Central Administration of Hydrogen Sulfide Donor NaHS Reduces Iba1-Positive Cells in the PVN and Attenuates Rodent Angiotensin II Hypertension.

Hydrogen sulfide (H2S) is a gaseous signaling molecule with neuromodulatory, anti-inflammatory, and anti-hypertensive effects. Here, we investigate whether chronic intracerebroventricular (ICV) infusion of sodium hydrosulfide (NaHS), an H2S donor, can alleviate angiotensin II (Ang II)-induced hypertension (HTN), improve autonomic function, and impact microglia in the paraventricular nucleus (PVN) of the hypothalamus, a brain region associated with autonomic control of blood pressure (BP) and neuroinflammation in HTN. Chronic delivery of Ang II (200 ng/kg/min, subcutaneous) for 4 weeks produced a typical increase in BP and sympathetic drive and elevated the number of ionized calcium binding adaptor molecule 1-positive (Iba1+) cells in the PVN of male, Sprague-Dawley rats. ICV co-infusion of NaHS (at 30 and/or 60 nmol/h) significantly attenuated these effects of Ang II. Ang II also increased the abundance of cecal Deltaproteobacteria and Desulfovibrionales, among others, which was prevented by ICV NaHS co-infusion at 30 and 60 nmol/h. We observed no differences in circulating H2S between the groups. Our results suggest that central H2S may alleviate rodent HTN independently from circulating H2S via effects on autonomic nervous system and PVN microglia.

The Frequency of Metabolic Syndrome and Serum Osteopontin Levels in Survivors of Childhood Acute Lymphoblastic Leukemia.

PURPOSE: Metabolic syndrome (MetS) and obesity have increasingly been reported in survivors of childhood cancer. Osteopontin (OPN) is primarily synthesized in adipose tissue and is thought to have a role in obesity and the development of insulin resistance (IR). The aim of this study was to investigate the frequency of MetS in survivors of acute lymphoblastic leukemia (ALL) and to establish the relationship between serum OPN levels and anthropometric measurements and glucose metabolism. METHODS: A total 50 survivors of ALL (median age: 10.5 years; post-treatment interval 4.54 ± 2.48 years), and 20 healthy children (median age: 11 years) were included in the study. Anthropometric measurements were taken, and serum glucose, insulin, homeostasis model assessment and IR index (HOMA-IR index), lipoprotein, thyroid hormone levels, and OPN levels were measured. RESULTS: Twenty-one (42%) survivors were overweight/obese, 2 (5.1%) survivors had MetS, 7 (14%) survivors had IR, and 19 (38%) survivors had dyslipidemia. Fasting insulin levels and HOMA-IR of the overweight/obese survivors were significantly higher than those of the normal-weight survivors (p < 0.05 and p < 0.01) and control group (p < 0.01 and p < 0.01). The serum OPN level was significantly lower in the overweight/obese survivor than in the normal-weight survivor and control group (37.42 ng/mL [range, 27.32-62.07], 69.02 ng/mL [range, 40.29-88.21], and 85.7 ng/mL [range 67.7-102.3]; p < 0.01, p < 0.001, respectively). Serum OPN levels were inversely correlated with anthropometric measurements and HOMA-IR index in all the subjects. CONCLUSION: Our results showed that obesity and IR are associated with decreased serum OPN levels in childhood survivors of ALL.

Functional Effects of Alagebrium (ALT-711)-Isolated Rat Carotid Artery.

OBJECTIVE: In our study, the effects of glycosylated protein cross-link breaker, alagebrium was investigated on isolated rat carotid artery using myography. Alagebrium showed vasodilator effect on carotid artery rings; particularly, this effect was significantly increased in endothelium-intact rings. MATERIALS AND METHODS: To clarify the vasodilator mechanism of alagebrium, different antagonists such as N(G)-Nitro-L-arginine methyl ester (L-NAME), glibenclamide, indomethacin, metoprolol, propranolol, tetraethylammonium, and calcium channel activator BAYK-8644 were used to reverse this effect. RESULTS: Relaxation% responses to alagebrium were more significantly increased in intact endothelium than in denuded arteries. Blocking vasodilation related to channels (K-ATP, PGI2, BKca) and receptors (ß1, ß2) did not reverse the relaxation response to alagebrium. Vasodilator response to alagebrium was only slightly decreased after L-NAME incubation and significantly decreased after BAYK-8644 incubation. CONCLUSION: Results of present study suggest that the mechanism of alagebrium-induced vasodilator effect may include the blockage of L-type calcium channels and partially of the nitric oxide synthase enzyme.

Effect of vitamin D supplementation on endothelial dysfunction in hemodialysis patients.

INTRODUCTION: Patients with chronic kidney disease (CKD) commonly experience 25-hydroxyvitamin D3 (25-OH-D3) deficiency, and these patients have a higher incidence of cardiovascular diseases (CVDs) due to endothelial dysfunction (ED). The aim of our study was to investigate the effect of 25-OH-D3 deficiency and its supplementation on ED in patients with CKD. METHODS: Twenty-nine uremic patients on dialysis and 20 healthy controls were evaluated for ED by high-resolution Doppler ultrasonography of the brachial artery. In addition, 25-OH-D3-deficient patients (25-OH-D3 < 30 nmol/L) with CKD and healthy controls were evaluated for ED before and after 8 weeks of oral vitamin D (cholecalciferol, 50,000 units) treatment. All subjects were evaluated for percent flow-mediated dilatation (%FMD), percent endothelium-independent nitroglycerin-induced vasodilatation (%NID), and bilateral carotid intima-media thickness (CIMT). FINDINGS: Patients on dialysis had lower %FMD and %NID 6.11 [2.27-12.74] and 10.96 [5.43-16.4], respectively, than controls 15.84 [8.19-22.49] and 21.74 [12.49-29.4], respectively (P < 0.05). Patients on dialysis had higher left and right CIMT (0.79 ± 0.15 and 0.78 ± 0.14, respectively) than controls (0.60 ± 0.09 and 0.59 ± 0.09, respectively; P < 0.05). In 25-OH-D3-deficient patients with CKD, after vitamin D treatment, %FMD was significantly increased in dialysis patients (10.25 [7.8-12.8]) compared to before supplementation (5.4 [2.77-6.15]; P < 0.001). DISCUSSION: These results indicated that dialysis patients had significantly lower blood 25-OH-D3 levels and higher CIMT than healthy subjects. In addition, vitamin D supplementation improved ED and increased %FMD in dialysis patients. Our findings suggest that vitamin D supplementation in dialysis patients might prevent CVD.

Matrix metalloproteinases are possible targets in monocrotaline-induced pulmonary hypertension: investigation of anti-remodeling effects of alagebrium and everolimus.

OBJECTIVE: In our study, sildenafil alone and everolimus or alagebrium in combination with sildenafil were investigated in terms of their additional therapeutic and anti-remodeling activity in monocrotaline-induced pulmonary hypertension (PH) model in rats. In particular, the inter-relationships between PH and matrix metalloproteinases (MMPs) were investigated. METHODS: The pulmonary artery responses of male Sprague Dawley rats were recorded using myography, and the quantities and activities of MMPs were analyzed in homogenates of the pulmonary arteries and lungs by enzyme-linked immunosorbent assays, activity assays, and gelatin zymography techniques. RESULTS: Our results indicated that the therapeutic effects of sildenafil were accompanied by its suppressor effects on MMP activity. It was also shown that everolimus or alagebrium in combination with sildenafil showed additional regulatory effects on MMPs as well as functional responses on pulmonary artery pressure. Therefore, the enzymes in the MMP superfamily are likely to be target molecules for the treatment of PH. CONCLUSION: In conclusion, MMPs were involved in the pathogenesis of PH, and our results suggested that the addition of everolimus or alagebrium to sildenafil therapy may be beneficial in PH. Our results indicated that agents that limit pulmonary vascular hypertrophy and inflammation via their anti-remodeling effects significantly ameliorate mortality and morbidity in PH.

Effects of tadalafil on hemorrhagic cystitis and testicular dysfunction induced by cyclophosphamide in rats.

INTRODUCTION: The protective and/or therapeutic potential of tadalafil (TDL) on cyclophosphamide (CP)-induced hemorrhagic cystitis (HC) and testicular dysfunction in rats was evaluated. MATERIALS AND METHODS: The animals except from the control group were divided into four groups and treated with saline, or 1, 5 or 10 mg/kg TDL orally (CP, TDL1, TDL5 and TDL10 groups, respectively) before and after CP injection. Body and organ weights, sperm count, cGMP, nitric oxide (NO), IL-6 and IL-10 levels in serum and bladder tissue, and serum testosterone (T), LH and FSH levels were determined. The histological analysis of bladder and testis was performed and the number of apoptotic cells was determined. RESULTS AND CONCLUSION: The CP group had decreased cGMP and NO levels in the bladder, serum T level (p < 0.05) and sperm count (p < 0.001) and higher IL-6 levels in serum and bladder (p < 0.01). Treatment with TDL resulted in increased cGMP (p < 0.001), NO (p < 0.05) and serum T (p < 0.05) levels. Histological analysis of the CP group showed severe HC in bladder and testicular damage. TDL-treated animals showed a dose-dependent improvement in all of these histological impairments. In conclusion, a selective inhibitor of phosphodiesterase-5 enzyme, TDL, showed a protective and/or therapeutic effect on CP-induced HC and testicular dysfunction in rats.

Acute and Subchronic Toxic Effects of the Fruits of Physalis peruviana L.

The fruit of Physalis peruviana L. (PPL) has been traditionally used as antispasmodic, diuretic, antiseptic, sedative, and analgesic all over the world. We aimed to perform qualitative content analysis of the fruits of PPL and to clarify the in vitro genotoxicity and in vivo acute and subchronic toxicity of the fruit. Lyophilized fruit juice does not induce genetic damage. In the acute toxicity studies, LD50 value of the fruit was found to be more than 5000 mg kg(-1) for both sexes. According to the subchronic toxicity studies, hepatic, renal, and hematological toxic effects were not induced in both sexes. Plasma troponin I (only in the group treated with 5000 mg kg(-1) of lyophilized fruit juice) and troponin T levels were significantly increased in male groups treated with lyophilized fruit juice compared to the control group. Furthermore, potassium level was significantly increased in the male group treated with 5000 mg kg(-1) of lyophilized fruit juice. These findings were considered to indicate the myocardial damage particularly in the male group treated with 5000 mg kg(-1) of lyophilized fruit juice. In conclusion, lyophilized fruit juice of PPL is shown to induce cardiac toxicity only at high doses and in male gender.

Assessment of the endothelial functions in monocrotaline-induced pulmonary hypertension.

Pulmonary hypertension (PH) is a life-threatening disease that causes endothelial dysfunction in the pulmonary vascular bed. Systemic endothelial dysfunction has also been reported in PH. This study compared the systemic and pulmonary vascular responses and some blood biomarkers of endothelial function in monocrotaline (MCT)-induced PH of rats. It also investigated the effect of sildenafil and iloprost treatment. MCT application induced elevation in the right ventricular pressures of the rat heart that had been reversed by sildenafil and iloprost treatment. Acetylcholine-induced endothelium-dependent relaxations of the isolated pulmonary artery were decreased in the PH group and this failure was reversed by sildenafil and iloprost treatment. Acetylcholine-induced endothelium-dependent relaxations of the isolated thoracic aorta were similar in all groups. Serotonin-induced contractions of the pulmonary artery were augmented by PH. In the isolated aorta, serotonin-stimulated contraction was not different in the control and MCT groups, but sildenafil and iloprost treatment decreased serotonin responses. The nitric oxide (NO) level in systemic circulation was not significantly changed by PH. However, sildenafil and iloprost treatments caused a decrease in the plasma level of NO. Asymmetric dimethylarginine levels in plasma were significantly decreased after MCT application and were not recovered by sildenafil and iloprost treatment. Total antioxidant capacity and H2S level of plasma were similar in all groups. Results of this study showed that MCT-induced PH caused specific toxic effects on pulmonary vasculature without any functional effects on the aorta. In addition, it was also demonstrated that sildenafil and iloprost treatments were effective in the MCT-induced PH.

Antinociceptive effects of gabapentin & its mechanism of action in experimental animal studies.

BACKGROUND & OBJECTIVES: Several studies have shown the possible analgesic effects of gabapentin, widely used as an antiepileptic. Thus, clinical studies have been carried out especially for neuropathic syndroms. This study was undertaken to investigate experimentally whether gabapentin has analgesic effects in mice and rats. METHODS: The mice were divided into 10 groups (n=7) with various treatments to assess central and peripheral antinociceptive activity of gabapentin. Hot plate, tail clip and tail flick tests were applied for the investigation of central antinociceptive activity and the writhing test was applied for the investigation of peripheral antinociceptive activity. In addition, we also evaluated the levels of PGE 2 and nNOS on perfused hippocampus slices of rats. RESULTS: Gabapentin showed a peripheral antinociceptive effect at all doses and a central antinociceptive effect at 30mg/kg dose. While the L-NAME and cyproheptadine changed the central and peripheral effects of gabapentin, naloxone did not change these effects. In vitro studies showed that gabapentin significantly increased nNOS level. PGE 2 and nNOS were found to have an important role in the antinociceptive effects of gabapentin at all doses and its combinations with L-NAME, cyproheptadine, indomethacine, and naloxone. As expected, PGE 2 levels decreased in all groups, while nNOS levels increased, which is believed to be an adaptation mechanism. INTERPRETATION & CONCLUSIONS: Our findings indicate that arachidonate, nitrergic and serotonergic systems play an important role in the antinociceptive activity of gabapentin except for the opioidergic system. Additionally, this effect occured centrally and peripherally. These effects were also mediated by nNOS and PGE2.

Relation of bosentan, iloprost, and sildenafil with growth factor levels in monocrotaline-induced pulmonary hypertension.

It is believed that growth factors play an important role in vascular remodeling that is evident in pulmonary hypertension (PH) pathogenesis. In the present study, the vascular endothelial growth factor (VEGF) levels in serum and pulmonary artery samples of rats have been analyzed with monocrotaline (MCT)-induced PH after treatments with iloprost, bosentan, and sildenafil. Serum VEGF and pulmonary artery VEGF levels were found to be significantly lower in MCT groups compared with control groups and significantly higher in treatment groups compared with MCT groups. In conclusion, treatment strategies directed at increasing VEGF levels may be reasonable in PH management.

The role of inflammation and COX-derived prostanoids in the effects of bradykinin on isolated rat aorta and urinary bladder.

Bradykinin, a vasoactive peptide, increases during inflammation and induces the formation of prostaglandins through specific receptor activation. Two types of receptors mediate the biological effects of bradykinin, B(1) and B(2) receptors. Although B(2) receptors are present in most tissues, B(1) receptors are expressed after inflammatory stimuli or tissue injury. Bradykinin has a high affinity for B(2) and a low affinity for B(1) receptors, whereas the opposite occurs for des-Arg(9)-bradykinin. Recently, it has been reported that nonsteroidal anti-inflammatory drugs have different inhibitory activities on cyclooxygenase isozymes, COX-1, COX-2, and COX-3. In the present study, we have investigated the contributions of different COX isozyme inhibitions and inflammation on bradykinin-induced effects of isolated rat aorta and urinary bladder smooth muscle contractions. Male Sprague-Dawley rats weighing 200-250 g were used in the study. The vasodilatory responses to bradykinin (1 nM-1 µM) were studied on isolated rat aorta rings contracted with norepinephrine (0.1 µM) following incubation with dipyrone (100, 700, and 2,000 µM). The relaxant responses of dipyrone (100, 700, and 2,000 µM) were also compared on the isolated rat urinary bladder contracted with bradykinin (n = 8). A bacterial lipopolysaccharide was used for the induction of inflammation (n = 8). The levels of PGE(2), PGF(1α), TXB(2), nitric oxide synthase (NOS), IL-10, and TNF-α were all determined in both the plasma and the perfusate of the aorta preparations (n = 5). The vasodilatory activities of bradykinin and des-Arg9-bradykinin were significantly increased upon the inhibition of COX-3 (dipyrone at 100 µM). These effects disappeared in the inflamed group. PGE(2), PGF1α, and TXB(2) were significantly high, but NOS activity was low in the aorta perfusate after the inhibition of COX-3. Dipyrone showed the relaxant activity of the urinary bladder contracted with bradykinin. The vasodilatory activity of des-Arg(9)-bradykinin was in the inflamed group but not in the non-inflamed group. Bradykinin did not contract urinary bladder in inflamed group. The results suggest that COX-induced products may play an important role in the bradykinin-induced rat aortic smooth muscle relaxations.

Effects of everolimus in combination with sildenafil in monocrotaline-induced pulmonary hypertension in rats.

In our study, we investigated the efficacy of everolimus in combination with sildenafil on hemodynamic and morphological parameters in rats with monocrotaline-induced pulmonary hypertension (PH). Right ventricular pressure (RVP), right ventricular hypertrophy, and the response to vasoconstrictor and vasodilator agents in pulmonary arteries as evaluated by myography and histopathological changes were compared among the groups. RVP and right ventricle/body weight ratios were increased in non-treated monocrotaline groups versus the controls; these increased ratios were decreased in the treated groups and were similar to control values. The contractile responses to endothelin-1 in the pulmonary arteries were decreased in the non-treated monocrotaline groups versus the control. In the treatment groups, contractile responses were similar to those in the controls. Responses to acetylcholine and sodium nitroprusside relaxation were decreased in non-treated monocrotaline groups but were improved significantly in the everolimus groups. Upon histopathological examination, the vascular hypertrophy and cardiac hypertrophy observed in monocrotaline groups were improved by the sildenafil and everolimus treatment. In particular, these improvements became remarkable, including the inflammatory changes, in the everolimus treatment groups. In the light of these results, sildenafil and everolimus in combination were more effective than sildenafil treatment alone in reversing the remodelling process without any cardiovascular toxic effects in the monocrotaline-induced PH model.

Polymeric cyclosporine-A nanoparticles for ocular application.

In the present study, cyclosporine A (CsA) was incorporated successfully into cationic Eudragit RS 100 nanoparticles (EPNs) aiming ocular application. Physicochemical characterization of the EPNs prepared was performed during the storage period of 6 months. Following in vitro release tests, sheep were used in in vivo studies where 100 microL of formulation was applied to both eyes (n = 6) under veterinarian supervision. Aqueous and vitreous humour samples were collected at predetermined time intervals and analyzed by enzyme immune assay (EIA). In vitro relase studies showed the extended release of the incorporated drug from the nanoparticles. However in vivo results demonstrated the prolonged residence time of CsA in the deeper layers (vitreous humour) of the eye with positively charged EPNs.

Cyclosporine-A incorporated cationic solid lipid nanoparticles for ocular delivery.

In the present study, Cyclosporine A (CsA) was successfully incorporated into cationic solid lipid nanoparticles (SLN) for ocular application. Physicochemical characterizations of SLNs were analysed in detail during the storage period of 6 months. Due to the better characteristics like smaller particle size (248.00 +/- 0.33 nm) with narrow size distribution (PI = 0.25 +/- 0.00), high zeta potential (50.30 +/- 0.78 mV) and more stable lipid structure, Dynasan 116 structured FD4 (0.1% CsA) formulation was chosen for in vivo studies. Sheep were used in in vivo studies and 200 microL of formulation was applied to sheep' eyes (n = 6) under veterinarian supervision. Samples were collected at pre-determined time intervals and were analysed by enzyme immune assay (EIA). CsA could be detected in both aqueous and vitreous humour samples for 48 h showing the ocular penetration of formulation. Release profiles were not decreased during 48 h indicating controlled and prolonged release of active agent from positively charged SLN formulations due to increased residence time in eyes. Similarities in CsA concentration data showed that inter-individual variance did not influence the ocular penetration of CsA when formulated as SLN.

Loss via peritoneal fluid as a factor for low 25(OH)D3 level in peritoneal dialysis patients.

BACKGROUND/AIMS: In patients with end-stage renal disease (ESRD), the 25-hydroxyvitamin D3 (25(OH)D3) level is known to be lower compared to that of the normal population. In the present study, we evaluated the influences of dialysis methods on the serum 25(OH)D3 level in patients with ESRD who are treated with hemodialysis and peritoneal dialysis. METHODS: Thirty-nine peritoneal dialysis (PD), 49 hemodialysis (HD) patients, and 33 healthy controls were included in the present study. The mean HD period was 30.38 +/- 21.81 months and the mean PD period was 26.35 +/- 24.04 months. Serum samples from the HD and PD patients and healthy controls were examined in terms of 25(OH)D3, intact parathyroid hormone (iPTH), and other biochemical laboratory tests. Additionally, the 25(OH)D3 level in the peritoneal fluid was analyzed in the PD group. RESULTS: The mean 25(OH)D3 levels in the control, HD, and PD groups were 26.63 +/- 10.89, 21.65 +/- 12.38, and 13.46 +/- 9.41 nmol/l, respectively (P < 0.001). The mean peritoneal fluid 25(OH)D3 level was 28.53 +/- 7.66 nmol/l. Moreover, blood and PD fluid 25(OH)D3 levels were 34 compared in the PD group. The 25(OH)D3 level in dialysate was higher than that of serum in PD patients (P < 0.001). CONCLUSION: The significantly lower blood levels of 25(OH)D3 in PD patients compared to those of HD patients were thought to be due to 25(OH)D3 loss via peritoneal fluid.

The effect of low-dose cholecalciferol and calcium treatment on posttransplant bone loss in renal transplant patients: a prospective study.

BACKGROUND/AIM: Posttransplant steroid doses have been reduced with the use of new and potent immunosuppressive agents. However, posttransplant osteoporosis is still a serious problem. Our aim in this study was to investigate the effect of low-dose cholecalciferol and calcium supplementation on bone loss after transplantation in renal transplant patients. METHODS: Fifty-eight renal transplantation patients were included in the study. Fourteen newly transplanted patients (group 1) and 44 renal transplantation patients with a graft age of at least six months (group 2) were involved. All patients received 400 IU/day orally cholecalciferol (vitamin D3) and 600 mg/day orally calcium replacement starting from the second day posttransplantation. All patients baseline serum and urine biochemistry, serum 25-hydroxy vitamin D3 (25 (OH)D3), and bone mineral density (BMD) tests were performed. Also, the same measurements were performed at the 12th month in group 1. RESULTS: After one year of treatment, BMDs were improved in group 1. Patients in group 1 had a nonsignificant increase of lumbar spine (8.12 +/- 18.64% of baseline BMD) and femoral total (7.10 +/- 13.48% of baseline BMD) BMD at the end of the first year. On the other hand, there was a significant increase in femoral neck (10.06 +/- 15.70% of baseline BMD, p < 0.05) measurements. The baseline results of group 2 were similar to group 1. In group 1, 25 (OH)D3 levels were increased while PTH levels were decreased at the end of the year. CONCLUSION: In renal transplant patients who use low-dose metilprednisolon and new immunosuppressive agents together, low doses of vitamin D3 and calcium replacement for one year provides a reduction in lumbar spine, femoral neck, and femoral total bone loss and prevents bone loss in group 2. In addition, it contributed to the normalization of PTH levels.

An alternative agent for radial arterial graft spasm: application of topical iloprost.

OBJECTIVE: This study is planned bringing about a new choice for the prophylaxis of RA spasm which is topical iloprost and compares its efficacy with papaverine and diltiazem. DESIGN: Twenty eight CABG patients with RA grafts were categorized into four groups by taking into account the topical vasodilator (papaverine, diltiazem, iloprost and saline) that was utilized during harvesting. Arterial segments were separated into four rings and were than soaked with KCL, norepinephrine, phenylephrine and serotonin. Then, acetylcholine was given to induce relaxation and the preparations were put to rest for 10 minute. RESULTS: The contraction response achieved by the vasoreactive agents was most effectively inhibited by papaverine. The effectiveness of the response obtained by iloprost was similar to that of papaverine and significantly stronger than that of diltiazem. Especially at high vasoreactive substance concentrations, diltiazem had a contraction close to that of the control while the protective effect was weaker than those of papaverine and iloprost. CONCLUSION: Iloprost can be recommended as a strong alternative to the topical agents used for preventing arterial graft spasm.

Preventive effects of Ginkgo biloba extract on ischemia-reperfusion injury in rat bladder.

AIMS: The aim of this experimental study was to evaluate the effects of Ginkgo biloba (EGb 761) on ischemia-reperfusion (I-R) injury in the rat bladder. METHODS: A bladder I-R injury was induced by abdominal aorta occlusion by ischemia for 30 min, followed by 45 min reperfusion in rats. The rats were divided into four groups of 7 rats each; the control, I-R, and I-R groups were pretreated intraperitoneally with 50 or 100 mg/kg G. biloba 60 min before ischemia induction. Contractile responses to carbachol through isolated organ bath studies were recorded, histological sections were evaluated by light microscopy, and TUNEL staining was performed for the evaluation of apoptosis. RESULTS: In the I-R group, the contractile responses of the bladder strips were lower than those of the control group (p < 0.01-0.001) and were restored by pretreatment with 100 mg/kg G. biloba (p < 0.05-0.001). Decreased polymorphonuclear leukocyte infiltration was detected in the G. biloba pretreatment groups when compared to the I-R group during histological evaluation. The ratio of TUNEL-positive nuclei was 1.84% in the I-R group, whereas it was decreased in both of the G. biloba pretreatment groups (p < 0.01, p < 0.01). CONCLUSION: Our data indicated that G. biloba has a preventive effect on I-R injury in rat urinary bladder.

4-difluoro-substituted phenl-5-oxohexahydroquinoline derivatives and their effects on calcium channels.

Twenty new methyl(ethyl) 2,6,6- or 2,7,7-trimethyl-5-oxo-4-(disubstituted phenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates and ten new N,N-diethyl-2,6,6- or 2,7,7-trimethyl-5-oxo-4-(disubstituted phenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide derivatives have been synthesised and screened for their calcium channel antagonistic activity. The compounds were synthesised by the Hantzsch reaction. Calcium antagonistic activities of the compounds were determined by the tests performed on isolated rat ileum and rat thoracic artery.

Effects of verapamil and nifedipine on different parameters in lipopolysaccharide-induced septic shock.

Septic shock has a high mortality rate due to the hypotension and circulatory disorder that occurs during its pathogenesis. Recently, humoral factors such as cytokines and nitric oxide became important in the complex pathophysiology of septic shock because there is a close relationship between the determined levels of these humoral factors and the responses to the therapy and survival periods. Verapamil and nifedipine are calcium channel blockers commonly used in the pharmacotherapy of cardiovascular disorders. In the present study these drugs were investigated in the rat septic shock model. In vivo hemodynamic parameters were recorded using a data acquisition system in endotoxin-induced septic shock in rats. The animals were followed for 5 h and blood pressure, rectal temperature, and ECG were recorded. Blood samples were collected at 1 h and 5 h time points after the injection of endotoxin, and serological samples were stored at -25 degrees C. Subsequently, tumor necrosis factor-alpha, interleukin-10 (enzyme-linked immunosorbent assay), and nitrite (Griess reagent) were determined in these serological samples. Significant correlations were observed between these humoral factors and the disordered hemodynamic factors. A reversal of changes was observed in the levels of serum cytokines, nitrite levels, and hemodynamic parameters with verapamil and nifedipine preadministration (P<0.05). Additionally, superoxide dismutase (SOD), catalase, and malondialdehyde (MDA) were determined in livers obtained from these animals at the end of the experiments, and these results were compared to hemodynamic parameters and cytokines. Nifedipine and verapamil increased the levels of MDA and SOD but did not change catalase activity.