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Nitric Oxide Pathway (nitric + oxide_pathway)
Selected AbstractsThe PFA-100Ô system for the assessment of platelet function in normotensive and hypertensive pregnanciesINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 2 2001Marco Marietta Platelet function was studied in 30 pregnant women: 14 normotensive (C), and 16 affected by pregnancy-induced hypertension (PIH). Platelet aggregometry (PA) on platelet-rich plasma according to Born was compared with the new PFA-100Ô System (Dade International Inc, Miami, USA). This device evaluates platelet function (expressed in seconds as closure time, CT) in anticoagulated whole blood ex vivo at high shear rates. PA (expressed as percentage of light transmission) and CT were measured at baseline and after incubation with L-Arginine (L-Arg). MANOVA for repeated measures showed that L-Arg incubation significantly decreased PA (F=7.2, P < 0.05) and increased CT (F=6.05, P < 0.05) in the whole population of pregnant women. Moreover, we analysed separately both parameters in C and in PIH subjects. No differences in PA were found in both groups, neither at baseline nor after L-Arginine incubation. In contrast, CT was significantly longer in PIH in comparison to C before (95.9 s vs. 84 s, P < 0.05) as well after (115 s vs. 92 s, P < 0.05) L-Arginine incubation. Data from PFA-100Ô confirm our previous reports that during pregnancy the L-Arginine: Nitric Oxide pathway regulates platelet function. In hypertensive patients a significant decrease in platelet function was found by using the PFA-100Ô system. [source] Nitric oxide and thyroid gland: modulation of cardiovascular function in autonomic-blocked anaesthetized ratsEXPERIMENTAL PHYSIOLOGY, Issue 3 2004Andrea Lorena Fellet We have previously reported that acute administration of NG -nitro- l -arginine methyl ester (l -NAME) increases the mean arterial pressure (MAP) and heart rate (HR) in autonomic-blocked (CAB) anaesthetized rats. In the present study we examined whether thyroid and adrenal glands are involved in these pressor and chronotropic responses. Sprague-Dawley rats were studied after bilateral vagotomy and ganglionic blockade with hexamethonium (10 mg kg,1), and stabilization of MAP with infusion of phenylephrine (PE) (6 ,g kg,1 min,1). The rats were divided into groups: L, CAB; PE, CAB + PE bolus (6 ,g kg,1); L-TX, thyroidectomy + CAB; L-AX, adrenalectomy + CAB; TX, only thyroidectomy; C, CAB. L, L-AX and L-TX groups received a bolus of l -NAME (7.5 mg kg,1). Triiodothyronine (T3), thyroxin (T4) and thyrotropin (TSH) levels were measured in L and L-TX rats before and after l -NAME administration. Reduced nicotamide adenine dinucleotide (NADPH) diaphorase activity was determined in heart and aorta of the TX group. The pressor response induced by l -NAME was similar in all groups. l -NAME-induced-tachycardia was associated with this rise in MAP. Adrenalectomy did not modify this chronotropic response, but it was attenuated by thyroidectomy. Thyroidectomy by itself decreased the circulating levels of T3 but it had no effect on the plasma levels of T4 and TSH. L and L-TX groups showed similar levels of circulating T4 and TSH, meanwhile the plasma level of T3 decreased in the L group. Nitric oxide synthase (NOS) activity in atria as well as in aorta was greater in the TX group compared with C. When autonomic influences are removed, the thyroid gland modulates intrinsic heart rate via a mechanism that involves, at least in part, the nitric oxide pathway. [source] Methylene blue inhibits angiogenesis in chick chorioallontic membrane through a nitric oxide-independent mechanismJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 2 2006N. Zacharakis Abstract Angiogenesis is the process of generating new blood vessels from preexisting vessels and is considered essential in many pathological conditions. The purpose of the present study was to evaluate the effect of methylene blue in chick chorioallantoic membrane angiogenesis model in vivo. In this well characterized model, methylene blue inhibited angiogenesis in a concentration-dependent manner. In addition, when methylene blue was combined with sodium nitroprusside, a spontaneous generator of nitric oxide, an inhibition of angiogenesis was evident which was comparable with that observed by the application of methylene blue alone. Sodium nitroprusside, alone, caused a significant inhibition in basal angiogenesis. These results provide evidence that methylene blue inhibits angiogenesis independently of nitric oxide pathway and suggest that methylene blue may be useful for treating angiogenesis-dependent human diseases. [source] Scutellarin-induced endothelium-independent relaxation in rat aortaPHYTOTHERAPY RESEARCH, Issue 11 2008Zhenwei Pan Abstract Scutellarin is a flavonoid extracted from the traditional Chinese herb, Erigeron breviscapus Hand Mazz. In the present study, the vasorelaxant effects of scutellarin and the underlying mechanism were investigated in isolated rat aorta. Scutellarin (3, 10, 30, 100 µm) caused a dose-dependent relaxation in both endothelium-intact and endothelium-denuded rat aortic rings precontracted with noradrenaline bitartrate (IC50 = 7.7 ± 0.6 µm), but not with potassium chloride. Tetraethylammonium, glibenclamide, atropine, propranolol, indomethacin and N(G)-nitro- l -arginine methyl ester had no influence on the vasorelaxant effect of scutellarin, which further excluded the involvement of potassium channels, muscarinic receptor, nitric oxide pathway and prostaglandin in this effect. Pretreatment with scutellarin decreased the tonic phase, but not the phasic phase of the noradrenaline bitartrate induced tension increment. Scutellarin also alleviated Ca2+ -induced vasoconstriction in Ca2+ -depleted/noradrenaline bitartrate pretreated rings in the presence of voltage-dependent calcium channel blocker verapamil. The noradrenaline bitartrate evoked intracellular calcium increase was inhibited by scutellarin. Scutellarin had no effect on phorbol-12,13-diacetate induced contraction in a calcium-free bath solution. These results showed that scutellarin could relax thoracic artery rings in an endothelium-independent manner. The mechanism seems to be the inhibition of extracellular calcium influx independent of the voltage-dependent calcium channel. Copyright © 2008 John Wiley & Sons, Ltd. [source] The Effect of Ovariectomy on Rat Vaginal Tissue Contractility and HistomorphologyTHE JOURNAL OF SEXUAL MEDICINE, Issue 2 2006F. Fatih Önol MD ABSTRACT Introduction., Ovarian hormones have an important role in age-related genital arousal disorders; however, our knowledge regarding possible vaginal wall morphology and contractility changes in low-hormonal states is limited. Aims., To investigate morphological and functional alterations in the vaginal tissue in a rat ovariectomy model and to show the differences between proximal and distal vagina. Methods., Six weeks following ovariectomy, vaginal tissues were examined under light and electron microscopy. Circularly cut distal and proximal tissues were studied in the organ bath under isometric tension and compared with age-matched controls. Contractile responses to electrical field stimulation (EFS), phenylephrine, carbachol, and the effects of alpha-1 and alpha-2 blockade on EFS-induced contractility were investigated. Relaxation responses to EFS and vardenafil were investigated in precontracted strips. Main Outcome Measures., Differences between control and ovariectomy groups in terms of vaginal tissue contractility and histomorphological properties. Results., Distal vagina showed different epithelial characteristics and a better-developed muscularis compared with proximal vagina. Ovariectomy caused thinning of the epithelium, severe degeneration in epithelial architecture, and smooth muscle atrophy. Contraction and relaxation responses of distal strips were significantly lower in ovariectomized rats. Contractile responses to neuropharmacological stimulation were insignificant in proximal strips of both groups. EFS-induced contractions in distal strips diminished significantly after alpha-1 and alpha-2 adrenergic blockade. EFS caused frequency-dependent relaxation responses in precontracted distal strips, which were significantly decreased after nitric oxide synthase inhibition. Conclusions., Ovariectomy causes significant alteration in rat vaginal tissue morphology and contractility. Contraction and relaxation responses of distal vagina are significantly greater compared with morphologically distinct proximal vagina. Alpha-1 and alpha-2 receptors are the main mediators of contraction in distal rat vaginal tissue whereas nitric oxide pathway may have at least a partial role in relaxation. Main mediators of the rat vaginal tissue relaxation and the effect of ovariectomy on this regulation are yet to be defined. Önol FF, Ercan F, and Tarcan T. The effect of ovariectomy on rat vaginal tissue contractility and histomorphology. J Sex Med 2006;3:233,241. [source] Endogenous nitric oxide synthase inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and deathBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2009Gregory J. Kato Summary Pulmonary hypertension (PH) in patients with sickle cell disease (SCD) is linked to intravascular haemolysis, impaired nitric oxide bioavailability, renal dysfunction, and early mortality. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases (NOS), is associated with vascular disease in other populations. We determined the plasma concentrations for several key arginine metabolites and their relationships to clinical variables in 177 patients with SCD and 29 control subjects: ADMA, symmetric dimethylarginine (SDMA), NG-monomethyl L-arginine (L-NMMA), N-omega-hydroxy-L-arginine (NOHA), arginine and citrulline. The median ADMA was significantly higher in SCD than controls (0·94 ,mol/l vs. 0·31 ,mol/l, P < 0·001). Patients with homozygous SCD had a remarkably lower ratio of arginine to ADMA (50 ,mol/l vs. 237, P < 0·001). ADMA correlated with markers of haemolysis, low oxygen saturation and soluble adhesion molecules. PH was associated with high levels of ADMA and related metabolites. Higher ADMA level was associated with early mortality, remaining significant in a multivariate analysis. Subjects with homozygous SCD have high systemic levels of ADMA, associated with PH and early death, implicating ADMA as a functional NOS inhibitor in these patients. These defects and others converge on the nitric oxide pathway in homozygous SCD with vasculopathy. [source] Biphasic effects of NMDA on the motility of the rat portal veinBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2000Z L Rossetti The effect of NMDA on the motility of the rat portal vein was studied in an isolated preparation. NMDA induced a concentration-dependent (10,7,10,4 M) increase of the contraction frequency (maximum increase, 148±6% of control at NMDA 10,4 M). The NMDA-induced excitatory response was prevented by the competitive NMDA receptor antagonists (±)-2-Amino-5-phosphonopentanoic acid (AP-5, 5×10,4 M) or (RS)-3-(2-carboxypiperazine-4-yl) propyl-1-phosphonic acid (CPP, 10,4 M). Tetrodotoxin (TTX, 10,6 M) or atropine (10,4 M) abolished the NMDA-induced increase of the portal vein motility and reversed the excitatory effect to a concentration-dependent inhibition (maximum inhibition, 52±8 and 29±7% of controls, respectively, at NMDA 10,3 M). Removal of the endothelium abolished the NMDA-induced inhibitory response. Sodium nitroprusside concentration-dependently (10,7,10,5 M) inhibited the portal vein motility, while L -NG -nitro-arginine methyl ester (L -NAME, 10,4 M) reversed the inhibitory effect of NMDA (in the presence of TTX), restoring the portal vein spontaneous activity to control values. These results show that NMDA modulates the portal vein motility in a biphasic manner: via indirect activation, through prejunctional NMDA receptors presumably located on intrinsic excitatory neuronal afferences, or via direct inhibition, through endothelial NMDA receptors activating the nitric oxide pathway. Overall these findings support the hypothesis of the existence of a peripheral glutamatergic innervation modulating the contractile activity of the rat portal vein. British Journal of Pharmacology (2000) 129, 156,162; doi:10.1038/sj.bjp.0703002 [source] Nitric oxide synthase in critically ischaemic muscle and alterations in isoform expression during revascularization surgery,BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 1 2008J. C. S. Tsui Background: Dysfunction of the nitric oxide pathway is implicated in peripheral arterial disease. Nitric oxide synthase (NOS) isoforms and NOS activity were studied in muscle from patients with critical leg ischaemia (CLI). Alterations in NOS during revascularization surgery were also assessed. Methods: Muscle biopsies were taken from patients with CLI undergoing amputation and also from patients undergoing femorodistal bypass at the start of surgery, after arterial clamping and following reperfusion. The presence of NOS within muscle sections was confirmed using reduced nicotinamide adenine dinucleotide phosphate diaphorase histochemistry. NOS isoform distribution was studied by immunohistochemistry. NOS mRNA and protein levels were measured using real-time reverse transcriptase,polymerase chain reaction and western blotting. NOS activity was assessed with the citrulline assay. Results: All three NOS isoforms were found in muscle, associated with muscle fibres and microvessels. NOS I and III protein expression was increased in CLI (P = 0·041). During revascularization, further ischaemia and reperfusion led to a rise in NOS III protein levels (P = 0·008). NOS activity was unchanged. Conclusion: Alterations in NOS I and III occurred in muscle from patients with CLI and further changes occurred during bypass surgery. Copyright © 2007 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] Therapeutic Potential of H11 Kinase for the Ischemic HeartCARDIOVASCULAR THERAPEUTICS, Issue 1 2007Ilan J. Danan ABSTRACT H11 kinase (H11K) is a small heat shock protein expressed predominantly in the heart and skeletal muscle, which plays a critical role in the maintenance of cardiac cell survival and in promoting cell growth through the activation of complementary signaling pathways. An overexpression of H11K was detected in various forms of heart disease, both in animal models and in patients, including acute and chronic ventricular dysfunction, and myocardial hypertrophy. Overexpression of H11K was reproduced in a cardiac-specific transgenic model, which led to significant progress in understanding the role and mechanism of action of the protein. Increased expression of H11K confers a cardioprotection that is equivalent to ischemic preconditioning; it promotes cardiac hypertrophy while maintaining contractile function. The overexpression of H11K is sufficient to activate most of the signaling pathways involved in cardiac cell growth and survival, including the phosphatidylinositol-3-kinase/Akt pathway, the AMP-dependent protein kinase, the PKC, pathway of ischemic preconditioning, the nitric oxide pathway of delayed cardioprotection, and the mTOR pathway of cell growth. As a result, the survival response triggered by H11K in the heart includes antiapoptosis, cytoprotection, preconditioning, growth, and metabolic stimulation. In addition to activating signaling pathways, H11K promotes the subcellular translocation and crosstalk of intracellular messengers. This review discusses the biological function of H11K, its molecular mechanisms of action, and its potential therapeutic relevance. In particular, we discuss how preemptive conditioning of the heart by H11K might be beneficial for patients with ischemic heart disease who would be at risk of further irreversible cardiac damage. [source] Hydrogen,potassium ATPase inhibitors induce relaxation on rabbit prostatic strips in vitroINTERNATIONAL JOURNAL OF UROLOGY, Issue 11 2002Ihsan Bagcivan Summary Background : To determine the relaxant effect of omeprazole and lansaprazole, hydrogen,potassium (H+,K+) ATPase inhibitors, on rabbit prostatic tissue in vitro. Methods : Male New Zealand white rabbits were sacrificed and their prostatic tissues were removed. The prostatic stromal strips were mounted in organ baths and relaxation responses were obtained in precontracted tissues with phenylephrine, carbachol and potassium chloride (KCl). Relaxation responses were controlled in the presence of various antagonists to explain the mechanism for relaxation exerted by omeprazole and lansaprazole. Results : Omeprazole and lansaprazole caused similar relaxation responses in the prostatic strips precontracted with phenylephrine, carbachol and KCl. The addition of prostaglandin synthase inhibitor indomethacin, nitric oxide synthase inhibitor L-NAME, potassium channel blockers, glibenclamide and tetraethylammonium into the organ baths did not change the relaxations induced by omeprazole and lansaprazole in vitro. Conclusion : Omeprazole and lansaprazole cause a relaxation in prostatic stromal tissue precontracted with phenyephrine, carbachol and KC1 in vitro. This relaxant effect is independent of H+,K+ ATPase inhibition. Additionally, cyclooxygenase and nitric oxide pathways do not contribute to this relaxant effect. Further studies are required to determine whether these drugs may have a beneficial effect in the non-operative treatment of benign prostatic hyperplasia. [source] The herbal preparation STW5 (lberogast®) has potent and region-specific effects on gastric motilityNEUROGASTROENTEROLOGY & MOTILITY, Issue 6 2004B. Hohenester Abstract, Functional dyspepsia (FD) is amongst the most common functional gastrointestinal disorders. Symptomatic treatment includes the use of herbal preparations whose effects on gastric motility are unclear. The present study aimed at investigating the effects of STW 5 (Iberogast®), a fixed combination of hydroethanolic herbal extracts, on gastric motility in vitro. Muscle strips from guinea-pig gastric fundus, corpus and antrum were set up in organ baths either in circular or longitudinal orientation. Addition of ethanol-free STW 5 to the organ baths (32,512 ,g mL,1) dose-dependently evoked a sustained and reversible relaxation of circular and longitudinal fundus and corpus muscle strips without changes in phasic activity. In contrast, antral muscle strips responded to STW 5 with a significant increase in the contractile force of phasic contractions without changes in tone. All effects were resistant to tetrodotoxin (0.5 ,mol L,1), atropine (1 ,mol L,1), , -conotoxin GVIA (0.5 ,mol L,1), capsaicin (1 ,mol L,1) or l -NAME (100 ,mol L,1), suggesting that neither nerves nor nitric oxide pathways were involved. These data demonstrate that STW 5 profoundly alters gastric motility in a region-specific but not layer-specific manner and thus implicates Iberogast® in the treatment of FD patients suffering from motility disorders with impaired fundus accommodation and/or antral hypomotility. [source] Emerging treatments for pulmonary arterial hypertensionTHE CLINICAL RESPIRATORY JOURNAL, Issue 3 2008Dermot S. O'Callaghan Abstract Introduction:, Pulmonary arterial hypertension (PAH) is a rare, progressive disease for which no cure exists. However, improved understanding of underlying pathophysiological mechanisms has led to the development of several effective treatments that improve haemodynamics and functional status. Objective:, An overview of emerging pharmacological approaches to the management of PAH is presented. Materials and methods:, A Medline search was performed for studies describing novel treatments and potential therapeutic targets relevant to PAH. Results:, Several different treatments that modulate abnormalities in the prostacyclin, endothelin and nitric oxide pathways have shown efficacy in randomised, controlled studies and are now licensed for use for PAH patients with advanced disease. Furthermore, there is now encouraging long-term survival data associated with use of these agents. A number of other targets with therapeutic potential have also been identified, such as serotonin, platelet-derived growth factor and vasoactive intestinal peptide. Recently, strategies involving combinations of different PAH-specific agents have emerged as a promising approach for those failing monotherapy. Conclusion:, The therapeutic options available for PAH has improved considerably in recent years and is likely to expand in the future. Please cite this paper as: O'Callaghan DS. Emerging treatments for pulmonary arterial hypertension. The Clinical Respiratory Journal 2008; 2: 132,140. [source] l -Arginine Inhibits Isoproterenol-Induced Cardiac Hypertrophy through Nitric Oxide and Polyamine PathwaysBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2008Yan Lin Nitric oxide exhibits antihypertrophic functions and inhibits cardiac remodelling. However, the metabolism of polyamines and the potential interactions with nitric oxide in cardiac hypertrophy remain unclear. We randomly divided Wistar rats into four treatment groups: controls, isoproterenol (ISO), ISO and l -arginine, and l -arginine. Isoproterenol (5 mg/kg/day, subcutaneously) and/or l -arginine (800 mg/kg/day, intraperitoneally) was administered once daily for 7 days. The expression of atrial natriuretic peptide mRNA was determined by reverse transcription,polymerase chain reaction, and fibrogenesis of heart was assessed by Van Gieson staining. Polyamines were measured with high-performance liquid chromatography, and plasma nitric oxide content and lactate dehydrogenase (LDH) activity were determined with a spectrophotometer. The expression levels of ornithine decarboxylase, spermidine/spermine N1-acetyltransferase (SSAT), endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) were analysed by Western blot. Heart-to-body weight ratio, left ventricle-to-body weight ratio, atrial natriuretic peptide mRNA expression, collagen fibres and LDH activity were elevated, both ornithine decarboxylase and SSAT proteins were up-regulated, and total polyamines were increased in the group treated with ISO. Additionally, the expression of iNOS was up-regulated, eNOS was down-regulated, and nitric oxide levels were low. Notably, cotreatment with l -arginine reversed most of these changes except for SSAT expression, which was further up-regulated. We propose that increased polyamines and decreased nitric oxide are involved in cardiac hypertrophy induced by ISO and suggest that l -arginine pre-treatment can attenuate cardiac hypertrophy through the regulation of key enzymes of the polyamine and nitric oxide pathways. [source] | ||||||||||