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 Prevalence of Potential Drug-Drug Interactions in CKD-A Retrospective Observational Study of Cerrahpasa Nephrology Unit.

Background and Objectives: Chronic kidney disease (CKD) is usually linked with polypharmacy and patients are invariably at risk of complex medication regimens. The present study was designed to estimate the potential drug-drug interactions (pDDIs) through the prescription patterns provided to patients of the Nephrology Transplant Unit of Cerrahpasa Medical Faculty patients. Materials and Methods: 96 patients were included in the study. pDDIs among every combination of the prescribed drug were analyzed using the Thomson Reuters Micromedex. Results: We found 149 pDDIs making 2.16 interactions per prescription with incidence rates of 69.7%. Approximately 4.1% of interactions were of significant severity, 75.1% moderate severity, and 20.8% were classified as minor pDDIs. The most frequent interactions were found between iron and aluminum, calcium or magnesium-containing products (21.37%), calcium channel blockers and beta-blockers (8.96%); and aspirin and aluminum, calcium, or magnesium-containing products (7.58%). We identified 42 drug pairs with probability of clinical significance. The most commonly reported clinical outcomes of the pDDIs were hypo- or hypertension (39.24%), decreased drug efficacy (24.05%), and arrhythmia (9.49%). Aluminum, calcium, or magnesium-containing drug products (33.10%) constituted the primary class of drugs involved in interactions. Conclusions: This study showed pharmacodynamics (49%), pharmacokinetics (42.94%) interactions, polypharmacy and gender as determinant of pDDIs. A comprehensive multicenter research is required to decrease the morbidity and ease the state burden.

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.

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.

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.

Role of bombesin and cholecystokinin receptors in gastric injury induced by hemorrhagic shock in the rat.

Bombesin has been shown to have trophic effects on the gastrointestinal tissue. Bombesin has direct mitogenic effects besides stimulating release of gastric hormones. The aim of this study was to investigate the effect of bombesin in hemorrhagic shock-induced stress ulcers in rats, and the role of cholecystokinin (CCK) receptors in this activity. Hemorrhagic shock was created by withdrawing 3 ml blood/200 g b.w. of rats. At the end of the 1-hour hypovolemic shock period, histological analysis, gastric ulcer index, gastric myeloperoxidase activity and gastric protein oxidation levels were determined. When given before the hemorrhage, subcutaneous bombesin (10 microg/kg) reduced macroscopically gastric ulcer index (p < 0.05). Blockade of CCK-A receptors with intraperitoneal MK-329 (1 mg/kg) did not reverse bombesin-induced gastroprotection. Blockade of CCK-B receptors with intraperitoneal L-365,260 (25 mg/kg) reversed bombesin-induced gastroprotection. Blockade of the two receptors resulted in no gastroprotection at all. It is concluded that bombesin treatment attenuated hemorrhagic shock-induced stress ulcers in rats via CCK receptors.