Cinnamon and cognitive function: a systematic review of preclinical and clinical studies.

Cinnamon is the inner bark of trees named Cinnamomum. Studies have shown that cinnamon and its bioactive compounds can influence brain function and affect behavioral characteristics. This study aimed to systematically review studies about the relationship between cinnamon and its key components in memory and learning. Two thousand six hundred five studies were collected from different databases (PubMed, Scopus, Google Scholar, and Web of Science) in September 2021 and went under investigation for eligibility. As a result, 40 studies met our criteria and were included in this systematic review. Among the included studies, 33 were In vivo studies, five were In vitro, and two clinical studies were also accomplished. The main outcome of most studies (n = 40) proved that cinnamon significantly improves cognitive function (memory and learning). In vivo studies showed that using cinnamon or its components, such as eugenol, cinnamaldehyde, and cinnamic acid, could positively alter cognitive function. In vitro studies also showed that adding cinnamon or cinnamaldehyde to a cell medium can reduce tau aggregation, Amyloid ß and increase cell viability. For clinical studies, one study showed positive effects, and another reported no changes in cognitive function. Most studies reported that cinnamon might be useful for preventing and reducing cognitive function impairment. It can be used as an adjuvant in the treatment of related diseases. However, more studies need to be done on this subject.

Hepatic regenerative response to long-term consumption of cinnamon-rich diet in aged rats.

Objective: The present study aimed to investigate the impact of cinnamon on liver regeneration in a rat model of partial hepatectomy (PH). Materials and Methods: Thirty-two old male Sprague-Dawley rats (12 weeks old) were randomly divided into two equal groups (n=16). One group was fed with a standard diet (control) while the other group was fed with the same diet containing 1% cinnamon for 41 weeks. Then, all animals were subjected to the PH procedure and their livers were studied on postoperative days 2, 10 and 28. The liver contents of hepatic growth factor (HGF), insulin, malondialdehyde (MDA), nitric oxide metabolites (NOx), superoxide dismutase (SOD) and tumor necrosis factor-alpha (TNF-α) were evaluated. Also, the serum levels of liver function markers (alanine aminotransferase (ALT) and aspartate aminotransferase (AST), MDA, NOx and SOD activity were measured. Results: The regenerated liver weight was significantly higher in cinnamon-treated animals than the controls on both day 10 and 28 post hepatectomy. The hepatic MDA levels in the cinnamon-treated animals were significantly lower than the control rats. Cinnamon led to a significant increase of SOD on day 2 after hepatectomy in serum and liver content. The basal level of HGF in the liver of cinnamon-consuming rats was significantly higher than in the control rats. Hepatic insulin level was significantly increased relative to baseline and control on day 2 in the cinnamon-consuming rats. Hepatic TNF-α levels dramatically decreased on postoperative days (POD) 2 relative to baseline in the control and cinnamon-treated rats. Conclusion: Long-term cinnamon consumption enhanced liver regeneration outcomes in old rats.

Effect of red beetroot juice on oxidative status and islet insulin release in adult male rats.

INTRODUCTION: Beetroot is rich in inorganic nitrate and it has been shown that inorganic nitrate has beneficial effects on metabolic syndrome. This study aims to investigate the effect of red beetroot juice (RBJ) on carbohydrate metabolism in adult insulin-resistant rats. MATERIALS AND METHODS: Sixteen male Wistar rats (32 weeks old) were divided into two equal groups: control and RBJ. Treatment with drinking water (control) and 100% RBJ (RBJ) was lasted for 5 weeks. At the end of the 4th week the intraperitoneal glucose tolerance test was performed and at the end of the study period animals were sacrificed and blood and tissue (aorta, heart, and liver) samples were collected. Furthermore, pancreatic islets were isolated and their insulin secretion activity was investigated in different glycemic conditions. RESULTS: Compared to the control group, RBJ-treated rats showed lower blood glucose and insulin levels in the glucose tolerance test. Serum and tissue levels of nitric oxide in the RBJ group were significantly higher than those in the control group. The liver peroxidation and serum aspartate transaminase levels were significantly increased in the RBJ-treated animals compared to the control group. The islets of RBJ group exhibited lower insulin secretion, especially in 16.7 mM glucose concentration (supraphysiologic condition) than control group. CONCLUSIONS: RBJ consumption improves glucose metabolism in rats via increasing nitric oxide metabolites in an insulin-independent manner. However, future studies are needed to minimize the potential hepatic adverse consequences.

Sex-specific endothelial dysfunction induced by high-cholesterol diet in rats: The role of protein tyrosine kinase and nitric oxide.

BACKGROUND AND AIMS: Atherosclerosis is a chronic process playing a crucial role in the pathogenesis of cardiovascular disease. Sex-specific differences in the incidence of atherosclerosis indicate that estrogen has a protective effect on the cardiovascular disease. However, the role of sex on endothelium responses in animal models of high cholesterol (HC) diet-induced atherosclerosis has not been fully investigated. This study was aimed to investigate vascular responses in HC-fed rats. METHODS AND RESULTS: Male and female Sprague rats (12-week-old) were treated with either a standard diet (n = 12 of each sex) or an HC enriched diet (n = 12 of each sex) containing 2% cholesterol for 24 weeks. HC treated animals (both sexes) showed increased levels of total cholesterol, LDL-cholesterol, triglyceride and blood pressure (BP) compared to control rats. While the BP of control rats (both sexes) was increased following aminoguanidine administration (AG, 100 mg/kg i.p.), it was not changed in HC animals (both sexes). The hypotensive effect of acetylcholine was significantly impaired in male HC-treated rats. In vitro experiments demonstrated that aortic rings from HC group (both sexes) had an increased contractile response to phenylephrine and a decreased vasodilatory response to acetylcholine. The vasorelaxant effect of acetylcholine in HC rats (only male) was improved by applying 10-5 M genistein (tyrosine kinase inhibitor) or AG. CONCLUSION: HC diet alters endothelium function through Nitric oxide (NO) and tyrosine kinase pathways in male rats.

The effects of quercetin on seizure, inflammation parameters and oxidative stress in acute on chronic tramadol intoxication.

BACKGROUND: Tramadol is a widely used synthetic opioid for moderate to severe pain. Some studies have shown that tramadol can increase oxidative stress in different tissues of the body. Quercetin is also a substance with various biological effects, including antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, and cardioprotective activities. The current investigation aimed at determining the effects of quercetin, with or without naloxone, on tramadol intoxication. METHODS: This study was performed on 30 male Wistar rats divided into five groups: Group I) control group: intraperitoneal injections of normal saline 0.9% for 14 days; Group II) tramadol: 25 mg/kg for 14 days, and then a 50 mg/kg acute dose injection on the last day; Group III) acute quercetin (single dose): tramadol injection as with the second group plus 100 mg/kg of quercetin on the last day; Group IV) chronic quercetin: tramadol injection similar to the second group plus quercetin 100 mg/kg for 14 days; Group V) quercetin plus naloxone: tramadol injection similar to the second group plus injection of quercetin 100 mg/kg + intravenous naloxone 2 mg/kg on the last day, followed by a 4 mg/kg/h injection of naloxone for six hours. The rats were monitored for six hours on the last day, relating to the number and severity of seizures. Finally, the samples were prepared for biochemical investigation of the serum level of oxidative stress markers (MDA, SOD, NOx), inflammatory factors (IL-6, TNF-α), biochemical parameters (ALT, AST, creatinine, glucose) and hematological assay. The liver, heart, kidney, cortex, cerebellum, and adrenal tissues were collected to investigate the redox state. RESULTS: None of the treatments had positive effects on the number and severity of seizures. Chronic administration of quercetin led to alteration of some blood parameters, including reduced hemoglobin level and elevated platelet counts. Acute on chronic tramadol administration resulted in a significant rise in AST, where different treatments failed to reduce their levels down to the control group. CONCLUSION: chronic administration of quercetin showed decreased oxidative/nitrosative stress in the liver, kidney, adrenal, and heart tissues. Quercetin plus naloxone decreased oxidative stress in the heart and adrenal tissues, but adverse effects on the brain cortex and hepatic function. Single-dose quercetin reduced cardiac oxidative stress.

Effects of naloxone and diazepam on blood glucose levels in tramadol overdose using generalized estimating equation (GEE) model; (an experimental study).

BACKGROUND: Tramadol is a synthetic opioid and poisoning is increasing around the world day by day. Various treatments are applied for tramadol poisoning. Due to the unknown effects of tramadol poisoning and some of its treatments on blood glucose levels, this study was conducted to investigate the overdose of tramadol and its common treatments (naloxone, diazepam), and their combination on blood glucose levels in male rats. METHODS: This study was conducted in 45 male Wistar rats. The animals were randomly divided into five groups of 9. They received a 75 mg/kg dose of tramadol alone with naloxone, diazepam, and a combination of both of these two drugs. On the last day, animals' tail vein blood glucose levels (BGL) were measured using a glucometer at different times, including before the tramadol injection (baseline) and 1 hour, 3 hours, and 6 hours after wards. The rats were anesthetized and sacrificed 24 h after the last injection. Blood samples were then taken, and the serum obtained was used to verify the fasting glucose concentration. Data were analyzed using SPSS software at a significance level of 0.05 using a one-way analysis of variance (ANOVA) and a generalized estimating equation (GEE). RESULTS: According to the GEE model results, the diazepam-tramadol and naloxone-diazepam-tramadol groups showed blood glucose levels five units higher than the tramadol group (p < 0.05). The diazepam-tramadol group had significantly higher blood glucose levels than the naloxone-tramadol group (p < 0.05). The mean blood glucose levels before the intervention, 3 hours and 6 hours after the injection of tramadol did not differ between the groups, but the blood glucose levels 1 hour after the injection of tramadol in the group of naloxone-tramadol were significantly lower than in the control group (p < 0.05). Blood glucose levels did not differ between the groups 24 h after injection of tramadol. CONCLUSION: The results of the present study showed tramadol overdose does not affect blood glucose levels. The diazepam-tramadol combination and the diazepam-naloxone-tramadol combination caused an increase in blood glucose levels.

The Effect of Cinnamaldehyde on iNOS Activity and NO-Induced Islet Insulin Secretion in High-Fat-Diet Rats.

INTRODUCTION: Obesity and insulin resistance are associated with alterations in nitric oxide level and insulin secretion. Previous studies demonstrated that cinnamaldehyde (CNMA) improved islet insulin secretion and restored nitric oxide (NO) level, but its underlying mechanisms have not been investigated. This study aimed to investigate the effect of CNMA on inducible nitric oxide synthase (iNOS) activity and NO-induced islet insulin secretion in high-fat-diet (HFD) treated rats. MATERIALS AND METHODS: Forty male Wistar rats (12 weeks old) were randomly divided into four equal groups, namely, control, CNMA, HFD, and HFD + CNMA. Control and CNMA groups were treated with standard laboratory animals' diet, while HFD and HDF + CNMA groups were fed with an HFD diet enriched with 25% W/W tail fat for 16 weeks. CNMA was administrated orally (20 mg/kg body weight, daily) during the study period. Islet insulin secretion and the inducible NOS activity in the presence or absence of L-NAME (NO synthase inhibitor, 5 mmol/L) were evaluated. RESULTS: L-NAME-suppressed insulin secretion in control, HFD, and HFD + CNMA groups; however, in the CNMA group, it could not exhibit such effect (P < 0.01). Islets of HFD-treated animals showed significantly higher iNOS activity than controls. CNMA treatment significantly suppressed iNOS activities in CNMA and HFD + CNMA groups compared with control and HFD, respectively. CONCLUSION: These results suggest that the beneficial effect of CNMA on insulin secretion might be due to its inhibitory effect on iNOS activity.

The effects of naloxone, diazepam, and quercetin on seizure and sedation in acute on chronic tramadol administration: an experimental study.

BACKGROUND: Tramadol is a widely used synthetic opioid. Substantial research has previously focused on the neurological effects of this drug, while the efficacy of various treatments to reduce the associated side effects has not been well studied. This study aimed to evaluate the protective effects of naloxone, diazepam, and quercetin on tramadol overdose-induced seizure and sedation level in male rats. METHODS: The project was performed with 72 male Wistar rats with an average weight of 200-250 g. The rats were randomly assigned to eight groups. Tramadol was administered intraperitoneally at an initial dose of 25 mg/kg/day. On the 14th day, tramadol was injected at 75 mg/kg, either alone or together with naloxone, diazepam, and quercetin (acute and chronic) individually or in combination. The rats were monitored for 6 h on the last day, and the number, the duration, and the severity of seizures (using the criteria of Racine) were measured over a 6-h observation period. The sedation level was also assessed based on a 4-point criterion, ranging from 0 to 3. Data were analyzed in SPSS software using Kruskal-Wallis, Chi-square, regression analysis, and generalized estimating equation (GEE) tests. The significance level was set at P < 0.05. RESULTS: The naloxone-diazepam combination reduced the number, severity, and cumulative duration of seizures compared to tramadol use alone and reduced the number of higher-intensity seizures (level 3, 4) to a greater extent than other treatments. Naloxone alone reduced the number and duration of seizures but increased the number of mild seizures (level 2). Diazepam decreased the severity and duration of seizures. However, it increased the number of mild seizures (level 2). In comparison with the tramadol alone group, the acute quercetin group exhibited higher numbers of mild (level 2) and moderate (level 3) seizures. Chronic quercetin administration significantly increased the number of mild seizures. In the GEE model, all groups had higher sedation levels than the saline only group (P < 0.001). None of the protocols had a significant effect on sedation levels compared to the tramadol group. CONCLUSION: The combined administration of naloxone and diazepam in acute-on-chronic tramadol poisoning can effectively reduce most seizure variables compared to tramadol use alone. However, none of the treatments improved sedation levels.

N-acetylcysteine dose-dependently improves the analgesic effect of acetaminophen on the rat hot plate test.

BACKGROUND: Acetaminophen (APAP) induced hepatotoxicity is a clinically important problem. Up to now, interventive therapy with n-acetylcysteine (NAC) has been considered as a gold-standard treatment for APAP overdose. However, no study has focused on the efficacy of these drugs' concurrent administration on probable enhancing therapeutic outcomes. Thus, this study was aimed to investigate the analgesic effect of co-administration of NAC and acetaminophen in male rats. The NAC-APAP drug formulation may demonstrate the stranger antinociceptive effect. METHODS: Forty-eight male Sprague-Dawley rats (12-14 weeks) randomly divided into six equal groups; control, APAP (received 300 mg/kg APAP), NAC (received 600 mg/kg NAC) and APAP+ NAC groups that received simultaneously 300 mg/kg APAP with 200-600 mg/kg NAC (AN200, AN400, AN600). All administrations were done orally for once. The antinociceptive effect was recorded by measurement of latency period on a hot plate in 30, 60, and 90 min after administrations. RESULTS: The results showed that NAC's concurrent administration with APAP, dose-dependently increased APAP analgesic effects (p< 0.0001). Moreover, NAC treatment exhibited an antinociceptive effect in 60 and 90 min, per se. The treatments had no adverse effect on liver enzymes and oxidative stress. CONCLUSION: Co-administration of NAC with APAP can improve the antinociceptive effect of APAP. It is suggested that this compound can enhance analgesic effects of APAP and eventually lead to a reduction in acetaminophen dose. Further studies are needed to evaluate the molecular mechanism of this hyper analgesic effect.

The effect of tramadol on blood glucose concentrations: a systematic review.

INTRODUCTION: Studies comprehensively summarizing the impact of tramadol use on glucose homeostasis are very sparse. Thus, the present study was performed to collect and summarize the latest information about this issue in a systematic way. AREAS COVERED: An exhaustive literature search was carried out using relevant keywords. Web of Sciences, PubMed, Scopus, and Google scholar were interrogated until 30 June 2019. Case-control, cohort, cross-sectional, clinical trial, case report, and animal studies that focused on the objective of the study were retrieved. This review summarizes the results of 761 papers on glycemic changes due to tramadol exposure. Thirty-six publications reported hypoglycemia and 17 hyperglycemia during tramadol use. Twenty-two studies either reported normal blood glucose concentrations, or did not observe any difference in the blood glucose levels following tramadol use. Finally, hypoglycemia was reported in diabetic individuals exposed to tramadol in 12 studies. EXPERT OPINION: The data suggest that primarily hypoglycemia but some degree of hyperglycemia has been reported with tramadol use. Importantly, all studies on tramadol use in diabetes reported hypoglycemia. Tramadol-induced hypoglycemia may be severe in some cases. The risk of alterations in glucose homeostasis accompanying tramadol exposure indicates time importance of careful blood glucose monitoring during tramadol use.

Effects of bentonite nanoparticles inhalation on lung tissue and blood antioxidant indices in a rat model.

Bentonite is an inorganic clay material that is often easily dispersed as fine particles by air and water circulation, and most people are exposed to different concentrations of bentonite particles. Therefore, the inhaled effects of bentonite nanoparticles (BNPs) were studied in Wistar rats. Seventy-five rats were divided into five groups of 15: four exposure groups (0.1, 0.5, 2, and 10 mg/m3 of BNPs) and one control group. The rats were exposed for 30, 60, and 90 days to BNPs for 5 days a week (6 h/day) in whole-body inhalation chambers. Blood samples were collected to measure the levels of antioxidant activity of the contents such as total antioxidant capacity (TAC) and malondialdehyde (MDA). X-ray diffraction and scanning electron microscopy were used to identify nanoparticles. The results showed no significant difference in the effect of nanoparticles on levels of TAC and MDA in the studied groups based on the concentrations of nanoparticles. However, the level of MDA increased significantly with extending exposure time; there was a significant increase in the level of MDA content 90 days postexposure compared to 30 days postexposure at concentrations of 0.5, 2, and 10 mg/m3. Histopathological examination showed that inhalation exposure of rats to BNPs led to different histopathologic responses in the lung tissue, such as inflammatory infiltration, granulomatous inflammation, acute neutrophilic reaction in the early stages, and lung fibrosis. At the lowest concentration, BNPs have low or no toxicity, and inhalation of these nanoparticles at low concentrations does not affect the levels of MDA and TAC content. However, increased concentration and exposure time caused correspondingly greater increases in MDA and more damage to lung tissue.

Tramadol and the occurrence of seizures: a systematic review and meta-analysis.

Introduction: Tramadol is a synthetic opioid which is commonly used around the world to relieve moderate to severe pain. One of the serious possible complications of its use is seizures. The present study aims to investigate and summarize the studies related to tramadol and occurrences of seizures after tramadol use and factors influencing these seizures.Methodology: Our systematic review is compliant with PRISMA guidelines. Two researchers systematically searched PubMed/Medline, Web of Sciences, and Scopus. Cohort, case-control, cross-sectional studies, and clinical trials. The risk of bias was assessed using the Newcastle-Ottawa Scale After article quality assessment, a fixed or random model, as appropriate, was used to pool the results in a meta-analysis. Heterogeneity between the studies was assessed with using I-square and Q-test. Forest plots demonstrating the point and pooled estimates were drawn.Results: A total of 51 articles with total sample size of 101 770 patients were included. The results showed that seizure event rate in the subgroups of tramadol poisoning, therapeutic dosage of tramadol, and tramadol abusers was 38% (95% CI: 27-49%), 3% (95% CI: 2-3%), 37% (95% CI: 12-62%), respectively. Tramadol dose was significantly higher in the patients with seizures than those without (mean differences: 0.82, CI 95%: 0.17-1.46). The odds for occurrence of seizures were significantly associated with male gender (pooled OR: 2.24, CI 95%: 1.80-2.77). Naloxone administration was not associated to the occurrence of seizures (pooled OR: 0.47, 95% CI: 0.15-1.49).Conclusions: Our results demonstrate that the occurrence of seizures in patients exposed to tramadol are dose-dependent and related to male gender, but not related to naloxone administration. Given that, most of the evidence derives from studies utilizing a cross-sectional design, the association of tramadol with seizures should not be considered to be definitively established.

Normal Insulin Secretion from Immune-Protected Islets of Langerhans by PEGylation and Encapsulation in the Alginate-Chitosan-PEG.

BACKGROUND: Pancreatic islet transplantation is one of the most promising strategies for treating patients with type I diabetes mellitus. OBJECTIVE: We aimed to assess the immunoisolation properties of the multilayer encapsulated islets using alginate-chitosan-PEG for immunoprotection and insulin secretion from the encapsulated islets induced under different glucose concentrations in vitro. MATERIALS AND METHODS: In this study, the islets were isolated from Wistar rats. The biological function (insulin secretion) of the immunoisolated islets following to PEGylation and encapsulation in the alginate-chitosan-PEG, separately, in addition to their immuno-protection in a co-culturing with the lymphocytes isolated from the male C57BL/6 mice were investigated, respectively. RESULTS: Alginate-chitosan-PEG decreased IL-2 secretion from the lymphocytes co-cultured with islets. Also, insulin secretion from the encapsulated and PEGylated groups was stimulated by glucose (i.e., 5.6 and 16.7 mM of glucose, respectively); showed insulin secretion similar to the naked islets, without coating, after 30 and 60 min of incubation. CONCLUSION: In conclusion, encapsulation and PEGylation have no negative effect on the insulin secretion and glucose sensitivity of the islets for all of the groups. Also, encapsulation decreased IL-2 secretion from the lymphocytes.

Nitrite increases glucose-stimulated insulin secretion and islet insulin content in obese type 2 diabetic male rats.

PURPOSE: Reduced bioavailability of nitric oxide (NO) is associated with pathogenesis of type 2 diabetes. Nitrite can act as a substrate for generation of systemic NO. The aim of this study was to examine the effects of nitrite administration on glucose-stimulated insulin secretion (GSIS) and islet insulin content in obese type 2 diabetic rats. METHODS: Male rats were divided into 4 groups: Control, control + nitrite, diabetes, and diabetes + nitrite. Sodium nitrite (50 mg/L in drinking water) was administered for 8 weeks. Diabetes was induced using high-fat diet and low-dose of streptozotocine. Serum levels of fasting glucose, insulin, and lipid profile were measured and the insulin resistance/sensitivity indices were calculated every 2 weeks. Glycated hemoglobin (HbA1C) was measured every month. At the end of the study, tissue levels of glucose transporter 4 (GLUT4) protein and serum interleukin-1 beta (IL-1ß) were measured as well as glucose and insulin tolerance test were done. GSIS from isolated pancreatic islets and islet insulin content were also determined. RESULTS: Nitrite administration significantly increased insulin secretion in both control and diabetic rats in presence of 16.7 mM glucose. Nitrite also significantly increased islet insulin content by 27% and 39% in both control and diabetic rats, respectively. Nitrite decreased elevated serum IL-1ß in diabetic rats (4.0 ± 0.2 vs. 2.9 ± 0.2 pg/mL, P = 0.001). In diabetic rats, nitrite also significantly increased tissue levels of GLUT4 by 22% and 26% in soleus muscle and epididymal adipose tissue, respectively. In addition, nitrite significantly improved glucose and insulin tolerance, insulin sensitivity, lipid profile, and decreased fasting glucose and insulin, but had no effect on HbA1C. CONCLUSIONS: Long-term nitrite administration increased both insulin secretion and insulin content in obese type 2 diabetic rats. In addition, nitrite therapy had favorable effects on glucose tolerance, insulin resistance, inflammation, and dyslipidemia in type 2 diabetic rats.

The beneficial in vitro effects of lovastatin and chelerythrine on relaxatory response to acetylcholine in the perfused mesentric bed isolated from diabetic rats.

Diabetes mellitus is associated with an increased risk of cardiovascular disease. Endothelial dysfunction (i.e. decreased endothelium-dependent vasorelaxation) plays a key role in the pathogenesis of diabetic vascular disease. The present study was undertaken to determine whether diabetes induced by streptozotocin alters mesenteric responses to vasodilators and, if so, to study the acute in vitro effects of lovastatin and chelerythrine. Endothelial function was assessed in constantly perfused preparation removed from rats, 12 weeks after treatment with either saline or streptozotocin (45 mg/kg, intraperitoneally). In pre-contracted mesenteric beds (with 100 microM phenylephrine) removed from diabetic rats, the concentration response curve to acetylcholine, but not to sodium nitroprusside, was significantly reduced. Perfusion with lovastatin (10 microM for 20 min) or chelerythrine (1 microM for 20 min) significantly improved the acetylcholine-mediated relaxation in preparations removed from diabetic but not control rats. Pre-incubation of tissue with N(G)-nitro-L-argenine methyl ester hydrochloride (10 microM for 20 min) inhibited the beneficial effect of lovastatin but not chelerythrine. Pre-treatment of tissue with indomethacin (10 microM for 20 min) did not modify the effects of lovastatin or chelerythrine on acetylcholine responses. The present results demonstrate that endothelial dysfunction induced by diabetes (in a resistant vasculature, such as rat mesenteric bed) may be improved by an acute exposure to either lovastatin or chelerythrine. Furthermore, our results suggest that the beneficial effect of lovastatin is mediated via the nitric oxide pathway.