics, and hypothyroidism. It has been proposed that alternate-day therapy with a statin and fibrate, spacing of doses in a single day, or use of lower doses of statins may prevent the development of myopathy. Currently, no predictable method to determine who is at risk for myopathy exists, nor is there a reliable screening test. Therefore, patients should be advised to watch for generalized muscle pain or weakness, and if it occurs, stop medications and report symptoms immediately.

Drug Therapy, Combination↗
PubMed2003

The statins as anticancer agents.

3-Hydroxy-3-methylgutaryl CoA reductase inhibitors, commonly referred to as the statins, have proven therapeutic and preventative effects in cardiovascular diseases. Recently, there are emerging interests in their use as anticancer agents based on preclinical evidence of their antiproliferative, proapoptotic, anti-invasive, and radiosensitizing properties. Inhibition of 3-hydroxy-3-methylgutaryl CoA reductase by the statins interferes with the rate-limiting step of the mevalonate pathway, leading to reduced levels of mevalonate and its downstream products, many of which play important roles in critical cellular functions such as membrane integrity, cell signaling, protein synthesis, and cell cycle progression. Perturbations of these processes in neoplastic cells by the statins may therefore result in control of tumor initiation, growth, and metastasis. The statins have demonstrated growth inhibitory activity in cancer cell lines and preclinical tumor models in animals. Phase I trials of statins in humans have demonstrated myotoxicity as their main dose-limiting toxicity, and Phase II trials in various tumor types are ongoing to evaluate their efficacy. Potential future directions in the development of the statins as anticancer agents include combinations with chemotherapeutic or other molecular-targeted agents, combinations with radiotherapy, maintenance therapy in minimal disease status, and as chemopreventive therapy.

Anticholesteremic Agents↗
PubMedDate not supplied

Decreased erythropoietin requirements in maintenance hemodialysis patients with statin therapy.

Inflammatory cytokines induce erythropoietin (EPO) resistance, anorexia, and suppression of hepatic albumin synthesis. Increased levels of C-reactive protein (CRP) have been associated with relative EPO resistance in dialysis patients. More recently, studies have shown that statin therapy decreases CRP. This study analyzed the effect of statin therapy on EPO requirements in dialysis patients. This retrospective, single center study stratified stable hemodialysis patients into two groups: Group 1, statin therapy (n = 19), and Group 2, nonstatin therapy (n = 19). Group 1 was subclassified into Group 1a (prestatin therapy) and Group 1b (poststatin therapy). Baseline demographics, biochemical parameters [serum lipid panel, hemoglobin (Hgb), transferrin saturation (TSAT), ferritin, parathyroid hormone (PTH), aluminum, albumin, KT/V, urea reduction ratio (URR), and protein catabolic rate (nPCR)] and EPO requirements (u/kg per treatment) were obtained. Poststatin labs were obtained at a mean of 4.7 months. Statistically significant changes were noted in Group 1 after initiation of statin therapy for cholesterol (174.68 +/- 53.8 to 142 +/- 32.7, p < 0.05), Hgb (10.61 +/- 1.2 to 12.48 +/- 0.79, p < 0.0005), ferritin (618 +/- 334.1 to 334 +/- 265, p < 0.05), and albumin (3.58 +/- 0.4 to 3.77 +/- 0.4, p < 0.005). EPO requirements decreased by 25%. Mean values for lipid panel showed reductions in cholesterol (18%), triglyceride (37.8%), and low density lipoprotein (LDL) (26%), as well as elevation in high density lipoprotein (HDL) (11%). These data suggest that statin therapy may decrease EPO requirements in dialysis patients. The improvement in EPO responsiveness may be caused by the effect of statins on CRP.

Adult↗
PubMed2003

Combination of statins and hormone replacement therapy in postmenopausal women is associated with increased bone mineral density.

Recent studies have shown that statins might be potent inhibitors of bone resorption and osteoclast number, and there is evidence for their bone anabolic effects. Statin treatment seems to protect against non-pathological fractures in older women. However, contradictory findings have been obtained. In this retrospective study we found that postmenopausal women on statins and hormone replacement therapy (HRT) showed higher bone mineral density than women on HRT alone. This evidence provides further confirmation of the effect of statins on bone turnover and shows that the combination of HRT and statins reduces the risk of bone fracture by virtue of the antiresorptive effect of HRT and the anabolic and antiresorptive effects of statins.

Absorptiometry, Photon↗
PubMed2003

Effect of statin therapy added to ACE-inhibitors on blood pressure control and endothelial functions in normolipidemic hypertensive patients.

OBJECTIVE: Endothelium-dependent vasodilatation is impaired in hypertension. Statins have been shown to improve endothelial functions in hyperlipidemic subjects. We aimed to investigate the effect of statins on endothelium-dependent flow mediated dilatation (FMD) and blood pressure (BP) in normocholesterolemic hypertensive patients. METHODS: This randomized prospective study consisted of 56 patients with newly diagnosed essential hypertension. All patients received angiotensin converting enzyme (ACE) inhibitor lisinopril (5 mg/day) as antihypertensive therapy, and half of them were randomized to simvastatin(20mg/day) irrespective of serum lipid levels. All subjects underwent brachial artery ultrasonographic examination for the measurement of FMD before randomization and at the end of 12 weeks treatment. RESULTS: A total of 39 patients completed the study (21 patients in the statin + ACE inhibitor group, and 18 patients in the ACE-inhibitor alone group). Blood pressure levels were substantially reduced in both groups after treatment. In statin+ ACE-inhibitor group systolic pressure reduced by 23% (p=0.0001) and diastolic BP reduced by 23% (p=0.0001). In ACE-inhibitor alone group these ratios were 20% (p=0.001) and 21% (p=0.001), respectively. Meanwhile, pulse pressure (PP) decreased by 25% in statin+ ACE-inhibitor group (P=0.0001) and by 16% in ACE inhibitor-alone group (p=0.0051). Baseline FMD was significantly impaired in overall patients with hypertension as compared with healthy controls (13+/-8 vs. 24+/-8 %, P = 0.001). After treatment FMD decreased by 23% in lisinopril alone group (p=0.054). There were no correlations between FMD improvement, LDL reduction, BP or PP changes in both groups. CONCLUSION: Addition of simvastatin to ACE-inhibitor treatment in newly diagnosed hypertensive patients with normal cholesterol levels, significantly reduced PP and facilitated BP control, but did not affect endothelium-dependent dilatation. Further long-term large scale studies are needed to clarify the effect of various statins on endothelial functions of either hypercholesterolemic or normocholesterolemic hypertensive patients.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Statins rise cytoplasmic calcium level [Ca2+]i in cultured endothelial cells.

Recently, we have shown that some HMG-CoA reductase inhibitors (statins) induce immediate pleiotropic effects in vascular endothelium both in vivo and in vitro, to mention only PGI2-mediated thrombolysis in rats and NO-mediated endothelium-dependent vasodilation in guinea pig coronary circulation. Here we look whether immediate endothelial effect of statins is associated with mobilization of intracellular calcium ions [Ca2+]i in cultured bovine aortic endothelial cells (BAEC). We analyzed the effects of various statins (atorvastatin, cerivastatin, simvastatin, lovastatin and pravastatin at concentration of 10-30 microM) on [Ca2+]i in BAEC in comparison to responses induced by bradykinin (Bk) (10 nM), adenosine diphosphate (1 microM), acetylcholine (100 nM), adrenaline (10 microM), serotonin (10 microM) or calcium ionophore A 23187 (0.1 microM) using FURA-2 according to fluorimetric method of Grynkiewicz et al. Basal [Ca2+]i level in BAEC was between 60 and 100 nM. Bk was the most potent to induce [Ca2+]i response. Delta[Ca2+]i induced by Bk was 331.9 +/- 19.49 nM (n = 36). Delta[Ca2+]i induced by statins (30 microM), i.e. atorvastatin, cerivastatin, simvastatin, lovastatin and pravastatin were 66.4 +/- 7.38% (n = 6), 54.8 +/- 10.12% (n = 5), 58.8 +/- 13.9% (n = 8), 27.7 +/- 7.19% (n = 5) and 0% (n = 5) of the response induced by Bk (10 nM), respectively. In summary, all statins tested, except pravastatin, induce immediate increase in [Ca2+]i in endothelium. This pleiotropic activity of statins in endothelium, most likely not related to the inhibition of HMG-CoA reductase, may represent an intracellular correlate for the immediate release of NO and PGI2 by these drugs that was reported by us previously.

Animals↗