Superior Mesenteric Artery Resistance Research Articles

Melatonin alleviated splanchnic hyperdynamic circulation and portosystemic collaterals in cirrhotic rats

AbstractChronic liver damages may end up with cirrhosis and portal hypertension, featured by splanchnic hyperdynamic circulation, angiogenesis, and collaterals formation. Melatonin is used to improve sleep quality, which exerts anti‐inflammatory, anti‐angiogenesis, and vascular actions without significant side effects. However, the relevant impacts on aforementioned derangements are unclear. Liver cirrhosis was induced by bile duct ligation in Sprague‐Dawley rats. The rats received melatonin (40 mg/kg/day, i.p.) or vehicle for 28 days. Experiments were performed on the 28th day when cirrhosis developed. In cirrhotic rats, melatonin treatment significantly increased superior mesenteric artery resistance and reduced the blood flow. Melatonin enhanced the portosystemic collateral responsiveness to arginine vasopressin, reduced mesenteric vascular area, shunting degree, and down‐regulated mesenteric MMP‐2 protein expression. Melatonin improved the splanchnic hyperdynamic circulation, portosystemic collateral shunting, and mesenteric angiogenesis in cirrhotic rats. These beneficial effects make melatonin potentially feasible in clinical setting, but further investigation is required.

Cediranib ameliorates portal hypertensive syndrome via inhibition of VEGFR-2 signaling in cirrhotic rats

Portal hypertension (PHT) is a syndrome caused by systemic and portal hemodynamic disturbances with the progression of cirrhosis. However, the exact mechanisms regulating angiogenesis-related responses in PHT remain unclear. Cediranib is a potent inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, exhibiting a greater affinity for VEGFR-2. Liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague–Dawley rats. Sham-operated rats were controls. BDL and sham rats were randomly allocated to receive Cediranib or vehicle after BDL. On the 28th day, portal hypertension related parameters were surveyed. Cediranib treatment could significantly reduce the portal pressure (PP) in BDL rats, while it did not affect the mean arterial pressure (MAP) in sham groups and BDL groups. Cediranib treatment could significantly affect the stroke volume (SV), cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), superior mesenteric artery (SMA) flow and SMA resistance in BDL groups and BDL with Cediranib groups. Cediranib treatment could improve the mesenteric vascular remodeling and contractility. Cediranib treatment significantly reduced mesenteric vascular density. And phospho-VEGFR-2 was significantly downregulated by Cediranib. On the other hand, phospho-endothelial Nitric Oxide Synthases (phospho-eNOS) expressions were upregulated. Cediranib not only improved splanchnic hemodynamics, extrahepatic vascular remodeling and vasodilation, but also alleviated intrahepatic fibrosis and collagen deposition significantly. Cediranib treatment could reduce intrahepatic angiogenesis between BDL-vehicle and BDL-Cediranib rats. In conclusion, Cediranib could improve extrahepatic hyperdynamic circulation by inhibiting extrahepatic angiogenesis through inhibition of the VEGFR-2 signaling pathway, portal collateral circulation formation, as well as eNOS-mediated vasodilatation and vascular remodeling, and at the same time, Cediranib improved intrahepatic fibrogenesis and angiogenesis, which together alleviate cirrhotic PHT syndrome.

The relationship of foetal superior mesenteric artery blood flow and the time to first meconium passage in newborns with late-onset foetal growth restriction

This study aimed to assess the relationship between the foetal superior mesenteric artery (SMA) Doppler and the time to first meconium passage (FMP) in foetuses with late-onset foetal growth restriction. This single-centre, prospective, observational, cohort study included 57 patients with late-onset FGR. The newborn infants were divided into two groups: preterm (36.8%) and term (63.2%). The time to FMP of the infants was compared to the foetal SMA parameters obtained within a week before delivery. The median time to FMP was similar between two groups (p = .31). The SMA pulsatility index (PI) was higher in the preterm group (p < .01). There was no correlation between foetal SMA PI or resistance index and time to FMP. In late-onset FGR infants, our study found no association between SMA Doppler measurements and time to FMP. However, a significant difference was detected in SMA PI between preterm and term infants. Impact Statement What is already known in this subject? Foetal growth restriction (FGR) can affect splanchnic circulation of the foetus and this alteration can be associated with some disorders including necrotising enterocolitis. What do the results of this study add? Superior mesenteric artery (SMA) Doppler indices are not associated with first meconium passage in neonates with late-onset foetal growth restriction. The pulsatility index of SMA is significantly higher in foetuses delivered before term. What are the implications of these findings for clinical practice and/or further research? Further research should be conducted to investigate the relationship between foetal SMA Doppler indices and neonatal gastrointestinal morbidities in foetuses with early onset FGR with Doppler anomalies. These studies can shed light from the prenatal to the postnatal period, allowing clinicians to predict potential problems and take precautions.

Fluid handling and blood flow patterns in neonatal respiratory distress syndrome versus transient tachypnea: a pilot study

BackgroundCardiovascular and renal adaptation in neonates with Respiratory Distress Syndrome (RDS) and Transient Tachypnea of the Newborn (TTN) may be different.MethodsNeonates ≥32 weeks were diagnosed with RDS or TTN based on clinical, radiologic and lung sonographic criteria. Weight loss, feeding, urine output, and sodium levels were recorded for the first 3 days, and serial ultrasounds assessed central and organ Doppler blood flow. A linear mixed model was used to compare the two groups.ResultsTwenty-one neonates were included, 11 with TTN and 10 with RDS. Those with RDS showed less weight loss (− 2.8 +/− 2.7% versus − 5.6 +/− 3.4%), and less enteral feeds (79.2 vs 116 ml/kg/day) than those with TTN, despite similar fluid prescription. We found no difference in urine output, or serum sodium levels. Doppler parameters for any renal or central parameters were similar. However, Anterior Cerebral Artery maximum velocity was lower (p = 0.03), Superior Mesenteric Artery Resistance Index was higher in RDS, compared to TTN (p = 0.02).ConclusionIn cohort of moderately preterm to term neonates, those with RDS retained more fluid and were fed less on day 3 than those with TTN. While there were no renal or central blood flow differences, there were some cerebral and mesenteric perfusion differences which may account for different pathophysiology and management.

Resistance Index of the Superior Mesenteric Artery: Correlation With Lactate Concentration and Kinetics Prediction After Cardiac Surgery.

Objective: This study aimed to measure blood flow changes in the superior mesenteric artery (SMA), using Doppler ultrasound, in post-cardiac surgery patients, to evaluate the correlation between the SMA resistance index (SMA-RI) and lactate concentrations.Methods: The patients' basic hemodynamics, blood gas parameters and lactate concentration were collected at admission. Simultaneously, the SMA blood flow parameters were collected using Doppler ultrasound with the patients in the supine position. The lactate concentrations were measured again at 2, 6, and 12-h time points after the first test. The length of intensive care unit stays and prognoses continued to be monitored.Results: A total of 67 patients were included. The SMA-RI correlated with the admission (r = 0.3117, P = 0.0102), 2-h (r = 0.5091, P < 0.0001), 6-h (r = 0.5061, P < 0.0001), and 12-h (r = 0.2483, P = 0.0428) lactate concentrations. The SMA-RI could predict the 2-h 10% [area under the curve (AUC) = 0.8294, P < 0.0001] and 6-h 40% lactate kinetics (AUC = 0.7708, P = 0.0012). The cut-off value was 0.83. When the SMA-RI was <0.83, the specificity and sensitivity were 86.38 and 75.56%, respectively for the prediction of the 2-h >10% lactate kinetics, and 64.71 and 75.00%, respectively, for the prediction of the 6-h >40% lactate kinetics. The lactate concentrations at admission, 2 and 6-h points were higher in the high-RI group (RI ≥ 0.83) and the intensive care unit stays were significantly longer than in the low-RI group (P = 0.0005).Conclusions: The increase in SMA-RI was associated with higher lactate concentrations and worse lactate kinetics in post-cardiac surgery patients. This may be related to intestinal hypoperfusion. The SMA-RI may be one of the indicators that should be monitored to guide resuscitation in these patients.

Интенсивность мезентериального кровотока и степень зрелости кишечника у новорожденных группы риска по развитию некротизирующего энтероколита

Актуальность. В последние годы распространяется использование ультразвукового исследования брюшной полости для диагностики некротизирующего энтероколита (НЭК) у новорожденных. На начальных стадиях заболевания толщина стенки кишки, эхогенность и перфузия увеличиваются вследствие воспаления кишечника и отека слизистой оболочки. При прогрессировании НЭК утончение стенки кишечника, отсутствие перфузии и перистальтики превалируют и предупреждают о возможности перфорации кишечника. Это является доказательством диагностического преимущества УЗИ в отношении оценки прогрессирования НЭК. В статье представлены некоторые результаты собственного опыта использования УЗИ брюшной полости для диагностики НЭК у преждевременно рожденных детей. Цель: оценить степень зрелости кишечника и связь между допплеровскими индексами кишечной перфузии и сосудистым сопротивлением в бассейне верхней брыжеечной артерии у недоношенных новорожденных на 1–5-е сутки жизни с риском развития НЭК. Материалы и методы. В статье проведено обследование случайно выбранных 34 недоношенных детей с малой и очень малой массой тела и со сроком гестации 28–36 недель от матерей с отягощенным течением беременности. Оценивались: максимальная систолическая скорость, конечная диастолическая скорость и средняя скорость кровотока при ≥ 5 последовательных циклах сердечных сокращений. На основании этих показателей был рассчитан пульсовой индекс. Результаты. После проведенного исследования на 1–5-е сутки жизни ретроспективно новорожденные были распределены по группам в зависимости от клинических диагнозов в конце раннего неонатального периода. Новорожденные группы риска, родившиеся в асфиксии тяжелой степени, с высокими показателями сосудистого сопротивления в верхней брыжеечной артерии на 1–5-е сутки жизни, а также при толщине стенки кишки менее 1,6 мм имеют повышенный риск развития НЭК. Выводы. Выявленные высокие показатели сосудистого сопротивления в верхней брыжеечной артерии на 1–5-е сутки жизни у недоношенных детей с очень низкой массой тела и высоким риском развития НЭК помогут принимать правильные клинические решения по тактике ведения и лечения, в том числе о начале энтерального питания и расширении его объема.

Non-invasive assessment of liver abnormalities in pediatric Fontan patients.

Liver abnormalities are well known among long-term survivors of Fontan palliation, which remains the definite surgery for complex congenital heart disease and single ventricle physiology. Pediatric data however are scarce. We assessed the prevalence and degree of liver abnormalities in pediatric Fontan patients through non-invasive investigations suitable for longitudinal follow-up. Thirty-five patients with a median age of 11.8years (5.2-16.6) and median time since Fontan of 6years (1.17-13.83) were studied. Each child underwent a blood test, liver Doppler ultrasound (US), and transient elastography (TE). Healthy children were used as controls for TE measurement. AST, ALT, γGT, and direct bilirubin were abnormal in respectively 12 (34%), 5 (14%), 24 (69%), and 7 (20%) patients, while platelet count was decreased in 7 (20%). Splenomegaly was present in 7 (20%) patients. Portal vein mean flow velocity was < 15cm/s in 19 (54%) patients indicative of portal hypertension. Twenty-two patients (63%) showed inferior vena cava collapsibility index values below 17%, indicating venous congestion. Hepatic artery and superior mesenteric artery resistance index were inversely correlated with time post Fontan (p < 0.05). TE values in Fontan patients were significantly higher than controls, with a median of 12.6 versus 4.6kPa (p < 0.001) and were already increased shortly after Fontan completion.Conclusion: Liver abnormalities are frequently observed in pediatric Fontan patients. The non-invasive investigations used were not able to confirm liver fibrosis or differentiate hepatic congestion from fibrosis. Based on our findings, we propose a prospective screening protocol with serial measurements of laboratory, (Doppler) US, and TE parameters. What is Known: • Hepatic dysfunction is a well-known consequence of the Fontan circulation. • The natural history of Fontan-associated liver disease in the pediatric age group remains unclear. What is New: • Liver abnormalities are frequently observed in pediatric Fontan patients; however, differentiating liver fibrosis and hepatic congestion with non-invasive investigations remains challenging.Sonographic Doppler measurements may improve our insight in both Fontan-associated liver disease development and the functioning of the Fontan circulation. • A prospective screening protocol is proposed to improve our ability to detect Fontan-associated liver disease early on and understand its natural history.

Insulin reverses major portal hypertension-related derangements in rats with liver cirrhosis and diabetes.

Liver cirrhosis is accompanied by increased intrahepatic resistance and angiogenesis-related portosystemic collaterals formation. Diabetic patients suffer from abnormal vasoresponsiveness and angiogenesis that can be ameliorated by glucose control. However, the relevant presentation is not clear in those with cirrhosis and diabetes, in whom insulin is the treatment of choice. Liver cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation (BDL) and sham rats were used as controls. Streptozotocin 60 mg/kg (STZ, i.p., to induce diabetes) or vehicle was injected. The rats received BDL and STZ injections were injected with insulin or vehicle. On the 29th day after the procedure, the groups were surveyed for (1) systemic and portal hemodynamics; (2) mesenteric vascular density; (3) severity of portosystemic collaterals; (4) hepatic resistance using in situ liver perfusion; (5) histology survey of mesentery and liver; and (6) mesentery angiogenesis- and liver fibrogenesis-related protein expressions. Compared with the cirrhotic rats, the cirrhotic diabetic rats had lower body weight, cardiac output, superior mesenteric arterial (SMA) resistance and portal venous (PV) resistance, and higher SMA and PV flow, which were mostly reversed by insulin. The cirrhotic diabetic rats also had increased mesenteric vascular density, and enhanced pERK, pAkt, VEGF, VEGFR2 protein expressions that were reversed by insulin. Insulin decreased the degree of shunting in the diabetic cirrhotic rats. Hepatic perfusion pressure and severity of liver fibrosis were not significantly influenced by diabetes and insulin treatment in the cirrhotic rats. In conclusion, diabetes aggravated hemodynamic derangements, mesenteric angiogenesis and collaterals in the cirrhotic rats, which were mostly ameliorated by insulin. Further clinical investigations are warranted.

The beneficial effects of curcumin in cirrhotic rats with portal hypertension.

In liver cirrhosis with portal hypertension, the uneven distribution of vasoactive substances leads to increased intrahepatic vascular resistance and splanchnic vasodilatation. Angiogenesis also induces increased portal inflow and portosystemic collaterals. The collaterals may induce lethal complications such as gastroesophageal variceal hemorrhage, but the therapeutic effect of vasoconstrictors is still suboptimal due to poor collateral vasoresponsivenss. Curcumin has aroused much attention for its antifibrosis, vasoactive, and anti-angiogenesis actions. However, whether it affects the aforementioned aspects is unknown. Liver cirrhosis was induced by common bile duct ligation (CBDL) in Sprague–Dawley rats. Sham-operated rats were controls. CBDL and sham rats were randomly allocated to receive curcumin (600 mg/kg per day) or vehicle since the 15th day after BDL. On the 29th day, portal hypertension related parameters were surveyed. Portosystemic collateral in situ perfusion was performed to evaluate vascular activity. Chronic curcumin treatment decreased portal pressure (PP), cardiac index (CI) and increased systemic vascular resistance (SVR) in cirrhotic rats. In splanchnic system, curcumin decreased superior mesenteric artery (SMA) flow and increased SMA resistance. Mesenteric angiogenesis was attenuated by curcumin. Acute administration of curcumin significantly induced splanchnic vasoconstriction. The mesenteric protein expressions of p-endothelial nitric oxide synthase (eNOS), cyclooxygenase (COX) 2 (COX2), vascular endothelial growth factor (VEGF), p-VEGF receptor 2 (VEGFR2), and p-Erk were down-regulated. In collateral system, curcumin decreased portosystemic shunting and induced vasoconstriction. In conclusion, chronic curcumin administration in cirrhotic rats ameliorated portal hypertension related hemodynamic derangements and portosystemic collaterals. Curcumin also attenuated splanchnic hyperdynamic circulation by inducing vasoconstriction through inhibition of eNOS activation and by decreasing mesenteric angiogenesis via VEGF pathway blockade.

The early postnatal blood flow characteristics in the superior mesenteric and coeliac arteries in late preterm neonates

Objectives: The objective of this study is to evaluate intestinal blood flow changes within the first 72 h in the late preterm infants in comparison with the healthy term neonates. Methods: In this prospective study, we analyzed Doppler flow velocity waveforms of superior mesenteric artery (SMA) and coeliac trunc (TC) in 20 late preterm and 20 term infants at the age of 2, 24, and 72 h. Results: Significant end-diastolic velocity (end-diastolic velocity (EDV)SMA) rise up to 24 h was documented in all patients (late preterm: −9.32 ± 9.48 to 17.01 ± 6.94; p < .05; term: −8 ± 5.74 to 12.39 ± 3.33; p < .001), associated with a conversion from negative values to positive ones. Reversed blood flow was documented in SMA at 2 h in 75% late preterm neonates. Preterm infants showed significantly higher mean peak systolic velocities (peak systolic velocity (PSV)SMA), end-diastolic velocities (EDVSMA) at 24 h and PSVTC at 72 h than term infants (p < .05). The resistance and pulsatility indices (PI) decreased within 24 h in both groups and inversely reflected the postnatal changes in EDVSMA. Mean PIAMS at 2 h was significantly higher in term neonates. Conclusion: Late preterm neonates show similar progressive postnatal increase in blood flow velocities accompanied with a decrease in vascular resistance in SMA and TC then term neonates.

Normothermic Ex-Vivo Perfusion of the Intestine

Purpose: Ischemia reperfusion injury is a major risk factor for short and long-term functional survival after intestinal transplantation. Normothermic machine perfusion is an emerging biotechnology designed to prevent the injury associated with cold storage. This study is the first to describe an experimental model of normothermic ex-vivo perfusion of the intestine. Such an innovative approach is critical for the further improvement in the clinical outcome after transplantation of such a uniquely vulnerable hollow organ. Methods: The intestine of 10 cardiac death pigs were retrieved, flushed with UW solution, and perfused using washed pig RBCs based colloid solution with Hct value of 10–15 % at 37[deg]C for 6-12h. The perfusion circuit consisted of pulsatile pump, heat exchanger, oxygenator, and organ basin. The superior mesenteric artery was cannulated with free drainage of the vein. Mean arterial pressure was 80–100 mmHg with a flow of 0.010-0.014 L/min/kg. Peptide based elemental formula was used for luminal nutrition. The perfusate was analyzed for pH, PO2, PCO2, glucose. Results: Four intestines were used to establish the model (G-1) and the remaining six constitute the study group (G-2). The warm and cold ischemia time, 30 to 58min and 90 to 360min, respectively. G-2 showed more active peristalsis compared to G-1 with minimal edema and better perfusion indices. Vascular resistance was significantly (P=0.05) lower (97 ± 25 vs 203 ± 40 dyn[middot]s/cm5) with higher (P=0.02) pH (7.22 ± 0.04 vs 7.0 ± 0.06) and better (P=0.01) O2 consumption (330 ± 57 vs 107 ± 23 ml/min). Interestingly, the enterocyte glucose production was significantly (P=0.04) higher in G-2 compared to G-1 (293 ± 43.8 vs 107 ± 19.3 mg/dl).FIGURE 1: Superior mesenteric artery resistance, pH, oxygen consumption, and glucose level after 6 hours of normothermic machine perfusion.Conclusion: The technical feasibility of intestinal normothermic ex-vivo perfusion was demonstrated and the physio-metabolic principals were successfully established. The perfusate glucose level is unprecedented reliable bioviability marker. Accordingly, further experimental and future clinical trials are warranted.

Quantitative echocardiographic measures in the assessment of single ventricle function post-Fontan: Incorporation into routine clinical practice.

Quantitative echocardiographic measurements of single ventricular (SV) function have not been incorporated into routine clinical practice. A clinical protocol, which included quantitative measurements of SV deformation (global circumferential and longitudinal strain and strain rate), standard deviation of time to peak systolic strain, myocardial performance index (MPI), dP/dT from an atrioventricular valve regurgitant jet, and superior mesenteric artery resistance index, was instituted for all patients with a history of Fontan procedure undergoing echocardiography. All measures were performed real time during clinically indicated studies and were included in clinical reports. A total of 100 consecutive patients (mean age = 11.95±6.8years, range 17months-31.3years) completed the protocol between September 1, 2014 to April 29, 2015. Deformation measures were completed in 100% of the studies, MPI in 93%, dP/dT in 55%, and superior mesenteric artery Doppler in 82%. The studies were reviewed to assess for efficiency in completing the protocol. The average time for image acquisition was 27.4±8.8 (range 10-62minutes). The average time to perform deformation measures was 10.8±5.5minutes (range 5-35minutes) and time from beginning of imaging to report completion was 53.4±13.7minutes (range 27-107minutes). There was excellent inter-observer reliability when deformation indices were blindly repeated. Patients with a single left ventricle had significantly higher circumferential strain and strain rate, longitudinal strain and strain rate, and dP/dT compared to a single right ventricle. There were no differences in quantitative indices of ventricular function between patients <10 vs. >10years post-Fontan. Advanced quantitative assessment of SV function post-Fontan can be consistently and efficiently performed real time during clinically indicated echocardiograms with excellent reliability.

Splanchnic blood flow and vasoactive mediators in acute pancreatitis

Introduction: Changes of microcirculation and endothelial dysfunction are an important step from mild to severe disease. Changes in splanchnic arteries in acute necrotizing pancreatitis are the consequence of the release of vasoactive mediators. Materials and methods: The study involved 53 acute pancreatitis patients (28 – severe, 25 – mild). We measured interleukin-6, C3a and endothelin-1 in the blood plasma. Flow in the visceral arteries was assessed with the help of the Doppler sonography. Results: Mild acute pancreatitis often not accompanied by hemodynamic disorders according to Doppler ultrasound during the first week of illness. Pancreatic necrosis is noted a steady increase in peak systolic blood flow velocity and resistance index in the common hepatic, splenic and superior mesenteric arteries during the first week. In patients with acute pancreatitis on admission identified increase the levels endothelin-1 and C3a. A significant increase of both substances determined only in severe acute pancreatitis. The IL-6 levels were increased in all patients. There was a significant direct correlation concentration of IL-6 with peak systolic velocity in the superior mesenteric artery, with an index of resistance in common hepatic and superior mesenteric arteries. There was a significant direct correlation concentrations of C3a with peak systolic in the common hepatic and splenic arteries, with an index of resistance in superior mesenteric artery. Conclusion: Changes in the quantitative and qualitative detection of Doppler spectrum are ahead echographic signs of necrotizing forms of pancreatitis in B-mode ultrasound. IL-6, endothelin-1, and C3a levels of correlates with disturbances in splanchnic blood flow.

Thalidomide Improves the Intestinal Mucosal Injury and Suppresses Mesenteric Angiogenesis and Vasodilatation by Down-Regulating Inflammasomes-Related Cascades in Cirrhotic Rats.

Background and AimsBy blocking TNFα-related effects, thalidomide not only inhibits hepatic fibrogenesis but improves peripheral vasodilatation and portal hypertension in cirrhotic rats. Nonetheless, the investigation of thalidomide's effects on splanchnic and collateral microcirculation has been limited. Our study explored the roles of intestinal and mesenteric TNFα along with inflammasome-related pathway in relation to cirrhosis and the splanchnic/collateral microcirculation.MethodsUsing in vivo and in vitro approaches, mechanisms of the effects of thalidomide on intestinal and mesenteric inflammatory, vasodilatory and angiogenic cascades-related abnormalities were explored in cirrhotic rats that had received 1-month thalidomide (C-T) treatment.ResultsIn cirrhotic rats, high tumor necrosis factor (TNF)α, vascular endothelial growth factor (VEGF) and nitric oxide (NO)x levels were associated with the NOD-like receptors protein 3 (NLRP3), IL-1β and caspase-1 inflammasome over-expression in splenorenal shunt and mesenteric tissues. The thalidomide-related inhibition of mesenteric and splenorenal shunt inflammasome expression was accompanied by a significantly decreased intestinal mucosal injury and inflammasome immunohistochemical staining expression. Suppression of various angiogenic cascades, namely VEGF-NOS-NO, was paralleled by a decrease in mesenteric angiogenesis as detected by CD31 immunofluorescence staining and by reduced portosystemic shunting (PSS) in C-T rats. The down-regulation of the mesenteric and collateral vasodilatory VEGF-NOS-NO cascades resulted in a correction of vasoconstrictive hypo-responsiveness and in an attenuation of vasodilatory hyper-responsiveness when analyzed by in situ perfusion of the superior mesenteric arterial (SMA) and portosystemic collaterals. There was also a decrease in SMA blood flow and an increase in SMA resistance in the C-T rats. Additionally, acute incubation with thalidomide abolished TNFα-augmented VEGF-mediated migration of and tube formation of human umbilical vein endothelial cells, which was accompanied by corresponding changes in inflammatory and angiogenic substances release.ConclusionsThe suppression of inflammasome over-expression by chronic thalidomide treatment ameliorates inflammatory, angiogenic and vasodilatory cascades-related pathogenic changes in the splanchnic and collateral microcirculation of cirrhotic rats. Thalidomide seems to be a promising agent that might bring about beneficial changes to the disarrangements of peripheral, hepatic, splanchnic and collateral systems in cirrhosis.

Early Impact of Fontan Operation on Enteric Protein Loss

Protein-losing enteropathy (PLE) is a challenging complication after a Fontan operation. Subclinical enteric protein loss may precede development of overt PLE. We evaluated the acute effects of Fontan circulation on enteric protein loss and mesenteric vascular resistance. A prospective cohort study was performed evaluating enteric protein loss in children undergoing Fontan operations. Stool alpha-1 antitrypsin (A1AT) concentration was measured in the preoperative, early postoperative, and intermediate postoperative (3-9 months) periods. The intestinal circulation was characterized by Doppler-derived resistance indices of the superior mesenteric artery (SMA), and serum albumin and protein levels were obtained. We enrolled 33 participants at a median age at operation of 3.0 years (interquartile range [IQR], 2.5-3.3 years). No clinical PLE was observed. Six of the 93 stool samples obtained had elevated A1AT levels (>54 mg/dL), with 2 abnormal samples at each of the 3 time points. Two of the 5 participants with elevated stool A1AT values had significant hemodynamic disturbances requiring intervention (junctional bradycardia or tricuspid stenosis). There was no difference in SMA resistance in the preoperative versus early postoperative periods (p = 0.9). Serum albumin levels were lower in the early postoperative period compared with the preoperative period (3.2 mg/dL [{IQR}, 2.9-3.5] versus 4.1 mg/dL; IQR, 3.4-4.5; p = 0.01) but did not correlate with abnormal stool A1AT concentration or SMA resistance indices. The Fontan operation does not commonly result in acute development of increased enteric protein loss. However, increased enteric protein loss may occur in children before or after a Fontan operation, particularly when hemodynamic disturbances are present.

The renal effects of droxidopa are maintained in propranolol treated cirrhotic rats

Droxidopa improves hemodynamic and renal alterations of cirrhotic rats without changing portal pressure. We aimed to evaluate the effects of a combined treatment with droxidopa and non-selective beta-blockers or statins in order to decrease portal pressure, while maintaining droxidopa beneficial effects. Acute studies combining droxidopa with carvedilol, propranolol or atorvastatin in four-week bile-duct ligated (BDL) rats and a chronic study combining propranolol and droxidopa for 5days in CCl4 -cirrhotic rats were performed. Hemodynamic values were registered and biochemical parameters from blood and urine samples analyzed. Bile-duct ligated rats treated with carvedilol+droxidopa showed no changes in mean arterial pressure (MAP) and portal pressure (PP) compared to vehicles. Atorvastatin+droxidopa combination also failed to reduce PP, but maintained the beneficial increase in MAP and superior mesenteric artery resistance (SMAR) and decrease in blood flow (SMABF) caused by droxidopa. In contrast, the acute administration of propranolol+droxidopa significantly reduced PP maintaining a mild increase in MAP and improving, in an additive way, the decrease in SMABF and increase in SMAR caused by droxidopa. This combination also preserved droxidopa diuretic effect. When chronically administered to CCl4 -cirrhotic rats, propranolol+droxidopa caused a decrease in PP, a significant reduction in SMABF and an increase in SMAR. The combination did not alter liver function and droxidopa diuretic and natriuretic effect, and even improved free water clearance. Droxidopa could be effective for the renal alterations of cirrhotic patients on propranolol therapy and the combination of both drugs may balance the adverse effects of each treatment.

Effects of Lactose‐Containing vs Lactose‐Free Infant Formula on Postprandial Superior Mesenteric Artery Flow in Term Infants

Dietary dextrose and fructose may promote vascular inflammation and endothelial dysfunction. In certain infant populations, altered postprandial mesenteric hyperemia (PPH) may increase risk for feeding intolerance. To compare superior mesenteric artery (SMA) PPH following feeds of lactose-containing (LC) formula vs lactose-free (LF; dextrose + sucrose) formula. In a 2 × 2 crossover study with 6 term newborns, 3 received LC first followed by LF 3 hours later. The remaining 3 received the reverse order. Ultrasound measures of pre- and postprandial SMA flow, diameter, and resistance were taken 5 minutes preprandial and 10, 30, and 40 minutes postprandial. Mean ± SD age and weight (n = 6) were 24.1 ± 2.3 hours and 3.1 ± 0.21 kg. Formula intake was similar for LC and LF (22.5 ± 2.8 mL and 25 ± 1.8 mL, respectively; P = .076). Both formulas increased SMA flow at 10 and 30 minutes. However, postprandial flow was greater for LC overall (P = .004) and especially at 30 minutes (LC 103 ml/min, 52% increase vs LF 92.7 ml/min, 31% increase; P = .014). For both formulas, vasodilation was seen at 10 and 30 minutes and was overall significantly greater following LC than following LF (9.1% VS 6.5%; P = .028). Both formulas elicited significant decreases in sma vascular resistance over the 10- to 30-minute period (overall P = .016). However, decreases did not differ across formulas (P = .672). The LC formula elicited a greater SMA PPH response than did LF. SMA flow for both formulas was within normal limits; thus, differences are likely inconsequential for a term newborn. However, in a vulnerable preterm infant, differences may become significant.

5-hydroxytryptamine (5-HT) reduces total peripheral resistance during chronic infusion: direct arterial mesenteric relaxation is not involved

Serotonin (5-hydroxytryptamine; 5-HT) delivered over 1 week results in a sustained fall in blood pressure in the sham and deoxycorticosterone acetate (DOCA)-salt rat. We hypothesized 5-HT lowers blood pressure through direct receptor-mediated vascular relaxation. In vivo, 5-HT reduced mean arterial pressure (MAP), increased heart rate, stroke volume, cardiac index, and reduced total peripheral resistance during a 1 week infusion of 5-HT (25 µg/kg/min) in the normotensive Sprague Dawley rat. The mesenteric vasculature was chosen as an ideal candidate for the site of 5-HT receptor mediated vascular relaxation given the high percentage of cardiac output the site receives. Real-time RT-PCR demonstrated that mRNA transcripts for the 5-HT2B, 5-HT1B, and 5-HT7 receptors are present in sham and DOCA-salt superior mesenteric arteries. Immunohistochemistry and Western blot validated the presence of the 5-HT2B, 5- HT1B and 5-HT7 receptor protein in sham and DOCA-salt superior mesenteric artery. Isometric contractile force was measured in endothelium-intact superior mesenteric artery and mesenteric resistance arteries in which the contractile 5- HT2A receptor was antagonized. Maximum concentrations of BW-723C86 (5- HT2B agonist), CP 93129 (5-HT1B agonist) or LP-44 (5-HT7 agonist) did not relax the superior mesenteric artery from DOCA-salt rats vs. vehicle. Additionally, 5-HT (10–9 M to 10–5 M) did not cause relaxation in either contracted mesenteric resistance arteries or superior mesenteric arteries from normotensive Sprague- Dawley rats. Thus, although 5-HT receptors known to mediate vascular relaxation are present in the superior mesenteric artery, they are not functional, and are therefore not likely involved in a 5-HT-induced fall in total peripheral resistance and MAP.

The effect of isradipine in acute altitude hypoxia on cerebral, renal, and splanchnic blood flow evaluated by Doppler measurements

Recent studies have suggested that calcium antagonists may have a beneficial effect on high altitude pulmonary edema, but the effect on regional blood flow distribution is unknown. This study by transcranial and duplex Doppler evaluated the effect of the calcium antagonist isradipine on cerebral, renal, and splanchnic blood flows in acute altitude hypoxia. Twelve healthy subjects were investigated at sea level and repeatedly after 3–56 hours at high altitude (4350 m). Before the ascent, the subjects were randomized to treatment with isradipine 5 mg/day (n=6) or placebo (n=6). We measured flow velocities in middle cerebral arteries; flow rates in internal carotid arteries, portal vein, and right renal artery; and resistance indices in middle cerebral, internal carotid, renal, superior mesenteric, and hepatic arteries. Hypoxia increased middle cerebral artery flow velocity by 30% (placebo,p<0.05) and 39% (isradipine,p<0.01); increased internal carotid artery flow rate by 57% (placebo,p<0.01) and 55% (isradipine,p<0.05); and decreased middle cerebral and internal carotid artery resistance indices without differences between placebo and isradipine groups. Superior mesenteric artery resistance index was lower in hypoxia with isradipine compared with placebo (p<0.05), suggesting a higher splanchnic blood flow. In conclusion, acute hypoxia induced an increase in cerebral blood flow. Besides decreasing superior mesenteric artery resistance index, prophylactic isradipine did not modulate the circulatory responses to acute hypoxia. The clinical significance of this increased splanchnic blood flow remains unclear.

The relationship between endotoxemia and hepatic endocannabinoids in cirrhotic rats with portal hypertension

Cirrhosis is characterized by endotoxemia and increased intrahepatic resistance, which is caused by hepatic fibrosis and endothelial dysfunction, as well as the activated endocannabinoids system, including cannabinoid (CB(1) and CB(2)) receptors. Besides accelerating hepatic fibrogenesis, endotoxins induce the release of circulating endocannabinoids and portal hypertension in cirrhosis. This study examines how suppression of endotoxemia by antibiotics affects intrahepatic resistance and the hepatic endocannabinoid system in bile-duct-ligated (BDL) rats. Measurements were performed that included: mean arterial pressure, cardiac index (CI), systemic vascular resistance, superior mesenteric arterial blood flow and resistance, PVP, plasma endotoxin and hepatic tumor necrosis factor-α (TNFα), anandamide and 2-arachidonylglycerol, hepatic expression of cannabinoid receptors, endothelial nitric oxide synthase (eNOS), phospho-eNOS, Akt, phospho-Akt and thromboxane synthase (TXS), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), hepatic fibrosis, and leukocyte infiltration. Hepatic endothelial dysfunction was evaluated in BDL rats receiving vehicle (BDL-V) or 2-weeks of ciprofloxacin (BDL-cipro). Plasma endotoxin and hepatic TNFα, anandamide and 2-arachidonylglycerol, expression of TXS, MMP-2, TIMP-2, hepatic fibrosis and infiltration of hepatic leukocytes, CI, PVP and intrahepatic resistance were significantly lower in BDL-cipro than in BDL-V rats. Conversely, systemic vascular resistance, eNOS and Akt phosphorylation were significantly higher in BDL-cipro than in BDL-V rats. Improvement of hepatic endothelial dysfunction was associated with lower expression of hepatic CB(1) and a higher expression of hepatic CB(2) in BDL-cipro rats. In cirrhotic rats, ciprofloxacin suppressed endotoxemia and the hepatic endocannabinoid system thus ameliorating hyperdynamic circulation and decreased intrahepatic resistance by preventing hepatic fibrogenesis and endothelial dysfunction.