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Vascular Effects (vascular + effects)
Selected AbstractsVascular effects of adenosine and its analoguesDRUG DEVELOPMENT RESEARCH, Issue 1-2 2001Debbie Prentice Abstract The main action of adenosine on vascular beds is vasodilation via A2 receptors. In addition, A1 receptors are found in some blood vessels, where they cause contraction. Traditionally, adenosine-induced vasodilation in vitro has been attributed to A2A receptor activation; however, it is now clear that A2B receptors are also involved in the regulation of vascular tone. Endothelium dependence of A2 receptor-mediated responses is variable; in some tissues they are blocked by removal of endothelium and/or inhibition of NO-synthase and in some they are not. In addition to A2 receptor-mediated relaxation, there is much evidence that relaxations to adenosine and some of its analogues can also be mediated by a mechanism which cannot be blocked by adenosine receptor antagonists. There is evidence that these responses are endothelium- and NO-independent and that, under conditions where adenosine is taken up into cells, relaxations to the endogenous ligand are entirely mediated by this mechanism, suggesting it is of physiological significance. Drug Dev. Res. 52:346,349, 2001. © 2001 Wiley-Liss, Inc. [source] Characterization of endothelial factors involved in the vasodilatory effect of simvastatin in aorta and small mesenteric artery of the ratBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2000Maria Álvarez De Sotomayor Vascular effects of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, were studied in conductance (aorta) and resistance vessels (branch II or III of superior mesenteric artery, SMA) of the rat (12,14 weeks old). Simvastatin produced relaxation of both aorta and SMA, with and without functional endothelium. These responses were inhibited by the product of HMG-CoA reductase, mevalonate (1 mmol l,1). In vessels with functional endothelium, the NO-synthase inhibitor, L -NG -nitroarginine (L -NOARG, 30 ,mol l,1), inhibited simvastatin-induced relaxation. In the presence of L -NOARG, relaxation to simvastatin was lower in vessels with endothelium than in endothelium-denuded arteries without L -NOARG. The cyclo-oxygenase inhibitor, indomethacin (10 ,mol l,1), abolished endothelium-dependent component of the response to simvastatin in both arteries. The combination of L -NOARG plus indomethacin did not produce further inhibition. The Tp receptor antagonist, GR 32191B (3 ,mol l,1), did not affect relaxation in aorta but it reduced response to low concentrations of simvastatin in SMA. However, the inhibitory effect of L -NOARG was less marked in the presence of GR 32191B in aorta but not in SMA. The endothelium-dependent relaxation to simvastatin was inhibited by the superoxide dismutase (SOD, 100 u ml,1) or by the tyrosine kinase inhibitor, genistein (30 ,mol l,1) in the two arteries. The present study shows that simvastatin produces relaxation of conductance and small arteries through mevalonate-sensitive pathway. The endothelium-dependent relaxation to simvastatin involves both NO and vasodilator eicosanoids by a mechanism sensitive to SOD, and to genistein. Also, the results highlighted participation in the aorta of endothelial vasoconstrictor eicosanoids acting on the Tp receptor after blockage of NO synthase only. British Journal of Pharmacology (2000) 131, 1179,1187; doi:10.1038/sj.bjp.0703668 [source] Uridine adenosine tetraphosphate affects contractility of mouse aorta and decreases blood pressure in conscious rats and miceACTA PHYSIOLOGICA, Issue 2 2010P. B. Hansen Abstract Aim:, In the anaesthetized rat, uridine adenosine tetraphosphate (Up4A) is a circulating, endothelium-derived vasoconstrictor presumably operating as such in un-anaesthetized animals. The present study investigated the in vivo effects of Up4A in conscious mice and rats, and its direct vascular effects in the mouse aorta in vitro. Methods:,In vivo, Up4A was given as step-up infusion at rates of 8,512 nmol min,1 kg,1 for 30 min periods in chronically catheterized rodents. In vitro, the effect of Up4A on rings of mouse aortae mounted in a myograph was tested. Results:, High doses of Up4A (mice: 512 nmol min,1 kg,1; rats: 128 nmol min,1 kg,1) caused hypotension (99 ± 4 to 64 ± 7 mmHg and 114 ± 3 to 108 ± 3 mmHg, respectively, both P < 0.01). In rats, Up4A significantly decreased sodium excretion by >75% and potassium excretion by ,60% without significant changes in urine flow. Exposure of phenylephrine-contracted rings to increasing concentrations of Up4A elicited contraction at 10,7 and 10,6 mol L,1 (18 ± 2% and 76 ± 16% respectively); unexpectedly, 10,5 mol L,1 caused a biphasic response with a contraction (19 ± 6%) followed by a relaxation (,46 ± 6%). No relaxation was observed when the concentration was increased further. Bolus exposure to 10,5 mol L,1 of Up4A caused contraction (+80 ± 2%). Added successively to untreated vessels, increasing concentrations of Up4A (10,7,10,5 mol L,1) induced a biphasic response of contraction followed by relaxation. Conclusion:, Up4A has direct biphasic effects on vascular smooth muscle of the mouse aorta but vasoconstriction dominates at low concentrations. In conscious rodents, step-up infusions of Up4A elicit hypotension and electrolyte retention. [source] Comparison of in vivo effects of nitroglycerin and insulin on the aortic pressure waveformEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 1 2004J. Westerbacka Abstract Background, Individuals whose platelets are resistant to the antiaggregatory effects of insulin in vitro are also resistant to the antiaggregatory effects of nitroglycerin (GTN). We have previously shown that insulin acutely diminishes central wave reflection in large arteries and that this action of insulin is blunted in insulin-resistant subjects. However, as yet, no studies have compared the haemodynamic effects of insulin and GTN on large arterial function in the same group of subjects. The aim of this study was to determine whether resistance to the haemodynamic effects of insulin is a defect specific to insulin or whether individuals resistant to the vascular actions of insulin are also resistant to GTN. Design and results, Dose,response characteristics of insulin and GTN on the aortic waveform were determined using applanation tonometry and pulse wave analysis (PWA) in seven healthy men (age 26 ± 1 year, BMI 25 ± 2 kg m,2). Three doses of sublingual GTN (500 µg for 1, 3 or 5 min) and insulin (0·5, 1 or 2 mU kg,1 min,1 for 120 min) were administered on three separate occasions. Both agents dose-dependently decreased central pulse pressure and the augmentation index (AIx) without changing brachial artery blood pressure. We next compared responses to insulin (2 mU kg,1 min,1 for 120 min) and sublingual GTN (500 µg for 5 min) in 20 nondiabetic subjects (age 50 ± 2 year, BMI 21·0,36·3 kg m,2). Again, both agents significantly decreased AIx. Although the vascular effects of insulin and GTN vascular were positively correlated [Spearman's r = 0·92 (95% confidence interval 0·81,0·97), P < 0·0001], the time-course for the action GTN was faster than that of insulin. Brachial systolic blood pressure remained unchanged during the insulin infusion (122 ± 3 vs. 121 ± 3 mmHg, 0 vs. 120 min) but aortic systolic blood pressure decreased significantly by 30 min (111 ± 3 vs. 107 ± 3 mmHg, 0 vs. 30 min, P < 0·01). Similarly, GTN decreased aortic systolic blood pressure from 119 ± 4 to maximally 112 ± 3 mmHg (P < 0·001) without significantly decreasing systolic blood pressure in the brachial artery. Conclusions, The effects of insulin and GTN on large arterial haemodynamics are dose-dependent and significantly correlated. The exact mechanisms and sites of action of insulin and GTN in subjects with insulin resistance remain to be established. [source] Pressor and vascular effects of cardiac glycosidesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue S2 2001W. Kirch Background: For the past two decades, it has generally been accepted ('Blaustein hypothesis') that cardiac glycosides such as ouabain and digoxin increase the sodium and calcium content of smooth muscle cells, so inducing arterial vasoconstriction and a rise in blood pressure. Recent data from an experimental study we carried out led us to question this assumption. Design: A retrospective literature survey covering 20 years and including animal and human studies was performed. Representative results are presented. Results: Contradictory effects of cardiac glycosides on blood pressure and vasculature have been described. Increased, decreased or unaltered blood-pressure values have been observed following administration of the glycosides ouabain, digoxin and digitoxin. Moreover, vasoconstricting as well as vasodilating effects of cardiac glycosides have been demonstrated. Several recent studies show that cardiac glycosides such as digoxin and digitoxin can lead to a reduction of at least diastolic blood pressure. Conclusion: A slight vasodilation of resistance vessels followed by a fall in diastolic blood pressure could be a contributing factor for the beneficial effects of cardiac glycosides in patients with congestive heart failure. This vasodilation may be caused by central (neurohumoral) effects of digitalis glycosides. [source] Thiazolidinedione derivatives in diabetes and cardiovascular disease: an updateFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2008Pantelis A. Sarafidis Abstract As the incidence and the public health impact of type 2 diabetes are constantly rising, treatment of hyperglycemia, prevention of diabetes-related complications are currently top medical priorities. Within the last decade several new classes of oral hypoglycemic agents were added to our armamentarium against diabetes. Among these new classes, the group of thiazolidinediones, which act through reduction of insulin resistance is perhaps the most widely used. For about 20 years, numerous background and clinical studies have evaluated the beneficial and adverse effects of these compounds. Current knowledge suggests that thiazolidinediones are as effective as metformin or sulfonylurea derivatives in improving glycemic control and exert several other beneficial metabolic and vascular effects, such as improvement in lipid profile, blood pressure lowering, redistribution of body fat away from the central compartment, microalbuminuria regression, reduction in subclinical vascular inflammation and others. On the other hand, currently used thiazolidinediones have well-established side effects, most important of which are fluid retention leading to weight gain and heart failure deterioration. Further, in the expectance of proper outcome studies to clarify the effects of these agents in cardiovascular morbidity and mortality, data from recent meta-analyses suggest that rosiglitazone may increase the risk for some cardiovascular outcomes. This article will discuss all the above issues attempting to provide an updated overview of this expanding field. [source] Cardiovascular and Metabolic Effects of High-dose Insulin in a Porcine Septic Shock ModelACADEMIC EMERGENCY MEDICINE, Issue 4 2010Joel S. Holger MD Abstract Objectives:, High-dose insulin (HDI) has inotropic and vasodilatory properties in various clinical conditions associated with myocardial depression. The authors hypothesized that HDI will improve the myocardial depression produced by severe septic shock and have beneficial effects on metabolic parameters. In an animal model of severe septic shock, this study compared the effects of HDI treatment to normal saline (NS) resuscitation alone. Methods:, Ten pigs were randomized to an insulin (HDI) or NS group. All were anesthetized and instrumented to monitor cardiovascular function. In both arms, Escherichia coli endotoxin lipopolysaccharide (LPS) and NS infusions were begun. LPS was titrated to 20 ,g/kg/hour over 30 minutes and continued for 5 hours, and saline was infused at 20 mL/kg/hour throughout the protocol. Dextrose (50%) was infused to maintain glucose in the 60,150 mg/dL range, and potassium was infused to maintain a level greater than 2.8 mmol/L. At 60 minutes, the HDI group received an insulin infusion titrated from 2 to 10 units/kg/hour over 40 minutes and continued at that rate throughout the protocol. Survival, heart rate (HR), mean arterial pressure (MAP), pulmonary artery and central venous pressure, cardiac output, central venous oxygen saturation (SVO2), and lactate were monitored for 5 hours (three pigs each arm) or 7 hours (two pigs each arm) or until death. Cardiac index, systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), O2 delivery, and O2 consumption were derived from measured data. Outcomes from the repeated-measures analysis were modeled using a mixed-effects linear model that assumed normally distributed errors and a random effect at the subject level. Results:, No significant baseline differences existed between arms at time 0 or 60 minutes. Survival was 100% in the HDI arm and 60% in the NS arm. Cardiovascular variables were significantly better in the HDI arm: cardiac index (p < 0.001), SVR (p < 0.003), and PVR (p < 0.01). The metabolic parameters were also significantly better in the HDI arm: SVO2 (p < 0.01), O2 delivery (p < 0.001), and O2 consumption (p < 0.001). No differences in MAP, HR, or lactate were found. Conclusions:, In this animal model of endotoxemic-induced septic shock that results in severe myocardial depression, HDI is associated with improved cardiac function compared to NS resuscitation alone. HDI also demonstrated favorable metabolic, pulmonary, and peripheral vascular effects. Further studies may define a potential role for the use of HDI in the resuscitation of septic shock. ACADEMIC EMERGENCY MEDICINE 2010; 17:429,435 © 2010 by the Society for Academic Emergency Medicine [source] Insulin restores glucose inhibition of adenosine transport by increasing the expression and activity of the equilibrative nucleoside transporter 2 in human umbilical vein endotheliumJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2006Gonzalo Muńoz L -Arginine transport and nitric oxide (NO) synthesis (L -arginine/NO pathway) are stimulated by insulin, adenosine or elevated extracellular D -glucose in human umbilical vein endothelial cells (HUVEC). Adenosine uptake via the human equilibrative nucleoside transporters 1 (hENT1) and 2 (hENT2) has been proposed as a mechanism regulating adenosine plasma concentration, and therefore its vascular effects in human umbilical veins. Thus, altered expression and/or activity of hENT1 or hENT2 could lead to abnormal physiological plasma adenosine level. We have characterized insulin effect on adenosine transport in HUVEC cultured in normal (5 mM) or high (25 mM) D -glucose. Insulin (1 nM) increased overall adenosine transport associated with higher hENT2-, but lower hENT1-mediated transport in normal D -glucose. Insulin increased hENT2 protein abundance in normal or high D -glucose, but reduced hENT1 protein abundance in normal D -glucose. Insulin did not alter the reduced hENT1 protein abundance, but blocked the reduced hENT1 and hENT2 mRNA expression induced by high D -glucose. Insulin effect on hENT1 mRNA expression in normal D -glucose was blocked by NG -nitro- L -arginine methyl ester (L-NAME, NO synthase inhibitor) and mimicked by S -nitroso- N -acetyl- L,D -penicillamine (SNAP, NO donor). L-NAME did not block insulin effect on hENT2 expression. In conclusion, insulin stimulation of overall adenosine transport results from increased hENT2 expression and activity via a NO-independent mechanism. These findings could be important in hyperglycemia-associated pathological pregnancies, such as gestational diabetes, where plasma adenosine removal by the endothelium is reduced, a condition that could alter the blood flow from the placenta to the fetus affecting fetus growth and development. J. Cell. Physiol. 209: 826,835, 2006. © 2006 Wiley-Liss, Inc. [source] Effect of ropivacaine on endothelium-dependent phenylephrine-induced contraction in guinea pig aortaACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 10 2007P. L. Lin Background:, Previous studies have shown that ropivacaine has biphasic vascular effects, causing vasoconstriction at low concentrations and vasorelaxation at high concentrations. This study was designed to examine the role of the endothelium during accidental intravascular absorption of ropivacaine, and to elucidate the mechanisms responsible. Methods:, Isolated guinea pig aortic rings were suspended for isometric tension recording. The effects of ropivacaine on endothelium-intact and endothelium-denuded aortic rings were assessed. Endothelium-intact aortic rings were pre-contracted with phenylephrine before being exposed to ropivacaine and acetylcholine, in order to generate and compare concentration,response curves. In the absence and presence of yohimbine, propranolol, atropine, indometacin, NG -nitro- l -arginine methyl ester (l -NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or methylene blue, the contractile response induced by ropivacaine was assessed on endothelium-intact aortic rings pre-contracted with phenylephrine. Results:, Ropivacaine (3 × 10,4 to 10,2 mol/l) produced vasoconstriction in endothelium-denuded aortic rings, whereas no such response was observed in aortic rings with intact endothelium. In phenylephrine pre-contracted intact aortic rings, ropivacaine induced a greater degree of vasorelaxation than did acetylcholine. Yohimbine, propranolol and atropine all failed to affect the relaxation responses induced by ropivacaine. However, pre-treatment with indometacin (cyclo-oxygenase inhibitor), l -NAME (nitric oxide synthase inhibitor), methylene blue (soluble guanylyl cyclase inhibitor) or ODQ (soluble guanylyl cyclase inhibitor), significantly decreased the ropivacaine-induced relaxation of endothelium-intact aortic rings (3 × 10,4 to 10,2 mol/l). Conclusions:, Ropivacaine elicits an endothelium-dependent vasorelaxation in phenylephrine pre-contracted aortic rings via the nitric oxide,cyclic guanosine 3,,5,-monophosphate pathway and the prostaglandin system. [source] Treatment of classic Kaposi sarcoma with a nicotine dermal patch: a phase II clinical trialJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 9 2008JJ Goedert Abstract Background, Kaposi sarcoma (KS), a malignancy of dermal endothelial cells that is caused by human herpesvirus 8 (HHV8) infection, is sensitive to perturbations of immunity. Nicotine might be effective against KS because of its immunologic and vascular effects and because smoking is associated with a low risk of KS. Objective and study design, We conducted a masked, randomized phase 2 clinical trial of transdermal nicotine and placebo patches to assess the safety and efficacy of nicotine against classic KS (cKS). Subjects and methods, Three cKS lesions, predominantly nodules, in each of 24 non-smoking patients were randomly assigned to 15 weeks continuous treatment with nicotine patch (escalated to 7 mg), identical masked placebo patch or no patch. Changes in lesion area and elevation from baseline through six follow-up visits, by direct measurement and by two independent readers using digital photographs of the lesions, were compared using non-parametric and regression methods. Changes in longitudinal levels of HHV8 antibodies and DNA in blood cells were similarly assessed. Results, There were no systemic or serious adverse events, and compliance was good. One patient resumed smoking and discontinued patches, and two patients withdrew at week 12 for unrelated indications. Six (29%) of the remaining 21 suspended use of patches to relieve local skin irritation; four of these six completed the trial at reduced dose. Treatment assignment was not associated with significant or consistent changes in cKS lesion area or elevation, HHV8 viral load or antibodies. Conclusion, Transdermal nicotine and placebo patches caused no serious toxicities but had no demonstrable effect on nodular cKS lesions or HHV8 levels. [source] Changes in vascularity and blood volume as a result of photodynamic therapy can be assessed with power Doppler ultrasonographyLASERS IN SURGERY AND MEDICINE, Issue 3 2006DECVDI, Stefanie Ohlerth Dr. Med.Vet. Abstract Background and Objectives One principal mechanism of photodynamic therapy (PDT) in tumors is destruction of tumor-associated vasculature. In the present study, the vascular effects of PDT in tumors were investigated with power Doppler ultrasonography. Materials and Methods Seven cutaneous squamous cell carcinomas in cats were treated. Tumors were examined via power Doppler ultrasonography before, 5 minutes, 1 hour, and 24 hours after PDT. Images were digitized for computer-aided assessment of vascularity and blood volume. Results Mean baseline tumor vascularity and blood volume were moderate. During PDT, a significant decrease in vascularity and blood volume was noted. Lowest values were found 24 hours after PDT. Conclusions Power Doppler ultrasonography represents a non-invasive modality to successfully monitor the vascular effects and thus, treatment efficacy, of PDT. Lasers Surg. Med. 38:229,234, 2006. © 2006 Wiley-Liss, Inc. [source] Combination of photodynamic therapy and immunomodulation: Current status and future trendsMEDICINAL RESEARCH REVIEWS, Issue 4 2008Yong-Gang Qiang Abstract Photodynamic therapy (PDT) has been used for the treatment of nonmalignant and malignant diseases from head to toe. Over the last decade its clinical application has gained increasing acceptance around the world. Pre-clinical studies demonstrate that, in addition to the direct local cytotoxicity and vascular effects, PDT can induce various host immune responses. Recent clinical data also show that improved clinical outcomes are obtained through the combination of PDT and immunomodulation. This review will summarize and discuss recent progress in developing innovative regimen of PDT combined with immunomodulation for the treatment of both nonmalignant and malignant diseases. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 4, 632,644, 2008 [source] Does dopexamine influence regional vascular tone and oxygenation during intestinal hypotension?ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 10 2002S. Lehtipalo Background: Local effects of dopexamine on intestinal vascular tone and oxygenation were investigated during intestinal hypotension. To this end, we employed an experimental model, in which the superior mesenteric arterial pressure (PSMA) was controlled by an adjustable perivascular clamp. This approach enabled us to keep the intestinal perfusion pressure (IPP) constant in the face of any systemic circulatory alterations. Methods: In 11 barbiturate-anesthetized pigs, we instrumented the superior mesenteric circulation for assessments of vascular resistance (RMES), IPP, jejunal mucosal perfusion (Laser Doppler) and intestinal tissue oxygenation (microoximetry). Measurements were carried out before and during dopexamine infusions (0.5 and 1.0 µg·kg,1·min,1) at a freely variable PSMA (i.e. the perivascular clamp fully open) and at a PSMA of 50 mmHg and 30 mmHg. Results: At a constant PSMA of 50 mmHg, dopexamine had no significant intestinal vascular effects. However, at a constant PSMA of 30 mmHg, both doses of dopexamine were associated with decreases in RMES. Effects of dopexamine on intestinal oxygen delivery and extraction were minimal during these procedures, while a minor decrease in intestinal tissue oxygen tension was observed during dopexamine administration at the lowest IPP level. Conclusion: At very low intestinal perfusion pressures (approximately 30 mmHg) dopexamine produces intestinal vasodilation in excess of what is produced by intrinsic autoregulation. This suggests that there is a vasodilatory reserve in the intestine under such conditions and that a pharmacological vasodilator like dopexamine may improve intestinal circulation during regional severe hypotension. [source] Is there an experimental basis for the development of ischaemic colitis as a result of 5-HT3 antagonist treatment?NEUROGASTROENTEROLOGY & MOTILITY, Issue 2 2007M. Camilleri Abstract, 5-HT3 antagonists are effective treatments for chemotherapy-induced emesis and diarrhoea and urgency and pain associated with irritable bowel syndrome. Reports of ischaemic colitis led to restricted use of the approved drug, alosetron. This article briefly reviews the controversial information from epidemiology and adverse reaction reports and addresses the experimental basis for the development of ischaemic colitis as a result of 5-HT3 antagonist treatment. The author reviews the potential factors based involved in the ischaemic colitis and ways in which this class of compound may influence those factors based on experimental evidence, including the literature on any vascular effects of these agents. Finally, the article addresses the theoretical basis for the constipation as a predisposing factor for the development of ischaemic colitis. The evidence reviewed suggests that further studies are needed to explore the principles to prove or disprove the association. [source] Post-translational Regulation of Endothelial Nitric Oxide Synthase (eNOS) by Estrogens in the Rat VaginaTHE JOURNAL OF SEXUAL MEDICINE, Issue 5 2010Biljana Musicki PhD ABSTRACT Introduction., Estrogens control vaginal blood flow during female sexual arousal mostly through nitric oxide (NO). Although vascular effects of estrogens are attributed to an increase in endothelial NO production, the mechanisms of endothelial NO synthase (eNOS) regulation by estrogens in the vagina are largely unknown. Aims., Our hypothesis was that estrogens regulate eNOS post-translationally in the vagina, providing a mechanism to affect NO bioavailability without changes in eNOS protein expression. Methods., We measured eNOS phosphorylation and eNOS interaction with caveolin-1 and heat shock protein 90 (HSP90) in the distal and proximal vagina of female rats at diestrus, 7 days after ovariectomy and 2 days after replacement of ovariectomized rats with estradiol-17, (15 µg). Main Outcome Measures., Molecular mechanisms of eNOS regulation by estrogen in the rat vagina. Results., We localized phospho-eNOS (Ser-1177) immunohistochemically to the endothelium lining blood vessels and vaginal sinusoids. Estrogen withdrawal decreased phosphorylation of eNOS on its positive regulatory site (Ser-1177) and increased eNOS binding to its negative regulator caveolin-1 (without affecting eNOS/HSP90 interaction), and they were both normalized by estradiol replacement. Protein expressions of phosphorylated Akt (protein kinase B) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) were not affected by estrogen status, suggesting that the effect of estrogens on eNOS (Ser-1177) phosphorylation was not mediated by activated AKT or ERK1/2. eNOS phosphorylation on its negative regulatory site (Ser-114) was increased in the vagina by estrogen withdrawal and normalized by estradiol replacement, implying that the maintenance of low phosphorylation of eNOS on this site by estradiol may limit eNOS interaction with caveolin-1 and preserve the enzyme's activity. Total eNOS, inducible NOS, caveolin-1, and HSP90 protein expressions were not affected by ovariectomy or estradiol replacement in the distal or proximal vagina. Conclusions., These results define novel estrogen signaling mechanisms in the vagina which involve eNOS phosphorylation and eNOS,caveolin-1 interaction. Musicki B, Liu T, Strong TD, Lagoda GA, Bivalacqua TJ, and Burnett AL. Post-translational regulation of endothelial nitric oxide synthase (eNOS) by estrogens in the rat vagina. J Sex Med 2010;7:1768,1777. [source] Reversal Blood Flow Component as Determinant of the Arterial Functional Capability: Theoretical Implications in Physiological and Therapeutic ConditionsARTIFICIAL ORGANS, Issue 3 2009Daniel Bia Abstract In several physiological, pathological, and therapeutic circumstances, the arterial blood flow is acutely modified, increasing, in some vascular segments the reversal (SSR) and oscillatory (SSO) components of the shear stress. Recently, in an in vivo model we found a relationship between acute changes in SSR and SSO, and variations in the arterial viscoelasticity. As the arterial viscoelasticity and diameter are the main determinants of the arterial buffering (BF) and conduit (CF) functions, changes in those functions could be expected associated with variations in SSR and SSO. The aim was to analyze the association between acute increases in SSR and SSO, and changes in the aortic CF and BF. Aortic flow, pressure, and diameter were measured in 16 sheep under basal and high reversal and oscillatory flow conditions (high SSR and SSO). Aortic BF and CF were quantified, and their potential association with the SSR and SSO components were analyzed. During high reversal flow rate conditions, a smooth muscle contraction-pattern was evidenced, with an increase in BF and a decrease in CF. Changes in BF and CF were associated with the changes in SSR and SSO. The acute effects on the arterial wall biomechanics of variations in SSR and SSO could contribute to comprehend their chronic effects, and the meaning of the acute vascular effects of changes in SSR and SSO would depend on the situation. Increases in SSR and SSO could be associated with smooth muscle tone increase-dependent changes in arterial BF and CF. [source] Vasopressin-induced facilitation of adrenergic responses in the rat mesenteric artery is V1 -receptor dependentAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2003J. O. Streefkerk Summary 1 The present study was designed to analyse the possible involvement of V1 - and V2 -receptors in vasopressin (AVP)-induced facilitation of the sympathetic nervous system. Furthermore, we aimed to determine whether the site of facilitation by AVP is located pre- or postsynaptically. 2 Electrical field stimulation (EFS) was applied on the rat mesteric artery to activate the sympathetic nervous system. In addition, we evaluated the direct vascular effects of AVP. The postsynaptic effect of AVP on the sympathetic nervous system was investigated by exposing the vessels to exogenous noradrenaline. These experiments were performed in the absence or presence of selective V1 and V2 receptor antagonists SR 49059 and SR 121463, respectively. Desmopressin was applied as a selective V2 agonist. 3 The direct vasoconstrictor effect of AVP was antagonized by SR 49059 and not by SR 121463. Desmopressin neither showed any direct vasoconstrictor effect nor produced vasodilatation after a precontraction induced by noradrenaline (10 ,m). The EFS-induced rise in vascular tone could be increased by a sub-pressor concentration of AVP. This fascilitation could be antagonized by SR 49059, but not by SR 121463. Desmopressin did not influence the increase in vascular tone during EFS. Vasoconstriction induced by exogenous noradrenaline could be facilitated by a sub-pressor concentration of AVP and this selective postsynaptic effect could be antagonized by V1 -receptor blockade. 4 In conclusion, the AVP-induced facilitation of the sympathetic nervous system is completely V1 -receptor dependent and at least partly postsynaptically mediated. [source] Inhaled tiotropium bromide and risk of strokeBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2009Anthony Grosso WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Conflicting studies have raised uncertainty over the vascular effects of the long-acting anticholinergic, tiotropium bromide. WHAT THIS STUDY ADDS , Our results show no increased risk of stroke with tiotropium bromide, or with inhaled anticholinergics in general. AIMS A recent communication from the United States Food and Drug Administration highlighted a possible increased risk of stroke associated with use of the relatively new inhaled anticholinergic drug, tiotropium bromide. Using the United Kingdom General Practice Research Database, we set out to assess the risk of stroke in individuals exposed to inhaled tiotropium bromide and two other inhaled treatments for airways disease. METHODS We used the self-controlled case-series that reduces confounding and minimizes the potential for biases in the quantification of risk estimates. RESULTS Of 1043 people with a diagnosis of incident stroke who had had at least one prescription for tiotropium bromide, 980 satisfied inclusion criteria. The age-adjusted incidence rate ratio for all-cause stoke in individuals exposed to tiotropium bromide (n= 980), ipratropium bromide (n= 4181) and fluticasone propionate/salmeterol xinafoate (n= 1000) was 1.1 [95% confidence interval (CI) 0.9, 1.3], 0.8 (95% CI 0.7, 0.9) and 1.0 (95% CI 0.9, 1.2), respectively. CONCLUSIONS We found no evidence of an increased risk of all-cause stroke for individuals exposed to commonly prescribed inhaled treatments for chronic obstructive pulmonary disease. [source] Gender-specific vascular effects elicited by chronic ethanol consumption in rats: a role for inducible nitric oxide synthaseBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2008C R Tirapelli Background and purpose: Epidemiological data suggest that the risk of ethanol-associated cardiovascular disease is greater in men than in women. This study investigates the mechanisms underlying gender-specific vascular effects elicited by chronic ethanol consumption in rats. Experimental approach: Vascular reactivity experiments using standard muscle bath procedures were performed on isolated thoracic aortae from rats. mRNA and protein for inducible NO synthase (iNOS) and for endothelial NOS (eNOS) was assessed by RT-PCR or western blotting, respectively. Key results: In male rats, chronic ethanol consumption enhanced phenylephrine-induced contraction in both endothelium-intact and denuded aortic rings. However, in female rats, chronic ethanol consumption enhanced phenylephrine-induced contraction only in endothelium denuded aortic rings. After pre-incubation of endothelium-intact rings with L -NAME, both male and female ethanol-treated rats showed larger phenylephrine-induced contractions in aortic rings, compared to the control group. Acetylcholine-induced relaxation was not affected by ethanol consumption. The effects of ethanol on responses to phenylephrine were similar in ovariectomized (OVX) and intact (non-OVX) female rats. In the presence of aminoguanidine, but not 7-nitroindazole, the contractions to phenylephrine in rings from ethanol-treated female rats were greater than that found in control tissues in the presence of the inhibitors. mRNA levels for eNOS and iNOS were not altered by ethanol consumption. Ethanol intake reduced eNOS protein levels and increased iNOS protein levels in aorta from female rats. Conclusions and implications: Gender differences in the vascular effects elicited by chronic ethanol consumption were not related to ovarian hormones but seemed to involve the upregulation of iNOS. British Journal of Pharmacology (2008) 153, 468,479; doi:10.1038/sj.bjp.0707589; published online 26 November 2007 [source] Ultrasound assessment of short-term ocular vascular effects of intravitreal injection of bevacizumab (Avastin®) in neovascular age-related macular degenerationACTA OPHTHALMOLOGICA, Issue 6 2010Philippe Bonnin Acta Ophthalmol. 2010: 88: 641,645 Abstract. Purpose:, Angiogenic inhibitors, alone or combined with other therapies, are believed to represent a promising treatment for neovascularization in age-related macular degeneration (wet AMD). They can maintain or improve visual acuity (VA), at least for the first 2 years. However, evolution to retinal atrophy cannot be ruled out and it may be useful to assess the effects of antiangiogenic therapy on retinal and choroidal circulation. Methods:, We carried out a pilot study in 15 patients with wet AMD. Time-averaged mean blood flow velocities (BFVs) in the central retinal, temporal posterior ciliary and ophthalmic arteries (CRA, TPCA and OA) were measured by ultrasound imaging before and 4 weeks after a single intravitreal injection of 1.25 mg bevacizumab in 0.05 ml. Patients underwent two ophthalmic examinations, before and 4 weeks after injection, including VA measurement and optical coherence tomography (OCT3) examination. Results:, In treated eyes, bevacizumab injection was followed by a significant improvement in VA (from 20/125 to 20/80; p = 0.0214), and a decrease in mean central macular thickness (from 392 ± 96 ,m to 271 ± 50 ,m; p = 0.0038). Mean BFV decreased by 10% in the CRA (p = 0.0226), 20% in the TPCA (p = 0.0026) and 20% in the OA (p = 0.0003). No effect was observed in fellow eyes. Conclusions:, Intravitreal bevacizumab acutely improved VA and reduced central macular thickness in wet AMD. Ultrasound imaging revealed that BFVs decreased in all retrobulbar arteries, suggesting that after local diffusion, bevacizumab exerts a short-term regional effect. Bevacizumab might therefore induce hypoperfusion of the whole eye, which may correspond to a vascular side-effect. [source] 3142: Radiation-induced lens opacities: towards a new strategy to address the low dose risk research with the European network DoReMiACTA OPHTHALMOLOGICA, Issue 2010P GOURMELON In 2010, a Network of Excellence called DoReMi was launched by the EURATOM FP7 programme. DoReMi will act during the next six years as an operational tool for the development of a research platform devoted to low dose risk research in Europe. The research activities of DoReMi are implemented within three work packages: WP5, WP6, and WP7, which are respectively concerned with the shape of the dose effect relationship, individual radiation sensitivity and non-cancer effects. The overarching objective of WP7 is to implement a long-term, integrated approach involving several disciplines, namely, epidemiology, radiobiology and toxicology, for the purpose of risk evaluation for radiation-induced non-cancer effects. One of the operational objectives of the DoReMi WP7 consists of undertaking feasibility studies addressing the issues of vascular effects, lens opacities and cognitive effects. The presentation to be given will provide the assembly with (i) information about the European low dose risk research strategy; (ii) latest knowledge about the epidemiological evidence of radiation-induced lens opacities; (iii) information about the feasibility study of lens opacities to be launched in a group of interventional cardiologists (iv) most promising mechanistic hypotheses for the development of radiation-induced lens opacities recognizing that while posterior subcapsular cataracts are characteristic of an exposure to ionizing radiation, several sets of data suggest that the broader category of posterior cortical cataracts may also be regarded as radiation-associated. Eventually the presentation will discuss the issue of a threshold for the development of radiation-induced lens opacities and list the scientific questions raised by the radiation protection community to the vision and eye research community. [source] Recent concerns surrounding HRTCLINICAL ENDOCRINOLOGY, Issue 2 2003Mary Armitage Summary Millions of women are treated with hormone replacement therapy (HRT) for relief of menopausal symptoms, including vasomotor flushes and sweats for which oestrogen is uniquely and highly effective. Others may continue longer-term treatment in the hope that HRT will help to prevent chronic disease. The preservation of bone mass with continuing oestrogen therapy and reduction of subsequent risk of fracture is well established. Observational studies of the metabolic and vascular effects of oestrogens have suggested a potential benefit in reducing the risk of vascular disease, but recently published randomized controlled trials demonstrate no evidence of benefit in women with established vascular disease or in apparently healthy women. The increased risks of breast cancer and thromboembolic disease have been confirmed in these trials, with evidence of increased risk of stroke. Observational data suggest there may be a small increased risk of ovarian cancer associated with longer-term use of HRT. The premature termination of one arm of the Women's Health Initiative randomized controlled trial caused concern among patients, doctors and pharmaceutical companies. There are difficulties in extrapolating the results from trials using a specific HRT product to advise women on the wide range of other hormone products, doses, combinations and routes of administration. However, in the absence of evidence that other products are safer, the data suggest that for many women the risks associated with long-term use of HRT outweigh the benefits. There are nonhormonal strategies for the prevention and treatment of osteoporosis. HRT is not, and has never been, licensed in the UK for the prevention or treatment of vascular disease, and the data suggesting potential benefit should now be regarded as biased. The absolute incidence of an adverse event is low, and the risk in an individual woman in a single year is very small, but the risks are cumulative over time with long-term use. The risk,benefit balance of each woman needs regular reappraisal with continued use. [source] | |||||||||||||