Effect of sulfasalazine on endothelium-dependent vascular response by the activation of Nrf2 signalling pathway.

Background: Diabetes mellitus leads to endothelial dysfunction and accumulation of oxygen radicals. Sulfasalazine-induced Nrf2 activation reduces oxidative stress in vessels. Thus, in the present study, we investigated the effects of sulfasalazine on endothelial dysfunction induced by high glucose. We also ascribed the underlying mechanism involved in glucose-induced endothelial dysfunction. Methods: For this experiment we used 80 Wistar Albino rats thoracic aorta to calculate the dose response curve of noradrenaline and acetylcholine. Vessels were incubated in normal and high glucose for 2 h. To investigate glucose and sulfasalazine effects the vessels of the high glucose group were pre-treated with sulfasalazine (300 mM), JNK inhibitor (SP600125), and ERK inhibitor (U0126) for 30 min. The dose response curve was calculated through organ bath. The eNOS, TAS, TOS, and HO-1 levels were estimated by commercially available ELISA kits. Results: In the high glucose group, the Emax for contraction was significantly higher (p < 0.001), and Emax for relaxation was lower than that of control. These functional changes were parallel with the low levels of eNOS (p < 0.05). High glucose vessel treated with sulfasalazine showed low Emax value for contraction (p < 0.001) however, the Emax for relaxation was significantly high (p < 0.001) when compared to high glucose group. In the JNK group, Emax for contraction and relaxation was inhibited (p < 0.001) compared to sulfasalazine treated vessels. HO-1 enzyme levels were significantly low (p < 0.01) with sulfasalazine but higher with ERK inhibitor (p < 0.05). Conclusion: High glucose induced endothelial dysfunction and sulfasalazine reduced damage in high glucose vessels by activating eNOS, antioxidant effect through HO-1 enzymes and particularly inducing Nrf2 via the ERK and JNK pathways.

The Effects of Cannabinoid Agonist, Heat Shock Protein 90 and Nitric Oxide Synthase Inhibitors on Increasing IL-13 and IL-31 Levels in Chronic Pruritus.

BACKGROUND: Heat shock protein 90 (Hsp90) inhibitor and cannabinoid agonists ameliorate dry skin-induced chronic itch. We have recently reported that cannabinoids, hsp90 and nitric oxide (NO) are involved in dry skin-induced itch. Here, we investigated the contribution of the Th2 cell signaling pathway to the antipruritic effect of the hsp90 inhibitor 17-Alilamino-17-demethoxygeldanamycin (17-AAG), nitric oxide synthase (NOS) inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and cannabinoid agonist WIN 55,212-2 on a dry skin-induced scratch. METHODS: Dry skin-induced chronic itching was created by topical application of AEW (acetone/diethyl ether/water). WIN 55,212-2 (1 mg/kg, i.p.), L-NAME (1 mg/kg, i.p.) and increasing doses of 17-AAG (1, 3 and 5 mg/kg,i.p.) were administered to Balb/c mice (for each group, n = 6). After these applications, skin tissues were taken from the nape region of all of the mice. Gene and protein expressions of IL-13 and IL-31 were evaluated in skin tissues by RT-PCR and immunohistochemistry, respectively. RESULTS: IL-13 and IL-31 mRNA expressions and immune positive cell counts were increased in the AEW applied groups. WIN 55,212-2 reduced both of the increased cytokines levels, while L-NAME decreased only the IL-13. 17-AAG dose-dependently reduced the increased cytokine levels. IL-13 and IL-31 levels significantly decreased following the co-administration of these agents. CONCLUSION: These results show that increased levels of IL-13 and IL-31 are associated with pruritus. Hsp90 inhibition and cannabinoid system activation may induce antipruritic effects through down-regulation of these cytokines.

Topical application of metformin accelerates cutaneous wound healing in streptozotocin-induced diabetic rats.

BACKGROUND: Diabetic chronic wound, which is one of the diabetic complications caused by hyperglycemia, characterized by prolonged inflammation has become one of the most serious challenges in the clinic. Hyperglycemia during diabetes not only causes prolonged inflammation and delayed wound healing but also modulates the activation of nuclear factor-kappa B (NF-κB) and the expression of matrix metalloproteinases (MMPs). Although metformin is the oldest oral antihyperglycemic drug commonly used for treating type 2 diabetes, few studies have explored the molecular mechanism of its topical effect on wound healing. Therefore, we aimed to investigate the molecular effects of topical metformin application on delayed wound healing, which's common in diabetes. METHODS AND RESULTS: In this context, we created a full-thickness excisional wound model in Wistar albino rats and, investigated NF-κB p65 DNA-binding activity and expression levels of RELA (p65), MMP2 and MMP9 in wound samples taken on days 0, 3, 7, and 14 from diabetic/non-diabetic rats treated with metformin and saline. As a result of our study, we showed that topically applied metformin accelerates wound healing by suppressing NF-κB p65 activity and diminishing the expression of MMP2 and MMP9. CONCLUSIONS: Diabetic wounds treated with metformin healed even faster than those in the control group that mimicked standard wound healing.

The Effects of the Heat Shock Protein 90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin, Cannabinoid Agonist WIN 55,212-2, and Nitric Oxide Synthase Inhibitor Nω-Nitro-L-Arginine Methyl Ester Hydrochloride on the Serotonin and Dry Skin-Induced Itch.

INTRODUCTION: In many types of itch, the interaction between immune system cells, keratinocytes, and sensory nerves involved in the transmission of itch is quite complex. Especially for patients with chronic itching, current treatments are insufficient, and their quality of life deteriorates significantly. OBJECTIVE: In this study, we aimed to investigate the role of the heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), cannabinoid agonist WIN 55,212-2, and nitric oxide (NO) synthase inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) in pruritus. METHODS: We created a serotonin (5-HT)-induced (50 µg/µL/mouse, i.d.) acute and acetone-ether-water (AEW)-induced chronic itching models. 17-AAG (1, 3, and 5 mg/kg, intraperitoneally [i.p.]), WIN 55,212-2 (1 mg/kg, i.p.), and L-NAME (1 mg/kg, i.p.) were applied to Balb/c mice. RESULTS: We found that 17-AAG suppressed the scratches of mice, depending on the dose. The itch behavior was reduced by WIN 55,212-2, but L-NAME showed no antipruritic effect at the administered dose. The combined application of these agents in both pruritus models showed synergism in terms of the antipruritic effect. Our results showed that NO did not play a role in the antipruritic effect of WIN 55,212-2 and 17-AAG. Increased plasma IgE levels with AEW treatment decreased with the administration of 17-AAG (5 mg/kg, i.p.) and WIN 55,212-2. CONCLUSION: These results demonstrate that Hsp90 may play a role in the peripheral pathway of pruritus, and cannabinoid agonists and Hsp90 inhibitors can be used together in the treatment of pruritus.

The Anti-Inflammatory Effects of Anacardic Acid on a TNF-α - Induced Human Saphenous Vein Endothelial Cell Culture Model.

BACKGROUND AND OBJECTIVE: Coronary bypass operations are commonly performed for the treatment of ischemic heart diseases. Coronary artery bypass surgery with autologous human saphenous vein maintains its importance as a commonly used therapy for advanced atherosclerosis. Vascular inflammation-related intimal hyperplasia and atherosclerotic progress have major roles in the pathogenesis of saphenous vein graft disease. METHODS: In our study, we investigated the effect of anacardic acid (AA), which is a bioactive phytochemical in the shell of Anacardium occidentale, on atherosclerosis considering its inhibitory effect on NF-κB. We observed relative ICAM-1 and NF-κB mRNA levels by qRT-PCR method in a TNF-α- induced inflammation model of saphenous vein endothelial cell culture after 0.1, 0.5, 1 and 5 µM of AA were applied to the cells. In addition, protein levels of ICAM-1 and NF-κB were evaluated by immunofluorescent staining. The results were compared between different concentrations of AA, and also with the control group. RESULTS: It was found that 5 µM, 1 µM and 0.5 µM of AA had toxic effects, while cytotoxicity decreased when 0.1 µM of AA was applied both alone and with TNF-α. When AA was applied with TNF-α, there was a decrease and suppression in NF-κB expression compared with the TNF-α group. TNF-α-induced ICAM-1 expression was significantly reduced more in the AA-applied group than in the TNF-α group. CONCLUSION: In accordance with our results, it can be said that AA has a protective role in the pathogenesis of atherosclerosis and hence in saphenous vein graft disease.

The Effects of Pitavastatin on Nuclear Factor-Kappa B and ICAM-1 in Human Saphenous Vein Graft Endothelial Culture.

OBJECTIVE: To study pitavastatin's effects on nuclear factor-kappa B (NF-κB ) and adhesion molecules in human saphenous vein graft endothelial culture indicating its pleotropic properties. MATERIALS AND METHOD: Low-dose (0.1 µM/L) and high-dose (1µM/L) pitavastatin calcium were administered as a frontline therapy in human saphenous endothelial cell culture, followed by induction of inflammation by TNF-α and determination of mRNA level alterations of ICAM-1 and NF-κB genes of endothelial cells using the qRT-PCR method. Additionally, immunofluorescence method was used to show the expression of NF-κB and ICAM-1. Finally, LDH levels were determined by the ELISA method to quantify cytotoxicity. RESULTS: ICAM-1 mRNA expression in the low-dose pitavastatin+TNF-α group was significantly higher than that in the TNF-α group and significantly lower than that in the high-dose pitavastatin+TNF-α group (for all comparisons, P = 0.001). The low-dose pitavastatin+TNF-α group had a similar NF-κB mRNA expression with TNF-α and high-dose pitavastatin+TNF-α groups. CONCLUSION: Pitavastatin increases ICAM-1 mRNA expression in saphenous vein endothelial cells. Furthermore, the effect of pitavastatin on adhesion molecules appears independent of NF-κB. Novel studies are needed in this field.

Receptor for advanced glycation end products gene polymorphisms in cardiac syndrome X.

Endothelial and microvascular dysfunction serve important roles in the formation and pathogenesis of cardiac syndrome X (CSX). Expression of receptor for advanced glycation end products (RAGE) is suggested to be increased in several conditions, including diabetes, inflammation and vascular diseases. In the present study, RAGE gene polymorphisms in patients with CSX and healthy controls were investigated. A total of 114 patients, diagnosed with CSX using coronary angiography results following complaints of angina and objective ischemia, and 103 healthy controls participated in the study. Whether there was a difference in genotype distributions of RAGE gene -374T/A, -429T/C and Glys82Ser polymorphisms between patients with CSX and healthy controls was investigated. Following DNA isolation from blood samples of the participants, the polymorphic regions were examined by quantitative polymerase chain reaction, and the genotyping results were statistically analyzed. When the genotypic distributions of -374T/A, -429T/C and Gly82Ser polymorphisms were investigated in patients with CSX and healthy controls, no statistically significant differences were identified between the two groups (P>0.05). Likewise, no statistically significant differences were observed in the allelic distributions of all 3 polymorphic regions (P>0.05). To the best of our knowledge, the present study also investigated the association between CSX and RAGE gene polymorphisms for the first time. No statistically significant differences in RAGE gene polymorphisms between the CSX and control groups were observed. We hypothesized that significant results may be obtained by increasing the numbers of patients and healthy controls in future studies.

Investigation of MTHFR gene C677T polymorphism in cardiac syndrome X patients.

BACKGROUND: Definition of Cardiac Syndrome X (CSX) refers to groups of patients with positive exercise stress test and normal epicardial coronary arteries on coronary angiography accompanied by chest pain. Although the etiology of CSX is not completely understood, there is a common consensus that its pathophysiology may be associated with endothelial dysfunction resulting in impaired coronary flow. Some polymorphisms observed on the MTHFR gene cause inactivation of the MTHFR enzyme, leading to hyperhomocysteinemia and homocysteinuria, which are prominent risk factors of cardiovascular and cerebrovascular diseases. It was aimed to explain the association of the endothelial dysfunction, which is thought to play a role in the pathophysiology of CSX, with C677T polymorphism on MTHFR gene based on genetic basis. METHODS: A total of 176 CSX patients and 196 healthy subjects with similar age and clinical features were compared in terms of C677T polymorphism of the MTHFR gene. RESULTS AND CONCLUSION: There was no significant difference in terms of MTHFR gene C677T polymorphism between CSX patients and controls. When genotypic distribution was compared based on gender in both patients and controls, no significant difference was found between male and female subjects (P>.05). As fasting blood sugar and urea values were significantly higher, alanine aminotransferase and gamma-glutamyl transferase levels were significantly lower in the patients than the controls (P<.05). Described family story of the patients was significantly higher than the controls (P<.05). These suggest that homocysteine metabolism in CSX is not directly related to the endothelial dysfunction and thus the effect on the microvascular circulation.

Plasma Betatrophin Levels of Subjects Classified with Normal, Impaired, and Diabetic Glucose Tolerance, and Subjects with Impaired Fasting Glucose.

This study was aimed to investigate whether betatrophin shows glucose intolerance or not. To access the plasma betatrophin levels after basal and glucose load, groups were classified as normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetic glucose tolerance (DGT) according to WHO 2012 criteria. An oral glucose tolerance test was performed on age-matched subjects (n=220) with a body mass index (BMI)<27 kg/m2. Subjects were categorized as normoglycemic (n=55), IFG (n=50), IGT (n=60), and DM (n=55) according to the WHO criteria. Baseline betatrophin levels in DGT are significantly higher than in NGT (p<0.005), IFG (p<0.004), and IGT (p<0.001). Male subjects have significantly higher betatrophin levels than female subjects (p<0.01). In DGT, betatrophin of male subjects was found to be significantly higher than the betatrophin of male subjects in NGT (p<0.04), IFG (p<0.01), and IGT (p<0.01). Significant relationship between betatrophin and both ages and HbA1c in all groups were observed. When ages were accepted as an independent factor, significant correlation between betatrophin and ages were found. Betatrophin is increased and associated with age and HbA1c in DGT. Males had higher betatrophin levels compared with females in DGT group. As no obvious betatrophin deficiency to substitute in IFG and IGT individuals were observed, betatrophin levels appeared to be related to the pathogenesis of the diabetic stages rather than prediabetic stages.

The Effects of Potassium Channels in Human Internal Mammary Artery.

BACKGROUND: Structural and functional changes in potassium channels of vascular smooth muscle cells may contribute to the development of diseases such as hypertension. We aim to investigate the vascular effects of potassium channel openers and blockers in human internal mammary artery (HIMA). METHODS: Remaining segments of HIMA from 18 consecutive patients undergoing coronary artery bypass surgery were obtained to examine the vascular effects of various potassium channel openers (staurosporine, hydrochlorothiazide and cromakalim) and potassium channel blockers (4-aminopyridin [4-AP], charybdotoxin [CTX] and glibenclamide [GLBC]). RESULTS: Noradrenaline (NA)-induced maximal contractions were inhibited by all 3 K+-channel blockers but only fully inhibited by 4-AP (95.6%). Only NA-induced contractions were reversed by CTX. Only K+-induced maximal contractions were significantly inhibited by 4-AP (95.6%, p < 0.05). Only acetylcholine-induced relaxation was fully inhibited by CTX. Only sodium nitroprusside-induced relaxations in potassium chloride-precontracted strips could be reversed by GLBC. CONCLUSIONS: Drugs affecting potassium channels may be useful in the treatment of hypertension and management of perioperative vasospasm during the coronary artery bypass surgery.

Does Inflammation Have a Role in the Pathogenesis of Cardiac Syndrome X? A Genetic-Based Clinical Study With Assessment of Multiple Cytokine Levels.

We compared Turkish patients with cardiac syndrome X (CSX) and controls with respect to serum pro- and anti-inflammatory cytokine levels, as well as the single-nucleotide polymorphisms located in the promoter regions of their related genes. This study included 111 consecutive patients angiographically diagnosed with CSX and 111 healthy controls with similar demographic characteristics. Serum interleukin (IL) 6, tumor necrosis factor α (TNF-α), and IL-10 levels were measured, and the genotypes of the patients and controls were determined using standard methods. Serum IL-6 and IL-10 levels were significantly higher in the CSX group than in the control group (P < .01, respectively). Serum TNF-α level was lower in the CSX group than in the control group (P < .001). On the other hand, participants with CSX and healthy controls were not significantly different with respect to the genotype distributions of IL-6, TNF-α, and IL-10 genes. As a result of our study, both pro-inflammatory and anti-inflammatory cytokines may play a role in the pathogenesis of CSX. In contrast, the studied gene polymorphisms did not influence CSX pathogenesis.

Δ9-tetrahydrocannabinol treatment improved endothelium-dependent relaxation on streptozotocin/nicotinamide-induced diabetic rat aorta.

OBJECTIVE: In this study, we investigated the possible effect of Δ(9)-tetrahydrocannabinol (THC), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, on metabolic control and vascular complications of diabetes in streptozotocin/nicotinamide (STZ/NIC) induced type 2 diabetes mellitus. MATERIAL AND METHODS: Type 2 diabetes was induced with 65 mg/kg STZ, 15 minute later 85 mg/kg NIC was given intraperitoneally (i.p.) to rats. Three days after diabetes induction, THC (3 mg/kg/day, i.p.) was given for 7 days to diabetic rats. Body weight and plasma glucose levels of rats were measured in all groups before and at the end of 3 weeks after diabetes induction. Acetylcholine (Ach) and sodium nitroprusside (SNP) potency and maximum relaxant effects were calculated on aortic rings pre-contracted with noradrenaline (NA). RESULTS: At the end of 3 weeks, blood glucose levels of diabetic group significantly increased in comparison with the control group. Increased plasma glucose levels were significantly decreased by the treatment of THC. Ach induced relaxation was impaired whereas endothelium-independent relaxation to SNP was unaffected on isolated diabetic rat aorta. THC treatment enhanced Ach induced relaxation on diabetic rat aortas. DISCUSSION: These results suggested that THC improved endothelium-dependent relaxation in STZ/NIC induced diabetic rat aorta and that these effects were mediated at least in part, by control of hyperglycemia and enhanced endothelial nitric oxide bioavailability.

Elevated serum gamma-glutamyltransferase levels in patients with dilated ascending aorta.

OBJECTIVE: This study aimed to evaluate the serum gamma-glutamyltransferase (GGT) levels as an indirect marker of elevated oxidative stress in patients with dilated ascending aorta. METHODS: The study was designed as an observational cross-sectional controlled study. One hundred consecutive patients with dilated ascending aorta and 50 consecutive controls with normal ascending aorta diameter were selected for the study by comprehensive transthoracic echocardiography (TTE). The aortic dilatation group was divided into two subgroups, according to the literature as the ectasia group (3.8-4.3 cm, 53 patients, 24 male and 29 female, mean age: 62.9±10.9 years) and the aneurysm group (≥4.4 cm, 47 patients, 18 male and 29 female, mean age: 65.5±11.1 years). The control group consisted of patients demonstrating no ascending aorta dilatation (≤3.7 cm, 50 patients, 24 male and 26 female, mean age: 62.7±9.2 years). ANOVA, Mann-Whitney U test, Pearson's correlation analysis, multivariate logistic regression analysis, and receiver-operator curve analysis were used for statistical analysis. RESULTS: Regarding the comparison of laboratory parameters between the patient and control groups, serum gamma-glutamyltransferase (GGT) levels were found to be statistically significantly higher in both of the aortic dilatation subgroups than in the control group (p<0.001). In the correlation analysis between the ascending aorta diameter and GGT, a statistically significant positive correlation was found (r=0.282, p<0.001). The multivariate regression analysis revealed a significant relationship between GGT and the proximal ascending aorta diameter (ß=0.131, odds ratio: 1.140, 95% CI: 1.060-1.225, p<0.001). CONCLUSION: GGT as a marker of oxidative stress may play a role in the pathogenesis of aneurysm of the ascending aorta.

Lectin-like oxidised LDL receptor-1 as a marker of endothelial dysfunction in Behçet's disease.

OBJECTIVES: The aim of this study was to examine the distribution of lectin-like oxidised LDL receptor-1 (LOX-1) levels in patients with active BD, possible association of LOX-1 with the oxidised LDL (oxLDL), endothelial nitric oxide synthase (eNOS), nitric oxide (NO), endothelin-1 (ET-1) levels, and to characterise the differences between patients with active BD and those with systemic lupus erythematosus( SLE) in terms of these parameters compared with healthy controls. METHODS: A total of 30 patients with active BD, 22 patients with SLE as patients controls, and 30 healthy subjects were enrolled in this study. RESULTS: Significantly lower eNOS ve NO levels were observed in patients with BD and SLE compared with healthy controls. oxLDL, LOX-1 ve ET-1 levels were significantly increased in active periods of patients with BD and SLE compared with healthy control. There was no significant difference in oxLDL levels between subjects with BD and SLE. LOX-1 levels were significantly higher in active periods of patients with BD than in SLE , ET-1 levels were significantly lower. CONCLUSIONS: Endothelial dysfunction parameters are elevated in patients with BD having active disease. The necessary measures should be considered in terms of risk of atherosclerosis in BD, especially for the early identification of endothelial damage by looking at LOX-1 levels.

The effects of alpha lipoic acid on liver cells damages and apoptosis induced by polyunsaturated fatty acids.

We studied the effect of alpha-lipoic acid (ALA) on the liver cell damages and apoptosis by n-6 polyunsaturated fatty acids (PUFA) rich diet in young rats. 24 Wistar rats were divided into four groups. During the study, 12 of them (control) were fed with standard chow and other 12 (n-6) were fed with the food containing high-fat n-6 for 8 weeks. At the end of the fourth week, control and n-6 groups were randomly divided into two groups and then, 4 weeks, 35 mg/kg ALA are injected. Groups; control, control+ALA, n-6, n-6+ALA. The liver tissue glutathione (GSH) activity was determined. Immunohistochemistry for caspase-3 and TUNEL method for apoptosis were performed. The GSH levels have significantly decreased (p<0,001), and vacuolization in the hepatocytes, infiltration and the collagen accumulation around the central vein, hepatic stellate cells in the sinusoids have increased in n-6 group compared with the other groups. TUNEL (p<0,001) and caspase-3 (p<0,001) positive cells increased in n-6 group whereas all degenerative observations decreased in n-6+ALA group. Our results demonstrate that the feeding with n-6 PUFA causes fatty liver, fibrosis development, inflammations and apoptosis in the liver of young rats. ALA has a beneficial effects on these degenerative effects.

Association of serum fetuin-A levels with heart valve calcification and other biomarkers of inflammation among persons with acute coronary syndrome.

PURPOSE: Fetuin-A is a multifunctional hepatic secretory protein that inhibits dystrophic vascular and valvular calcification. Our aim was to evaluate the relationship among fetuin-A levels, heart valve calcification and other biomarkers of inflammation in patients with acute coronary syndrome (ACS). METHODS: The associations among serum fetuin-A concentrations, mitral annular (MAC) and aortic valve calcification and other biomarkers of inflammation (hs-CRP, ferritin, fibrinogen, white blood cell count (WBC), erythrocyte sedimentation rate (ESR), albumin levels) were evaluated in ACS patients and healthy controls. The study included 95 patients (mean age 61.8 ± 12.10 years) and 81 healthy controls (mean age 48.33 ± 9.19 years). RESULTS: Fetuin-A levels were significantly lower in patients with ACS than in healthy controls (0.76 ± 0.23 and 1.10 ± 0.45 g/L, respectively; p < 0.001). Fetuin-A was lower in patients with mitral annular calcification (p = 0.007) and aortic (p = 0.001) valve calcification. In patients with ACS, there was a negative correlation among serum urea (r = -0.377; p < 0.001) and creatinine (r = -0.232; p = 0.024) levels and fetuin-A, and a negative correlation among WBC (r = -0.156; p = 0,132), ESR (r = -0.214; p = 0.037), hs-CRP (r = -0.220; p = 0.032) levels and fetuin-A. A positive correlation was seen between albumin and fetuin-A (r = 0.362; p < 0.001). Multivariate logistic regression analysis revealed that fetuin-A was the variable that had a significant effect on ACS (p = 0.020 OR = .015; (95% CI)(0.000-0.520). CONCLUSION: Fetuin-A levels decrease in patients with acute coronary syndromes, independent of heart valve calcification. Fetuin-A may therefore act as a negative acute phase protein after myocardial infarction.

The in vitro effects of iloprost with other vasodilators on the human internal thoracic artery.

PURPOSE: We aimed (a) to analyze the effects of iloprost as a vasodilator on the human internal thoracic artery (ITA) and (b) to compare these effects with the effects of other vasodilators now being used in the clinic. METHODS: Following transfer into only Krebs solution or into Krebs solution containing papaverine or iloprost, human ITA strips were then incubated only in Krebs or in Krebs with vasodilators that are generally used in clinical practice, such as diltiazem or glyceryl trinitrate. Cumulative concentration-contraction curves for noradrenaline (NA) and KCl were then established for these strips. Student's t-test and one-way analysis of variance followed by Tukey-Kramer tests were used to compare differences between groups. A p <0.05 was used to indicate significance. RESULTS: Among the transfer solutions, papaverine (6.50 ± 0.20) and iloprost (7.33 ± 0.13) were significantly more potent than Krebs (8.46 ± 0.75, p <0.001 and p <0.05) with regard to preventive effect on precontracted ITA with NA. Iloprost significantly relaxed the NA-induced precontracted ITA strips in the Krebs, papaverine, and iloprost groups. Diltiazem significantly relaxed the precontracted ITA with KCl in all storage groups. CONCLUSION: Iloprost may also prevent perioperative ITA spasm, but should be tested in the clinical setting.

Effect of glucagon-like peptide-1(7-36) and exendin-4 on the vascular reactivity in streptozotocin/nicotinamide-induced diabetic rats.

We investigated the vascular effects of glucagon-like peptide-1 (GLP-1) and Exendin-4 in type 2 diabetic rat aortae. Studies were performed in a normal control group (NC) (0.2 ml i.p. saline, n = 10), streptozotocin (STZ)/nicotinamide diabetic control group (DC) (a single dose of 80 mg/kg STZ i.p. injection 15 min after administration of 230 mg/kg nicotinamide i.p.), GLP-1 (GLPC) control group (1 microg/kg twice daily i.p. for 1 month, n = 10), Exendin-4 control group (EXC) (0.1 microg/kg twice daily i.p. for 1 month, n = 10), GLP-1-treated diabetic group (GLPT) (1 microg/kg twice daily i.p. for 1 month, n = 10), and Exendin-4-treated diabetic group (EXT) (0.1 microg/kg twice daily i.p. for 1 month, n = 10). One month of GLP-1 and Exendin-4 treatment significantly decreased the blood glucose levels of diabetic rats (113 +/- 2 mg/dl, p < 0.001, and 117 +/- 1 mg/dl, p < 0.001, respectively versus 181 +/- 9 mg/dl in the DC group). Sensitivity (pD2) and maximum response (% Max. Relax) of acetylcholine-stimulated relaxations in the DC group (pD2: 6.73 +/- 0.12 and 55 +/- 6, respectively) were decreased compared with the non-diabetic NC group (pD2: 7.41 +/- 0.25, p < 0.05, and 87 +/- 4, p < 0.01). Treating diabetic rats with GLP-1, pD2 values and with Exendin-4, Max. Relax %values of aortic strips to acetylcholine returned to near non-diabetic NC values (pD2: 7.47 +/- 0.15, p < 0.05, and 87 +/- 3, p < 0.01, respectively). Maximal contractile responses (Emax) to noradrenaline in aortic strips from the diabetic DC group (341 +/- 27 mg tension/mg wet weight) were significantly decreased compared with the non-diabetic NC (540 +/- 66 mg tension/mg wet weight, p < 0.001) and the GLPT group (490 +/- 25 mg tension/mg wet weight, p < 0.05). There were no significant differences in pD2 values of aortic strips to noradrenaline from all groups. Emax to KCl in aortic strips from the DC group (247 +/- 10 mg tension/mg wet weight, p < 0.01) was significantly decreased compared with non-diabetic NC group (327 +/- 26 mg tension/mg wet weight). Treating diabetic rats with GLP-1 (GLPT), Emax values of aortic strips to KCl returned to near non-diabetic NC values (271 +/- 12 mg tension/mg wet weight). GLP-1 and (partially) Exendin-4 treatment could improve the increased blood glucose level and normalize the altered vascular tone in type 2 diabetic rats.

What are the reactivities of coronary arteries harvested from the hearts exposed to cold ischemic preservation?

This study was designed to determine the effects of pretransplant ischemic hypothermic period on reactivities of major coronary arteries. Eleven pigs were used. Right, left anterior descending and circumflex coronary arteries harvested from 6 pigs following single dose of cardioplegia and cardiectomy. The same procedures were performed in 5 pigs after 6 hours static 4 degrees C hypothermic preservation of the hearts. Strips prepared from these 3 coronary arteries were placed in organ chambers and contractions with acetylcholine and histamine and KCL and dilatations with noradrenaline following submaximal contractions with acetylcholine and histamine were documented. There was no statistically significant difference between results taken from both groups. The pretransplant period (until 6 hours) does not cause important differences on the reactivities of coronary arteries.

Low-cost antibiotic loaded systems for developing countries.

Treatment of osteomyelitis with local antibiotic delivery systems has become a common practice in orthopaedic surgery. This study attempted to show that locally produced pure or bioglass reinforced plaster of Paris, hydroxyapatite and sodium alginate are promising biomaterials and mainly because of economical reasons and availability, may be an alternative in clinical practice, especially for developing countries. A total of 32 rabbits were divided into four groups (n:8). In group A, sodium alginate + cephazoline; in group B, plaster of Paris + bioglass + cephazoline; in group C, plaster of Paris + hydroxyapatite + cephazoline and in group D, plaster of Paris + cephazoline were used. The blood serum cephazoline concentrations were analyzed by high performance liquid chromatography on days 1 to 10 everyday and then at days 13, 17, 18, 24, 25 and 30. The mean values +/- standard deviations and median values of blood serum antibiotic concentrations for groups A, B, C and D were 1.45 +/- 0.40 (1.42) mcg/ml, 1.53 +/- 0.64 (1.31) mcg/ml, 1.92 +/- 0.39 mcg/ml (1.90) and 1.41 +/- 0.65 (1.25) mcg/ml, respectively. The detected antibiotic level was constantly over the minimum inhibitory concentration for Staphylococcus aureus. In conclusion, it can be stated that these materials are promising as a antibiotic delivery system even with simple production methods.