Effect of Topical Phenylephrine 2.5% on Episcleral Venous Pressure in Normal Human Eyes.

Purpose: Phenylephrine has been shown to affect intraocular pressure (IOP) but the mechanism of action is poorly understood. However, its action as a vasoconstrictor suggests possible effects on episcleral venous pressure (EVP). In this study, we evaluated the effect of phenylephrine on EVP and IOP in healthy subjects. Methods: Forty eyes of 20 subjects were included. Each subject received 3 drops of phenylephrine 2.5% in one eye at 1-minute intervals. The fellow eye served as control. Blood pressure, heart rate, and IOP and EVP of both eyes were measured at baseline, 15 minutes, and 60 minutes after instillation of phenylephrine. IOP was measured by pneumatonometry. EVP was assessed by using a computer-controlled episcleral venomanometer. Changes in IOP, EVP, blood pressure, and heart rate at 15 and 60 minutes were analyzed by paired t-tests. Results: IOP increased 15 minutes after instillation of phenylephrine in both treated (P = 0.001) and control eyes (P = 0.01) and returned to baseline at 60 minutes. The change in IOP at 15 minutes was not significantly different between the 2 groups. EVP in treated eyes was unchanged at 15 minutes (P = 0.8) but decreased significantly at 60 minutes (P < 0.001). In control eyes, there was no change in EVP at any time (P > 0.6). There were no significant changes from baseline in systolic and diastolic blood pressure and heart rate after instillation of phenylephrine. Conclusions: IOP elevation associated with topical phenylephrine is not caused by an increase in EVP in healthy subjects. Instead, EVP decreases with phenylephrine, but the mechanism remains to be determined.

Vasopressor Responsiveness Beyond Arterial Pressure: A Conceptual Systematic Review Using Venous Return Physiology.

ABSTRACT: We performed a systematic review to investigate the effects of vasopressor-induced hemodynamic changes in adults with shock. We applied a physiological approach using the interacting domains of intravascular volume, heart pump performance, and vascular resistance to structure the interpretation of responses to vasopressors. We hypothesized that incorporating changes in determinants of cardiac output and vascular resistance better reflect the vasopressor responsiveness beyond mean arterial pressure alone.We identified 28 studies including 678 subjects in Pubmed, EMBASE, and CENTRAL databases.All studies demonstrated significant increases in mean arterial pressure (MAP) and systemic vascular resistance during vasopressor infusion. The calculated mean systemic filling pressure analogue increased (16 ±â€Š3.3 mmHg to 18 ±â€Š3.4 mmHg; P = 0.02) by vasopressors with variable effects on central venous pressure and the pump efficiency of the heart leading to heterogenous changes in cardiac output. Changes in the pressure gradient for venous return and cardiac output, scaled by the change in MAP, were positively correlated (r2 = 0.88, P < 0.001). Changes in the mean systemic filling pressure analogue and heart pump efficiency were negatively correlated (r2 = 0.57, P < 0.001) while no correlation was found between changes in MAP and heart pump efficiency.We conclude that hemodynamic changes induced by vasopressor therapy are inadequately represented by the change in MAP alone despite its common use as a clinical endpoint. The more comprehensive analysis applied in this review illustrates how vasopressor administration may be optimized.

Episcleral Venous Pressure and the Ocular Hypotensive Effects of Topical and Intracameral Prostaglandin Analogs.

There is a limit beyond which increasing either the concentration of a prostaglandin analog (PGA) or its dosing frequency fails to produce increases in ocular hypotensive efficacy with topical dosing. Intracameral PGA dosing with a bimatoprost implant, however, does not exhibit the same intraocular pressure (IOP)-lowering plateau at studied concentrations, and the maximum-achievable ocular hypotensive effects are not yet known. This suggests that the bimatoprost intracameral implant may activate another mechanism of action in addition to the mechanism(s) activated by topical application. Episcleral venous pressure (EVP) is a key determinant of IOP, and experimental manipulation of the episcleral vasculature can change both EVP and IOP. The recent observation that topical and intracameral PGA drug delivery routes produce different patterns of conjunctival hyperemia suggested that the differences in the IOP-lowering profiles may be caused by differing effects on the episcleral vasculature. Recent experiments in animals have shown that topical PGAs increase EVP, while the bimatoprost intracameral implant causes a smaller, transient increase in EVP, followed by a sustained decrease. The increase in EVP could be limiting the IOP-lowering efficacy of topical PGAs. In contrast, the decrease in EVP associated with the bimatoprost implant could explain its enhanced IOP-lowering effects. Further research on EVP as a target for IOP lowering is indicated to improve our understanding of this potentially important pathway for treating patients with glaucoma.

Metabolomics discloses potential biomarkers to predict the acute HVPG response to propranolol in patients with cirrhosis.

BACKGROUND: In cirrhosis, a decrease in hepatic venous pressure gradient (HVPG) > 10% after acute iv propranolol (HVPG response) is associated with a lower risk of decompensation and death. Only a part of patients are HVPG responders and there are no accurate non-invasive markers to identify them. We aimed at discovering metabolomic biomarkers of HVPG responders to propranolol. METHODS: Sixty-six patients with cirrhosis and HVPG ≥ 10 mm Hg in whom the acute HVPG response to propranolol was assessed, were prospectively included. A targeted metabolomic serum analysis using ultrahigh-performance liquid chromatography coupled to mass spectrometry was performed. Different combinations of 2-3 metabolites identifying HVPG responders (HVPG reduction > 10%) were obtained by stepwise logistic regression. The best of these model (AUROC, Akaike criterion) underwent internal cross-validation and cut-offs to classify responders/non-responders was proposed. RESULTS: A total of 41/66 (62%) patients were HVPG responders. Three hundred and eighty-nine metabolites were detected and 177 were finally eligible. Eighteen metabolites were associated to the HVPG response at univariate analysis; at multivariable analysis, a model including a phosphatidylcholine (PC(P-16:0/22:6)) and a free fatty acid (20:2(n-6), eicosadienoic acid) performed well for HVPG response, with an AUROC of 0.801 (0.761 at internal validation). The cut-off 0.629 was the most efficient for overall classification (49/66 patients correctly classified). Two cut-off values allowed identifying responders (0.688, PPV 84%) and non-responders (0.384, NPV 82%) with undetermined values for 17/66 patients. Clinical variables did not add to the model. CONCLUSIONS: The combination of two metabolites helps at identifying HVPG responders to acute propranolol. It could be a useful non-invasive test to classify the HVPG response to propranolol.

Bimatoprost sustained-release intracameral implant reduces episcleral venous pressure in dogs.

OBJECTIVE: To determine the effect of a bimatoprost sustained-release intracameral implant (Bimatoprost SR) on episcleral venous pressure (EVP) in normal dogs. METHODS: Normotensive beagle dogs were randomized to receive Bimatoprost SR 30 µg (n = 7) or sham injection (needle insertion only, n = 7) in one eye on day 1. EVP was measured with an episcleral venomanometer through day 65. Episcleral aqueous outflow vessels were identified using fluorescence imaging following intracameral injection of indocyanine green in one additional animal. A separate cohort of dogs that had been trained for conscious intraocular pressure (IOP) measurements received Bimatoprost SR 30 µg (n = 8) in one eye; IOP was evaluated through day 66. RESULTS: Baseline mean EVP was 10.0 mmHg in the Bimatoprost SR group and 10.4 mmHg in the sham group. Eyes treated with Bimatoprost SR exhibited a transient increase in mean EVP that peaked at day 8, followed by a decrease to levels below baseline. From day 29 to day 65, the change in mean EVP from baseline ranged from -2.4 to -3.9 mmHg (P < 0.05 vs. sham). Baseline mean IOP in eyes treated with Bimatoprost SR was 14.9 mmHg, and a steady IOP reduction was maintained through day 66. Bimatoprost SR-treated eyes exhibited a selective, sustained dilation of aqueous outflow vessels that was not observed in sham-treated eyes. CONCLUSIONS: In normal dogs, Bimatoprost SR was associated with a transient increase in EVP followed by a sustained decrease. Changes in EVP were accompanied by a sustained dilation of aqueous outflow vessels.

Magnolol inhibits venous remodeling in mice.

Due to gravity the venous vasculature in the lower extremities is exposed to elevated pressure levels which may be amplified by obesity or pregnancy. As a consequence, venules dilate and may be slowly transformed into varicose or spider veins. In fact, chronically elevated venous pressure was sufficient to cause the corkscrew-like enlargement of superficial veins in mice. We hypothesized that biomechanical activation of endothelial cells contributes to this process and investigated the inhibitory capacity of Magnolol in this context - a natural compound that features multiple properties counteracting cellular stress. While Magnolol did not influence endothelial capillary sprout formation, it interfered with proliferation, ERK1/2 activity, gelatinase activity as well as baseline production of reactive oxygen species in these cells or murine veins. The anti-oxidative and anti-proliferative capacity of Magnolol was mediated through stimulation of heme oxygenase-1 expression. Finally, local transdermal application of Magnolol attenuated pressure-mediated development of varicose/spider veins in mice and was accompanied by the absence of proliferating and MMP-2 positive endothelial cells. Collectively, our data identified Magnolol as a potent inhibitor of biomechanically evoked endothelial cell activity during pressure-mediated venous remodeling processes which contribute to the development of varicose and spider veins.

Effect of Cromakalim Prodrug 1 (CKLP1) on Aqueous Humor Dynamics and Feasibility of Combination Therapy With Existing Ocular Hypotensive Agents.

Purpose: Cromakalim prodrug 1 (CKLP1) is a water-soluble ATP-sensitive potassium channel opener that has shown ocular hypotensive properties in ex vivo and in vivo experimental models. To determine its mechanism of action, we assessed the effect of CKLP1 on aqueous humor dynamics and in combination therapy with existing ocular hypotensive agents. Methods: Outflow facility was assessed in C57BL/6 mice by ex vivo eye perfusions and by in vivo constant flow infusion following CKLP1 treatment. Human anterior segments with no trabecular meshwork were evaluated for effect on pressure following CKLP1 treatment. CKLP1 alone and in combination with latanoprost, timolol, and Rho kinase inhibitor Y27632 were evaluated for effect on intraocular pressure in C57BL/6 mice and Dutch-belted pigmented rabbits. Results: CKLP1 lowered episcleral venous pressure (control: 8.9 ± 0.1 mm Hg versus treated: 6.2 ± 0.1 mm Hg, P < 0.0001) but had no detectable effect on outflow facility, aqueous humor flow rate, or uveoscleral outflow. Treatment with CKLP1 in human anterior segments without the trabecular meshwork resulted in a 50% ± 9% decrease in pressure, suggesting an effect on the distal portion of the conventional outflow pathway. CKLP1 worked additively with latanoprost, timolol, and Y27632 to lower IOP, presumably owing to combined effects on different aspects of aqueous humor dynamics. Conclusions: CKLP1 lowered intraocular pressure by reducing episcleral venous pressure and lowering distal outflow resistance in the conventional outflow pathway. Owing to this unique mechanism of action, CKLP1 works in an additive manner to lower intraocular pressure with latanoprost, timolol, and Rho kinase inhibitor Y27632.

Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: a randomised placebo-controlled trial.

BACKGROUND AND AIMS: Carvedilol is effective in the primary prophylaxis for large oesophageal varices. We investigated its use in preventing progression of small to large oesophageal varices. METHODS: Consecutive cirrhotics with small oesophageal varices were prospectively randomised to either carvedilol (n=70) or placebo (n=70) and followed up for a minimum of 24 months. Endoscopy was done at baseline and six monthly intervals. Hepatic vein pressure gradient (HVPG) was measured at baseline and at 12 months. The primary endpoint was development of large varices. RESULTS: Baseline characteristics in two groups were comparable. The predominant aetiology of cirrhosis was non-alcoholic fatty liver disease in both the groups. The mean dose of carvedilol administered was 12±1.67 mg/day and the target heart rate achieved was 58±3 bpm. A higher proportion of patients in carvedilol group had non-progression to large varices than placebo (79.4% vs 61.4%; p=0.04); the mean time of non-progression to large varices was 20.8 months (95% CI 19.4 to 22.4) in carvedilol group and 18.7 months (95% CI 17.1 to 20.4) in placebo group (p=0.04). There was a modest reduction of HVPG at 1 year in carvedilol group (-8.64%) compared with placebo (+0.33%) (p=0.22). None of the patients in either group died of variceal bleeding or liver-related causes. No major adverse events were observed in either group. CONCLUSIONS: Carvedilol is safe and effective in delaying the progression of small to large oesophageal varices in patients with cirrhosis. TRIAL REGISTRATION NUMBER: NCT01196507; post-results.

The significance of underlying cardiac comorbidity on major adverse cardiac events after major liver resection.

BACKGROUND: The risk of postoperative adverse events in patients with underlying cardiac disease undergoing major hepatectomy remains poorly characterized. METHODS: The NSQIP database was used to identify patients undergoing hemihepatectomy and trisectionectomy. Patient characteristics and postoperative outcomes were evaluated. RESULTS: From 2005 to 2012, 5227 patients underwent major hepatectomy. Of those, 289 (5.5%) had prior major cardiac disease: 5.6% angina, 3.1% congestive heart failure, 1% myocardial infarction, 54% percutaneous coronary intervention, and 46% cardiac surgery. Thirty-day mortality was higher in patients with cardiac comorbidity (6.9% vs. 3.7%, P = 0.008), including the incidence of postoperative cardiac arrest requiring cardiopulmonary resuscitation (3.8% vs. 1.2%, P = 0.001) and myocardial infarction (1.7% vs. 0.4%, P = 0.011). Multivariate analysis revealed that functional impairment, older age, and malnutrition, but not cardiac comorbidity, were significant predictors of 30-day mortality. However, prior percutaneous coronary intervention was independently associated with postoperative cardiac arrest (OR 2.999, P = 0.008). CONCLUSION: While cardiac comorbidity is not a predictor of mortality after major hepatectomy, prior percutaneous coronary intervention is independently associated with postoperative cardiac arrest. Careful patient selection and preoperative optimization is fundamental in patients with prior percutaneous coronary intervention being considered for major hepatectomy as restrictive fluid management and low central venous pressure anesthesia may not be tolerated well by all patients.

Giving Priority to Lipid Administration Can Reduce Lung Injury Caused by Epinephrine in Bupivacaine-Induced Cardiac Depression.

BACKGROUND AND OBJECTIVES: Epinephrine is usually administered in concert with a lipid emulsion during local anesthetic toxicity. However, the timing and role of epinephrine administration in combination with a lipid emulsion remain unclear. Specifically, the temporal association of epinephrine and lipid emulsion administration with related changes in pulmonary vascular pressures that may lead to pulmonary edema and hemorrhage needs to be determined. METHODS: This study consisted of 2 parts, experiments A and B. In experiment A, 24 adult male Sprague-Dawley rats were randomly divided into 3 groups (n = 8) to receive 1 of 3 treatments. All rats were anesthetized with an intraperitoneal injection of chloral hydrate, and anesthesia was maintained by sevoflurane. Each treatment group was initially given an infusion of bupivacaine (15 mg/kg) in order to produce cardiac depression. Group 1 (A-LEN) received a 30% lipid infusion (3 mL/kg) followed by a rapid epinephrine bolus (10 µg/kg), which was then followed by a normal saline infusion (3 mL/kg). Group 2 (A-NEL) first received a normal saline infusion (3 mL/kg) followed by a rapid epinephrine bolus, which was then followed by a 30% lipid emulsion. Group 3 (A-NEN, considered a control group) first received a normal saline infusion (3 mL/kg) followed by a rapid epinephrine bolus (10 µg/kg), which was then followed by another normal saline infusion (3 mL/kg). Lipid and normal saline infusions were administered over 1 minute, whereas epinephrine was injected rapidly. The continuous monitoring of blood pressure, heart rate, pulmonary arterial pressure, and pulmonary venous pressure occurred for 30 minutes. After the 30-minute monitoring period, lung tissue was sampled, and bronchoalveolar lavage fluid was collected. In experiment B, the experimental model and resuscitation protocol were similar to experiment A (B-LEN and B-NEL groups). In this arm of the experiment, bupivacaine concentrations of cardiac tissue were determined after the second minute of normal saline infusion. RESULTS: The A-LEN group produced the best rate pressure product when compared with the A-NEL or A-NEN group (P = 0.045, P = 0.011, respectively). In regard to pulmonary venous pressure, the A-LEN group was lower than the A-NEL or A-NEN group (P = 0.031, P = 0.006, respectively). Animals in the A-NEL and A-NEN groups rapidly developed pulmonary edema after infusion of epinephrine. The wet-to-dry ratio of the lungs in the A-LEN group was lower than that of the lungs in the A-NEL group (P = 0.024).The lung permeability index of the A-LEN group was lower than that of the A-NEL group (P = 0.011). In experiment B, concentrations of bupivacaine in cardiac tissue and plasma of the B-LEN group were lower than those of the B-NEL group (P = 0.001, P = 0.03, respectively). CONCLUSIONS: Giving priority to the administration of a lipid emulsion before the administration of epinephrine can reduce lung injury in bupivacaine-induced cardiac depression in rats.

The effect of propofol on haemodynamics: cardiac output, venous return, mean systemic filling pressure, and vascular resistances.

BACKGROUND: Although arterial hypotension occurs frequently with propofol use in humans, its effects on intravascular volume and vascular capacitance are uncertain. We hypothesized that propofol decreases vascular capacitance and therefore decreases stressed volume. METHODS: Cardiac output (CO) was measured using Modelflow(®) in 17 adult subjects after upper abdominal surgery. Mean systemic filling pressure (MSFP) and vascular resistances were calculated using venous return curves constructed by measuring steady-state arterial and venous pressures and CO during inspiratory hold manoeuvres at increasing plateau pressures. Measurements were performed at three incremental levels of targeted blood propofol concentrations. RESULTS: Mean blood propofol concentrations for the three targeted levels were 3.0, 4.5, and 6.5 µg ml(-1). Mean arterial pressure, central venous pressure, MSFP, venous return pressure, Rv, systemic arterial resistance, and resistance of the systemic circulation decreased, stroke volume variation increased, and CO was not significantly different as propofol concentration increased. CONCLUSIONS: An increase in propofol concentration within the therapeutic range causes a decrease in vascular stressed volume without a change in CO. The absence of an effect of propofol on CO can be explained by the balance between the decrease in effective, or stressed, volume (as determined by MSFP), the decrease in resistance for venous return, and slightly improved heart function. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register: NTR2486.

Effect of topical anesthesia on episcleral venous pressure in normal human subjects.

PURPOSE: Topical anesthetics can reduce episcleral venous pressure (EVP) and IOP in rabbits. In this study, we investigated the effect of topical anesthesia on EVP in normal human subjects. METHODS: We included in this study 30 eyes of 15 healthy volunteers who were habitual soft contact lens wearers. The EVP was measured before and at 5 and 10 minutes after instillation of topical proparacaine 0.5% in one eye. The EVP was measured by using a custom objective venomanometer. We compared EVP at 5 and 10 minutes after proparacaine to EVP before instilling proparacaine. RESULTS: There was no significant difference between EVP in eyes receiving topical anesthetic at 5 or 10 minutes (7.2 ± 2.2 and 7.6 ± 2.7 mm Hg, respectively; mean ± SD) compared to contralateral eyes (6.9 ± 2.5 and 7.3 ± 2.6 mm Hg, respectively; P > 0.10). As well, EVP was not significantly different 5 or 10 minutes after topical anesthesia compared to baseline in either the eyes receiving anesthetic or the contralateral eyes (all P > 0.10; minimum detectable difference, 1.4-1.9 mm Hg, α = 0.05, ß = 0.20, n = 30 eyes). CONCLUSIONS: The EVP in human eyes is not affected significantly by topical anesthetics.

Prevention of Rebleeding From Esophageal Varices in Patients With Cirrhosis Receiving Small-Diameter Stents Versus Hemodynamically Controlled Medical Therapy.

BACKGROUND & AIMS: Patients with cirrhosis and variceal hemorrhage have a high risk of rebleeding. We performed a prospective randomized trial to compare the prevention of rebleeding in patients given a small-diameter covered stent vs those given hepatic venous pressure gradient (HVPG)-based medical therapy prophylaxis. METHODS: We performed an open-label study of patients with cirrhosis (92% Child class A or B, 70% alcoholic) treated at 10 medical centers in Germany. Patients were assigned randomly more than 5 days after variceal hemorrhage to groups given a small covered transjugular intrahepatic portosystemic stent-shunt (TIPS) (8 mm; n = 90), or medical reduction of portal pressure (propranolol and isosorbide-5-mononitrate; n = 95). HVPG was determined at the time patients were assigned to groups (baseline) and 2 weeks later. In the medical group, patients with an adequate reduction in HVPG (responders) remained on the drugs whereas nonresponders underwent only variceal band ligation. The study was closed 10 months after the last patient was assigned to a group. The primary end point was variceal rebleeding. Survival, safety (adverse events), and quality of life (based on the Short Form-36 health survey) were secondary outcome measures. RESULTS: A significantly smaller proportion of patients in the TIPS group had rebleeding within 2 years (7%) than in the medical group (26%) (P = .002). A slightly higher proportion of patients in the TIPS group experienced adverse events, including encephalopathy (18% vs 8% for medical treatment; P = .05). Rebleeding occurred in 6 of 23 patients (26%) receiving medical treatment before hemodynamic control was possible. Per-protocol analysis showed that rebleeding occurred in a smaller proportion of the 32 responders (18%) than in nonresponders who received variceal band ligation (31%) (P = .06). Fifteen patients from the medical group (16%) underwent TIPS placement during follow-up evaluation, mainly for refractory ascites. Survival time and quality of life did not differ between both randomized groups. CONCLUSIONS: Placement of a small-diameter, covered TIPS was straightforward and prevented variceal rebleeding in patients with Child A or B cirrhosis more effectively than drugs, which often required step-by-step therapy. However, TIPS did not increase survival time or quality of life and produced slightly more adverse events. Clinical Trial no: ISRCTN 16334693.

Effect of AR-13324 on episcleral venous pressure in Dutch belted rabbits.

PURPOSE: AR-13324 is a potential new drug for the treatment of patients with glaucoma that has been shown to lower intraocular pressure (IOP) by increasing trabecular outflow facility and decreasing aqueous production. The present study tested the hypothesis that AR-13324 also lowers IOP by reducing episcleral venous pressure (EVP). METHODS: In Dutch Belted (DB) rabbits (n=11), arterial pressure (AP), IOP, carotid blood flow (BFcar), heart rate (HR), and EVP were measured invasively. Animals were dosed with AR-13324 (0.04%, topical, n=6) once daily for 3 days. On day 3, the animals were anesthetized, and then, measurements were obtained before dosing with AR-13324 or vehicle (n=5) and for 3 h after dosing. The data (mean±standard error of the mean) were analyzed by repeated measures ANOVA with post hoc testing. Retrospective baseline data from prior similar studies in New Zealand White rabbits were also compiled. RESULTS: Baseline values were as follows: AP, 101±3 mmHg; IOP; 33±3 mmHg; EVP, 16±1 mmHg; BFcar, 41±4 mL/min; and HR, 330±6 bpm. Three hours after AR-13324 dosing, IOP was reduced by 39%±7% (P<0.001) and EVP decreased by 35%±4% (P<0.05); after vehicle dosing, IOP was reduced by 24%±4% (P<0.05) and EVP increased by 25%±5% (P<0.05). AP, BFcar, and HR were unchanged. CONCLUSIONS: AR-13324 produces statistically significant lowering of EVP in DB rabbits. In addition, the baseline values for AP, IOP, EVP, BFcar, and HR in the DB rabbit are higher than those previously reported in the New Zealand rabbit.

Lower-limb veins are thicker and vascular reactivity is decreased in a rat PCOS model: concomitant vitamin D3 treatment partially prevents these changes.

Polycystic ovary syndrome (PCOS) causes vascular damage to arteries; however, there are no data for its effect on veins. Our aim was to clarify the effects of dihydrotestosterone (DHT)-induced PCOS both on venous biomechanics and on pharmacological reactivity in a rat model and to test the possible modulatory role of vitamin D3 (vitD). PCOS was induced in female Wistar rats by DHT treatment (83 µg/day, subcutaneous pellet). After 10 wk, the venous biomechanics, norepinephrine (NE)-induced contractility, and acetylcholine-induced relaxation were tested in saphenous veins from control animals and from animals treated with DHT or DHT with vitD using pressure angiography. Additionally, the expression levels of endothelial nitric oxide synthase (eNOS) and cyclooxygenase (COX-2) were measured using immunohistochemistry. Increased diameter, wall thickness, and distensibility as well as decreased vasoconstriction were detected after the DHT treatment. Concomitant vitD treatment lowered the mechanical load on the veins, reduced distensibility, and resulted in vessels that were more relaxed. Although there was no difference in the endothelial dilation tested using acetylcholine (ACh), the blocking effect of N(G)-nitro-l-arginine methyl ester (l-NAME) was lower and was accompanied by lower COX-2 expression in the endothelium after the DHT treatment. Supplementation with vitD prevented these alterations. eNOS expression did not differ among the three groups. We conclude that the hyperandrogenic state resulted in thicker vein walls. These veins showed early remodeling and altered vasorelaxant mechanisms similar to those of varicose veins. Alterations caused by the chronic DHT treatment were prevented partially by concomitant vitD administration.

Oral probiotic VSL#3 attenuates the circulatory disturbances of patients with cirrhosis and ascites.

BACKGROUND & AIMS: The modulation of gut flora constitutes a therapeutic tool in patients with liver disease, but some of its modalities require further investigation. Here, we evaluated the effects of probiotics on the hepatic and systemic haemodynamic alterations of advanced liver disease. METHODS: Seventeen patients with cirrhosis and ascites were prospectively included, five of whom abandoned this study prematurely. Hepatic and systemic haemodynamic evaluations were performed at baseline and after 6 weeks of receiving an oral VSL#3 probiotic preparation. Peripheral blood analyses included the evaluation of cytokines (TNF-alpha, IL-1beta, IL-6), bacterial translocation [bacterial DNA and lipopolysaccharide-binding protein (LBP)] and nitric oxide end-products (NOx). RESULTS: In 12 patients completing this study, the oral administration of VSL#3 resulted in reductions of the hepatic venous pressure gradient (HVPG, P < 0.001), cardiac index and heart rate (both P < 0.01) and in increases of the systemic vascular resistance (P < 0.05) and mean arterial pressure (P = 0.06). HVPG decreased at least 10% from baseline in eight patients (67%). Serum sodium increased in most patients (P < 0.01). All these changes were unrelated to the detection of bacterial DNA or to the levels of LBP, pro-inflammatory cytokines or NOx. No significant adverse effects were observed. CONCLUSION: Administration of the probiotic mixture VSL#3 improved the hepatic and systemic haemodynamics and serum sodium levels in patients with cirrhosis. Our results identify major effects of probiotics in liver disease and provide the rationale for assessing their therapeutic potential against the progression of portal hypertension and its complications in future clinical trials.