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Background: This study aimed to examine the effects of nesfatin-1 on thoracic aorta vasoreactivity and to investigate the inotropic and chronotropic effects of nesfatin-1 on the spontaneous contractions of the isolated rat atria. Methods: Isolated right atria and thoracic aorta were used in organ baths. The reactivity of the thoracic aorta was evaluated by potassium chloride (KCl), phenylephrine (Phe), acetylcholine (ACh), and sodium nitroprusside (SNP). The effects of nesfatin-1 on the spontaneous contractions of the rat atria were also examined. Results: Nesfatin-1 (0.1-100 ng/ml) produced a concentration-dependent relaxation response in rat thoracic aorta. The relaxant responses to nesfatin-1 were inhibited by the removal of endothelium, NO synthase blocker N-nitro-L-arginine methyl ester (L-NAME, 10−4 M), and soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10-5 M). Nesfatin-1 (10 ng/ml, 30 min) increased the relaxation responses to either ACh or SNP, and the contractile response to both Phe and KCl did not significantly change in the arteries that were incubated with nesfatin-1 compared with the controls. The thoracic aorta contractions induced by the stepwise addition of Ca2+ to a high KCl solution with no Ca2+ were not significantly changed by nesfatin-1. Under calcium-free conditions, the contractions of the thoracic aorta rings incubated with nesfatin-1 in response to Phe were not significantly lower than those of the rings from the control rats. Nesfatin-1 showed positive inotropic and chronotropic effects on rat atria. Conclusion: Nesfatin-1 significantly changed the vascular responsiveness in rat thoracic aorta and produced positive inotropic and chronotropic effects on rat atria. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to investigate the effect of chronic exendin-4 (Ex-4) treatment on corpus cavernosum (CC) dysfunction in methylglyoxal (MGO) administered rats. Methods Male rats were divided into four groups as control, MGO (75 mg/kg/day in drinking water for 12 weeks), MGO + low-dose Ex-4 (0.1 μg/kg twice daily subcutaneously for 12 weeks concomitant with MGO), and MGO + high-dose Ex-4 (1 μg/kg twice daily subcutaneously for 12 weeks concomitant with MGO). Nitric oxide (NO)-mediated endothelium-dependent and neurogenic CC relaxations were evaluated by acetylcholine (ACh) and electrical field stimulation (EFS), respectively. Apoptosis was determined by TUNEL. Endothelial nitric oxide synthase (eNOS), phosphorylated eNOS ( p -eNOS), NADPH oxidase subunit gp91phox (NOX2), and Rho kinase (ROCK2) expressions in CC were investigated by immunohistochemistry. Levels of the malondialdehyde (MDA) and advanced oxidation protein products (AOPP) were also measured. Results In MGO administered rats, both endothelium-dependent and neurogenic CC relaxations were significantly impaired as compared to controls. Apoptotic cell death and levels of MDA and AOPP increased significantly in MGO administered rats. eNOS and p -eNOS expressions decreased significantly in MGO group, while gp91phox expressions increased significantly. The diminished relaxation in response to ACh or EFS as well as the changes in expression of proteins in MGO groups were significantly improved by exendin-4 treatment. TUNEL-positive cells, and levels of MDA and AOPP in MGO group rats were also significantly reduced by exendin-4. Conclusion Exendin-4 treatment improves NO-mediated CC relaxations in MGO administered rats probably by inhibiting NADPH oxidase. [ABSTRACT FROM AUTHOR]

The present study was designed to evaluate the cardioprotective effects of nesfatin-1, a novel peptide with anorexigenic properties, in rats with isoproterenol (ISO)-induced myocardial infarction (MI), and to further investigate the role of Akt/GSK-3β signaling pathway in the protective effect of nesfatin-1. To induce MI, ISO was subcutaneously injected into the rats for two consecutive days at a dosage of 85 mg/kg/day. ISO-induced myocardial damage was indicated by elevated levels of cardiac specific troponin-T, enhanced myocardial expression of proinflammatory cytokines (interleukin-1β, interleukin-6 and tumor necrosis factor-α), and increased number of cells with apoptotic and necrotic appearance in the myocardial tissue. Levels of p -Akt/Akt and p -GSK-3β/GSK-3β significantly decreased in heart tissue after ISO-induced MI. However, intraperitoneal administration of nesfatin-1 (10 μg/kg/day) elicited a significant cardioprotective activity by lowering the levels of cardiac troponin-T and proinflammatory cytokines, indicating the protective effect of nesfatin-1 against ISO-induced MI. The biochemical findings were further confirmed by histopathological examination, which was demonstrated by reduced number of apoptotic and necrotic cells. Moreover, expressions of p -Akt/Akt and p -GSK-3β/GSK-3β in the myocardium of MI group rats were significantly increased by nesfatin-1 administration, suggesting that nesfatin-1, which appears to possess anti-apoptotic and anti-inflammatory properties, may confer protection against ISO-induced MI via an Akt/GSK-3β-dependent mechanism. [ABSTRACT FROM AUTHOR]

Abstract: Although the oxidative stress and inflammation are closely related with breast cancer, there is no study directly examining the possible changes in vascular functions in the presence of breast carcinoma. The goal of the present study was to evaluate changes in vascular reactivity in tumor-bearing mice. In this study, highly metastatic breast carcinoma cells which were derived from liver or brain metastasis of 4T1 murine breast carcinoma (4TLM and 4TBM, respectively), and 67NR cells which were tumorigenic but non-metastatic cells were used. Female Balb-c mice 8–10weeks old were divided into following groups: (1) control, (2) injected with 67NR, (3) injected with 4TLM, and (4) injected with 4TBM orthotopically. Thoracic aorta was removed 23–25days after injection of tumor cells. Isometric tension studies were performed in response to potassium chloride (KCl), phenylephrine (Phe), acetylcholine (ACh, an endothelium-dependent vasodilator), and sodium nitroprusside (SNP, an endothelium-independent vasodilator). Endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (Ser 1177) (p-eNOS), gp91phox, and tumor necrosis factor-α (TNF-α) expressions in aortic tissues were demonstrated by immunohistochemistry. The level of TNF-α in vascular tissue was measured by ELISA. The presence of tumor was resulted in significant inhibition of response to ACh in both 4TLM and 4TBM injected mice, but not 67NR injected mice. Furthermore, both KCl and Phe-induced contraction of thoracic aorta was not changed significantly in tumor-bearing animals. eNOS and p-eNOS expressions decreased while gp91phox and TNF-α expressions increased in endothelium of 4TLM and 4TBM mice compared to 67NR injected and control mice. Moreover, TNF-α levels of thoracic aorta in mice with metastatic breast carcinoma were significantly higher than that of 67NR mice. Tumor-induced endothelial dysfunction determined by ACh-induced relaxation improved by superoxide dismutase (SOD), apocynin (a NADPH oxidase inhibitor), and infliximab (a TNF-α monoclonal antibody). The findings of this study suggest that the presence of metastatic breast carcinoma may cause a significant reduction in endothelium-dependent relaxation of thoracic aorta via NADPH oxidase-mediated oxidative stress and TNF-α production. [Copyright &y& Elsevier]

The aim of this study was to evaluate the relaxant effect of taurine, one of the most commonly employed dietary supplements, in rat corpus cavernosum (CC), and to further investigate the contribution of possible underlying mechanisms. Strips of CC were suspended in an organ bath system for isometric tension studies. Taurine (10-80 mmol/l) produced a concentration-dependent relaxation response in rat CC. Endothelial removal did not cause a significant inhibition of the relaxation response to taurine. Incubation of endothelium-denuded CC strips with the nonselective potassium channel blocker tetraethylammonium (10 mmol/l), the ATP-sensitive potassium (KATP) channel blocker glibenclamide (10 μmol/l), the inward rectifier potassium (Kir) channel inhibitor barium chloride (30 μmol/l), and the large conductance calcium-activated potassium channel inhibitor iberiotoxin (0.1 μmol/l) significantly inhibited the relaxant responses to taurine. However, taurine-induced relaxation was not inhibited by the voltage-dependent potassium channel inhibitor 4-aminopyridine (1 mmol/l). On the other hand, taurine (20 mmol/l, 30 min) inhibited both intracellular and extracellular calcium-dependent contraction in CC strips. These findings suggest that taurine induced relaxation of CC via an endothelium-independent pathway. The activation of KATP channels, Kir channels and calcium channels is thought to play an important role in endothelium-independent relaxation of CC, but other direct effects on calcium dynamics may also contribute to its relaxant effect. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes involved in a wide variety of biological processes including DNA repair and maintenance of genomic stability following genotoxic stress, and regulates the expression of various proteins at the transcriptional level as well as replication and differentiation. However, excessive activation of PARP has been shown to contribute to the pathogenesis of several diseases associated with oxidative stress (OS), which has been known to play a fundamental role in the etiology of male infertility. Based on the degree and type of the stress stimulus, PARP directs cells to specific fates (such as, DNA repair vs. cell death). A large volume of accumulated evidence indicates the presence of PARP and its homologs in testicular germ line cells and its activity may offer a key mechanism for keeping DNA integrity in spermatogenesis. On the other hand, a possible role of PARP overactivation in OS-induced male reproductive disorders and in human sperm is gaining significance in recent years. In this review, we focus on the findings about the importance of PARP-1 and PARP-2 in male reproduction and possible involvement of PARP overactivation in various clinical conditions associated with male infertility. [ABSTRACT FROM AUTHOR]

Environmental exposure to pesticides may cause serious health risks including fertility and reproductive function. The aim of this study was to highlight whether there is a relationship between exposure to abamectin and male fertility parameters of farmworkers. Twenty male farmworkers who were using abamectin and 20 men not exposed to pesticides were recruited as experimental and control groups, respectively. Semen analysis, molecular markers of sperm maturity and serum reproductive hormone levels were evaluated. In experimental group, high plasma abamectin levels were detected. These men have decreased sperm motility. Moreover, diminished molecular markers of sperm maturity, such as decreased hyaluronic acid ( HA) binding of sperm, increased numbers of aniline blue positive sperm and increased percentage of creatine kinase ( CK) positive sperm, were observed in abamectin-exposed men. Their serum testosterone, LH and FSH levels did not change significantly. We conclude that exposure to abamectin may impair male fertility by effecting semen quality. [ABSTRACT FROM AUTHOR]

Abstract: Despite the known adverse effects of abamectin pesticide, little is known about its action on male fertility. To explore the effects of exposure to abamectin on male fertility and its mechanism, low (1mg/kg/day) and high dose (4mg/kg/day) abamectin were applied to male rats by oral gavage for 1week and for 6weeks. Weight of testes, serum reproductive hormone levels, sperm dynamics and histopathology of testes were used to evaluate the reproductive efficiency of abamectin-exposed rats. Abamectin level was determined at high concentrations in plasma and testicular tissues of male rats exposed to this pesticide. The testes weights of animals and serum testosterone concentrations did not show any significant changes after abamectin exposure. Abamectin administration was associated with decreased sperm count and motility and increased seminiferous tubule damage. In addition, significant elevations in the 4-hydroxy-2-nonenal (4-HNE)-modified proteins and poly(ADP-ribose) (PAR) expression, as markers for oxidative stress and poly(ADP-ribose) polymerase (PARP) activation, were observed in testes of rats exposed to abamectin. These results showed that abamectin exposure induces testicular damage and affects sperm dynamics. Oxidative stress-mediated PARP activation might be one of the possible mechanism(s) underlying testicular damage induced by abamectin. [Copyright &y& Elsevier]

Recent studies have clearly reported that there is a relationship between endotoxemia and acute renal injury. The aim of this study was to investigate whether treatment with the new potent PARP inhibitor PJ34 could prevent the acute renal injury induced by lipopolysaccharide (LPS). Endotoxemia was induced by LPS injection (10 mg/kg, i.v.). LPS increased blood urea nitrogen (BUN) levels from 22 ± 0.54 mg/dL to 45.7 ± 5.79 mg/dL (p < 0.05). The plasma creatinine levels were 0.38 ± 0.02 mg/dL and 0.47 ± 0.03 mg/dL for the control and LPS groups, respectively. In addition, urinary excretion of N-acetyl-β-d-glucosaminidase (NAG, a marker of renal tubular damage) was increased after LPS injection. By light microscopy, structural renal damage was observed in the LPS-treated group. However, PJ34 treatment (10 mg/kg, i.p.) attenuated LPS-induced renal injury, as indicated by plasma BUN and creatinine levels, urinary NAG excretion, and renal histology. These results indicated that the overactivation of the PARP pathway may have a role in LPS-induced renal impairment. Hence, pharmacological inhibition of this pathway might be an effective intervention to prevent endotoxin-induced acute renal injury. [ABSTRACT FROM AUTHOR]

The main function of vitamin K1 is to act a co-factor for gamma-glutamyl carboxylase. However, it has also been shown to lessen oxidative stress. This study was aimed to evaluate the effect of vitamin K1 supplementation on vascular responsiveness and oxidative status in rats that underwent femoral osteotomy. Twenty-four male rats were divided into three groups to serve as sham, osteotomy and vitamin K1 groups. Indices of oxidative stress (catalase), and oxidative damage (malondialdehyde) were analysed in erythrocytes. In order to evaluate vascular reactivity, concentration-response curves to phenylephrine, angiotensin II, 5-hydroxytryptamine, bradykinin and histamine were constructed. The findings of this study clearly show that oxidative stress clearly increases after femoral osteotomy in rats. Also, this operation causes a significant depression in vascular responsiveness to contracting agents and endothelium-dependent vasodilators. However, vitamin K1 supplementation prevents vascular hyporeactivity by reducing oxidative stress and may represent a novel approach during osteotomy healing. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: This study was aimed to examine the effects of homocysteine (Hcy) on vascular responsiveness of guinea-pig isolated pulmonary arteries and to investigate possible underlying mechanisms. In order to evaluate vascular reactivity, isometric tension studies were performed in response to potassium chloride (KCl), phenylephrine (Phe), acetylcholine (ACh), and sodium nitroprusside (SNP). Incubation of pulmonary artery rings with Hcy (10−3 M, 180min) resulted in significant inhibition of response to ACh (an endothelium-dependent vasodilator)(E max: 55.3±6.7 vs. 13.1±2.0*, P<0.05) while SNP (an endothelium-independent vasodilator)-induced relaxation was not changed significantly. Furthermore, Hcy enhanced KCl- and Phe-induced contraction of pulmonary artery rings (E max: 1568±81 vs. 2101±145* mg for KCl and 1081±101 vs. 1544±117* mg for Phe, P<0.05). Pulmonary artery ring contractions induced by stepwise addition to Ca2+ to high KCl solution with no Ca2+ were also significantly augmented by Hcy incubation (E max: 1750±121 vs. 2295±134* mg, P<0.05). To investigate mechanisms of Hcy action, additional sets of experiments involving rings incubation with Hcy alone or with addition of Tiron (an intracellular superoxide anion scavenger, 10−2 M), PJ34 (an inhibitor of polyADP-ribose polymerase, 3×10−6 M), and combination of two antioxidant enzymes superoxide dismutase (SOD, 100U/ml) and catalase (CAT, 120U/ml) for 180min. The findings of our study clearly show that all these co-treatments significantly prevented the development of endothelial dysfunction induced by Hcy. Furthermore, the effect of Hcy on KCl- and Phe-induced contraction was significantly inhibited by the concomitant incubation with either SOD plus CAT, Tiron or PJ34. This study demonstrates that Hcy causes a significant alteration in vascular reactivity of pulmonary arteries, and this alteration seems to be via oxidative stress in pulmonary artery endothelium with subsequent DNA damage and activation of poly(ADP-ribose) polymerase (PARP) pathway. [Copyright &y& Elsevier]

Variations in vascular reactivity and morphology of proximal and distal saphenous vein might affect its performance as a bypass conduit. Because peri- or postoperative graft spasm or intimal hyperplasia reduces patency, we compared the reactivity and morphology of human proximal and distal saphenous vein conduits. Isometric tension studies were performed in response to potassium chloride (80 mM), phenylephrine (10-8 - 10-5 M), norepinephrine (10-8 - 10-5 M), and angiotensin II (10-11 - 10-7 M). Relaxant responses were tested with acetylcholine (10-9 - 10-5 M), sodium nitroprusside (10-10 -10-6 M), and diltiazem (10-10 - 10-4 M). Also, vein segments from proximal and distal leg saphenous vein grafts were collected for histopathologic investigation. In proximal and distal saphenous vein segments, we also examined the structure of intima, media, and adventitia, and we evaluated the smooth muscle cell/extracellular matrix ratio in the media. There was no significant difference (P > 0.05) between proximal and distal venous segments in response to vasoconstrictors or vasodilators. Similarly, investigation by light microscopy was unable to show any significant difference between proximal and distal conduits in vascular structure. The smooth muscle cell/extracellular matrix ratio was also similar in these graft materials. Our failure to find functional or morphologic differences between proximal and distal saphenous vein segments suggests that there is no advantage in using one of these preparations over the other as a conduit in coronary artery bypass operations. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies clearly show that there is a relationship between endotoxemia and impaired vascular responsiveness. The aim of this study was to investigate whether treatment with the new potent PARP inhibitor PJ34 could prevent the vascular hyporesponsiveness induced by lipopolysaccharide (LPS). Endotoxemia was induced in rats by LPS injection (20mgkg-1, i.p.). Administration of LPS caused a decrease in mean blood pressure and an increase in heart rate. In endothelium-denuded rings of thoracic aorta from untreated rats, contractile responses to KCl and phenylephrine decreased after LPS injection. Furthermore, there was a significant loss of endothelium-dependent vasodilatation in response to acetylcholine in LPS-treated rats. The animals pretreated with PJ34 (10mgkg-1, i.p., 30min before LPS injection), the effect of LPS on vascular responsiveness was lower than the untreated ones. Pretreating the animals with PJ34 before the LPS challenge prevented the decline in mean blood pressure. However, this did not result in significant changes to the heart rate. The inhibitory effect of LPS treatment on both KCl- and phenylephrine-induced contraction responses was significantly antagonized by PJ34. Additionally, pretreatment of the rats with PJ34 attenuated the LPS-induced endothelial dysfunction in endothelium-intact aorta rings. This study demonstrates that PARP activation in the vascular system is an important contributory factor to the impaired vascular responsiveness associated with endotoxic shock. Hence, the pharmacological inhibition of PARP pathway might be an effective intervention to prevent endotoxin-induced vascular hyporesponsiveness. [Copyright &y& Elsevier]

Recent studies have clearly shown that there is a relationship between hyperhomocysteinemia and endothelial dysfunction. However, the effect of poly(ADP-ribose) polymerase (PARP) inhibition on homocysteine (Hcy)-induced endothelial damage has not been investigated. In this study, we investigated whether the loss of endothelial function in rat aortic rings preincubated with Hcy is dependent upon the PARP pathway within the vasculature. Preincubation of rat aortic rings with Hcy (1 mmol/l; 180 min) significantly inhibited endothelium-dependent relaxation in this tissue. This inhibitory effect was significantly reduced in the presence of both superoxide dismutase (100 U ml–1) and catalase (100 U ml–1) together with Hcy. Similarly, preincubation for 180 min with either N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride (PJ34; 3 μmol/l) or 3-aminobenzamide (3 mmol/l), structurally different PARP inhibitors, also significantly prevented the development of endothelial dysfunction induced by Hcy. Further incubation of aortic rings with these PARP inhibitors for 60 min after exposure to Hcy for 180 min, at least in part, improved the endothelium-dependent relaxation responses. Thus, our results suggest that intraendothelial PARP activation may be associated with endothelial dysfunction in hyperhomocysteinemic conditions and that inhibition of this pathway may present a novel pharmacological approach to prevent Hcy-induced endothelial damage. Suprisingly, inhibition of the PARP pathway not only prevents the endothelial dysfunction mediated by Hcy, but is also able to rapidly improve it. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Summary 1 The aim of the present study was to investigate the role of several possible neurotransmitters in mediating non-adrenergic, non-cholinergic (NANC) relaxation, and the effects of phosphodiesterase (PDE) III and V inhibitors on adrenergic and NANC relaxation in branch pulmonary artery (PA) of guinea-pig. 2 Under the NANC conditions, electrical field stimulation (EFS, 60 V, 0.2 ms, 20 Hz) induced a tetrodotoxin-sensitive relaxation of the histamine-precontracted PA rings. The nitric oxide (NO) synthase inhibitor N [sup G] -nitro-l-arginine methyl ester (l-NAME, 10[sup -4] m) and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10[sup -5] m) partially inhibited the EFS-induced relaxation. The inhibitory effect of l-NAME was reversed completely by l-arginine (10[sup -3] m), but not d-arginine (10[sup -3] m). 3 This NANC relaxation was attenuated by 8-phenyltheophylline (10[sup -5] m), a P[sub 1] -purinoceptor antagonist. 4 The NANC response was potentiated by 10[sup -6] m zaprinast, a type V PDE inhibitor, but was unaffected by 3 × 10[sup -6] m milrinone, a type III PDE inhibitor. 5 Sodium nitroprusside (SNP) caused a concentration-dependent vasodilator effect which was potentiated by zaprinast, but unaffected by milrinone. Moreover, the effect of combination of zaprinast with milrinone was not significantly different from that observed with zaprinast alone. 6 Isoprenaline produced a concentration-dependent vasodilatation in branch PA of guinea-pig which was potentiated by both zaprinast and milrinone, the efficacy of milrinone being greater than zaprinast. 7 These results suggest that both nitrergic and purinergic pathways are involved in mediating the NANC relaxation in branch PA of guinea-pig. The combination of PDE III or V inhibitors with vasorelaxant drugs may be a hopeful approach for the treatment of pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the effect of pravastatin treatment on diminished corpus cavernosum (CC) function associated with aging. Methods: Male rats were divided into three groups as adult rats (12-14 weeks old), aged rats (72-80 weeks old) and aged rats given 10 mg/kg/d pravastatin in drinking water for six weeks. Blood pressure was measured by tail-cuff method. Total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglycerides and testosterone levels were estimated in blood. Changes in expression levels of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS) (Ser-1177), neuronal nitric oxide synthase (nNOS), NADPH oxidase subunit gp91phox, Rho A and Rho kinase (ROCK2) in CC were assessed by immunohistochemistry. Nitric oxide (NO)-mediated endothelium-dependent and neurogenic CC relaxation were evaluated by acetylcholine (ACh, 0.1 nM-100 µM) and electrical field stimulation (EFS; 30 V, 5 ms, 2-32 Hz), respectively. Results: In aged rats, NO-mediated, both endothelium-dependent and neurogenic CC relaxation, were significantly impaired as compared to adult rats. Besides, eNOS, p-eNOS and nNOS expressions decreased significantly in CC from aged rats, while gp91phox, RhoA and ROCK2 expressions increased significantly. The diminished relaxation in response to ACh or EFS as well as the changes in expression of these proteins in aged rats were significantly improved by pravastatin treatment. Conclusion: Pravastatin improves NO-mediated CC relaxations of aged rats probably by inhibiting NADPH oxidase/Rho kinase pathways, and this effect does not seem to be associated with lipid lowering effect of this drug. [ABSTRACT FROM AUTHOR]

Abstract  The effect of hyperhomocysteinemia induced by pretreatment with methionine 12 weeks prior to the study on the responses induced by γ-aminobutyric acid (GABA), electrical field stimulation (EFS), and ATP have been evaluated in isolated rat duodenum. In the presence of adrenergic and cholinergic blockade, EFS (60 V, 1 ms, 1–3 Hz) induced frequency-dependent relaxations of the preparation. GABA and ATP also caused submaximal relaxation of the rat duodenum. The relaxations induced by GABA, EFS, and ATP were not significantly changed in duodenal tissues from hyperhomocysteinemic rats compared with control rats. GABA- and EFS-induced relaxations were inhibited by N-nitro-l-arginine methyl ester (L-NAME; 3 × 10−4 M) in both hyperhomocysteinemic and control rats. On the other hand, L-NAME incubation did not affect ATP-induced relaxation. These results suggest that hyperhomocysteinemia does not cause an important impairment on non-adrenergic non-cholinergic innervation of the rat duodenum. [ABSTRACT FROM AUTHOR]

Background: This study aims to investigate the histopathological and analgesic effects of intrathecal administration of dexmedetomidine, preservative-free racemic ketamine, and magnesium sulfate in Sprague Dawley rats. This study included 40 male Sprague Dawley rats weighing between 240 and 260 g. After the intrathecal catheterization, the rats were randomly divided into four groups. Following the baseline measurements, no drugs were administered in the control group (group C). Simultaneously, 0.02 ml (1 μgr/kg) of dexmedetomidine was administered in group D, 0.02 ml (1 mg/kg) preservative-free racemic ketamine in group K and 0.02 ml (0.05 mg/kg) magnesium sulfate in group M via intrathecal route. Concomitantly, the hot-plate test was used to measure the analgesic effect of drugs. For histopathological evaluation, the rats were sacrificed to obtain the medulla spinalis. Results: The hot-plate test revealed that the mean response time was 6.3 ± 1.2 s in baseline measurements without medication. However, prolongation in the mean response times of the drug-administered groups to the hot-plate test was also observed. Upon histopathological examination, myelin degeneration was detected in all study groups. No inflammation was observed in rats in group D, whereas inflammation was noted in only two rats in group K. Concerning the presence of red neurons, the only group that differed from the control group belonged to group K. Conclusions: Dexmedetomidine, preservative-free racemic ketamine, and magnesium sulfate have an analgesic effect when administered intrathecally in rats. Of these drugs, preservative-free racemic ketamine stands out as the most histopathologically safe drug. [ABSTRACT FROM AUTHOR]

Varicocele is ordinarily accompanied by testicular damage and male infertility. Several theories have been proposed to explain the detrimental effect of varicocele on testis tissue, including the possible effects of oxidative stress. The poly( ADP-ribose) polymerase ( PARP) pathway has been established as a major downstream intracellular pathway of oxidative stress. Recently we have reported that PARP pathway has been activated in varicocele-induced rat testicular damage model. The aim of the present study was to investigate the possible protective effect of PARP inhibition in varicocele-associated testicular damage. Fifty male Wistar rats were divided into five groups: control, sham, varicocele-induced, varicocele-induced 1,5-isoquinolinediol ( ISO, a PARP inhibitor)-treated, and ISO treated groups. The ISO-treated rats received intraperitoneal injections of 3 mg/kg ISO daily for 13 weeks. After 13 weeks of varicocele induction, body and testes weights were investigated in all groups. Histopathology of testes were evaluated by light microscopy. Expressions of PAR, p53 and cytochrome c were detected by immunohistochemistry and cleaved PARP-1, PAR, p53 and cytochrome c by western blot. The degree of apoptosis was determined by TUNEL. Light microscopy revealed testicular damage comprising various degrees of seminiferous tubule degeneration in varicocele-induced rats and their testes weights decreased significantly, whereas ISO administration prevented it. Expressions of cleaved PARP-1, PAR, cytochrome c, and p53 increased significantly in varicocele-induced rats, whereas the level of these molecules were similar to controls in varicocele-induced rats treated with ISO. In conclusion, increased PARP activation in testes seems to be related with testicular damage and apoptosis associated with varicocele and pharmacological inhibition of this pathway might be an effective intervention to prevent varicocele-induced testicular injury. [ABSTRACT FROM AUTHOR]

Aim. The aim of this study was to investigate whether poly(ADP-ribose) polymerase (PARP) inhibition improves endothelin-1 (ET-1)-induced endothelial dysfunction (ED). Methods. Isolated rat thoracic aorta rings were incubated with ET-1 (10 nmol/L) in the presence or absence of either polyethylene glycol-superoxide dismutase (PEG-SOD; a cell-permeable superoxide radical scavenger, 41 U/mL) plus apocynin (a NADPH oxidase inhibitor, 300 µmol/L) or PJ34 (an inhibitor of polyADP-ribose polymerase, 3 µmol/L) for 18 h. Isometric tension studies were performed in response to acetylcholine (ACh; an endothelium-dependent vasodilator), sodium nitroprusside (SNP; an endothelium-independent vasodilator), and phenylephrine (Phe). PARP-1 and PAR (an end-product of PARP activity) expressions were evaluated by both Western blot and immunohistochemistry. Results. Incubation of thoracic aorta rings with ET-1 resulted in a significant inhibition of the response to ACh, while SNP-induced relaxation was unaffected. The contractile response to Phe increased in arteries that were incubated with ET-1. PARP-1 and PAR expressions increased after ET-1 incubation. The diminished vasoreactivity as well as changes in expressions of PARP-1 and PAR in ET-1-incubated vessels were improved by both PEG-SOD plus apocynin and PJ34. Conclusion. Our studies demonstrate that ED induced by ET-1 seems to be effected via oxidative stress in the thoracic aorta endothelium with subsequent activation of the PARP pathway. [ABSTRACT FROM AUTHOR]

Nephrotoxicity is one of the serious dose-limiting complications of methotrexate (MTX) when used in the treatment of various malignancies and nononcological diseases. The aim of this study was to investigate the role of poly(adenosine diphosphate ribose) polymerase (PARP) activity in MTX-induced nephrotoxicity. Rats were divided into 4 groups as control, MTX treated (MTX, 7 mg/kg per d, intraperitoneally [ip], once daily for 3 consecutive days), MTX plus 1,5-isoquinelinediol (ISO, a PARP inhibitor, 3 mg/kg per d, i.p.) treated, or ISO treated. Histopathology of kidneys was evaluated by light microscopy. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay was used to analyze apoptosis in kidney sections. Blood urea nitrogen (BUN), serum creatinine, and urinary N-acetyl-β-d-glucosaminidase (NAG) were used as biochemical markers of MTX-induced renal injury. Our results showed that MTX administration significantly increased BUN, serum creatinine, and urinary NAG levels. The PARP-1 and PAR (a product of PARP activity) expression and apoptotic cell death were also markedly increased in renal tubules after MTX administration. The ISO treatment attenuated MTX-induced renal injury, as indicated by BUN and serum creatinine levels, urinary NAG excretion, and renal histology. The PARP inhibitor treatment reduced PARP-1 and PAR expression to levels similar to that of controls. These results revealed that ISO may have a protective effect against the nephrotoxic effects of MTX by inhibiting PARP activation. This is the first study that demonstrates the role of PARP activation in MTX-induced nephrotoxicity and tubular apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study was to investigate the role of poly(ADP-ribose)polymerase (PARP) activity in vancomycin (VCM)-induced renal injury and to determine whether 1,5-isoquinelinediol (ISO), a PARP inhibitor agent, could be offered as an alternative therapy in VCM-induced renal impairment. Rats were divided into four groups as follows: (i) control (Group 1); (ii) VCM-treated (Group 2); (iii) VCM plus ISO-treated (Group 3); and (iv) ISO-treated (Group 4). VCM (200mg/kg, i.p., twice daily) was administered to Groups 2 and 3 for 7 days. ISO (3mg/kg/day, i.p.) treatment was started 24h before the first administration of VCM and continued for 8 days. After the 14th VCM injection, the animals were placed in metabolic cages to collect urine samples. All the rats were sacrificed by decapitation, blood samples were taken in tubes and kidneys were excised immediately. Blood urea nitrogen (BUN) and plasma creatinine, and urinary N-acetyl-β-d-glucosaminidase (NAG, a marker of renal tubular injury) were used as markers of VCM-induced renal injury in rats. Light microscopy was used to evaluate semi-quantitative analysis of the kidney sections. Poly(ADP-ribose) (PAR, the product of activated PARP) and PARP-1 expressions in renal tissues were demonstrated by immunohistochemistry and Western blot. VCM administration increased BUN levels from 8.07±0.75mg/dL to 53.87±10.11mg/dL. The plasma creatinine levels were 0.8±0.04mg/dL and 3.38±0.51mg/dL for the control and VCM-treated groups, respectively. Also, urinary excretion of NAG was increased after VCM injection. Besides, there was a significant dilatation of the renal tubules, eosinophilic casts within some tubules, desquamation and vacuolization of renal tubule epithelium, and interstitial tissue inflammation in VCM-treated rats. In VCM-treated rats, both PAR and PARP-1 expressions were increased in renal tubular cells. ISO treatment attenuated VCM-induced renal injury, as indicated by BUN and plasma creatinine levels, urinary NAG excretion, and renal histology. PARP inhibitor treatment also decreased PAR and PARP-1 protein expressions similar to that of controls. Herewith, the overactivation of the PARP pathway may have a role in VCM-induced renal impairment and pharmacological inhibition of this pathway might be an effective intervention to prevent VCM-induced acute renal injury. [Copyright &y& Elsevier]

Examines the effect of GABA and selective GABA agonists and antagonists on neurally induced tracheal contractions. Prevalence of auto-antibodies of GAD in animal models for insulin-dependent diabetes mellitus; Identification of greater GABA inhibitory effects in the trachea; Decrease in the response to electrical field stimulation.