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Previous studies have not defined the contribution of the splanchnic circulation to the total intravascular volume change associated with selective alpha adrenergic receptor stimulation. Since the splanchnic circulation is responsible for the total volume changes associated with other types of selective autonomic receptor stimulation, the present study was undertaken to examine the influence of alpha adrenergic receptor stimulation on splanchnic intravascular volume, the hemodynamic mechanism responsible for the splanchnic volume change, and the contribution of the splanchnic volume change to the change in total volume. In 35 anesthetized dogs, blood from the vena cavae was drained into an extracorporeal reservoir and returned to the right atrium at a constant rate so that changes in total intravascular volume could be measured as reciprocal changes in reservoir volume. Phenylephrine infusion (100 micrograms/min) for 20 min in 28 dogs was associated with a decrease in total volume of 64 +/- 17 (SEM) ml (P less than 0.0001). The response was abolished by either alpha adrenergic blockade or evisceration but was not attenuated by beta adrenergic blockade, sinoaortic baroreceptor denervation, ganglionic blockade, or splenectomy. In 5 animals with separate splanchnic perfusion and drainage, total and splanchnic volumes decreased 59 +/- 8 ml (P less than 0.0001) and 317 +/- 20 ml (P less than 0.0001), respectively, while transhepatic vascular resistance increased 17 +/- 4 cm H2O X min/l (P less than 0.0001). These responses were abolished after alpha adrenergic blockade. Thus, splanchnic volume decreases with alpha adrenergic receptor stimulation, despite an increase in hepatic resistance to splanchnic venous outflow. The splanchnic volume decrement is entirely responsible for the total volume decrement.
BACKGROUND: Intraabdominally insufflated carbon dioxide (CO2) during laparoscopy may have a specific effect on splanchnic circulation that may be unrelated to the effects of increased intraabdominal pressure alone. Therefore, the influences of insufflation with CO2 versus air on splanchnic circulation were compared. METHODS: Pigs were chronically instrumented for continuous recording of mesenteric artery, portal venous, inferior vena cava, and pulmonary arterial blood flow and portal venous pressure. After induction of anesthesia, CO2 or air was insufflated in 14 and 10 pigs, respectively. With the pigs in the supine position, intraabdominal pressure was increased in steps of 4 mmHg up to 24 mmHg by graded gas insufflation. RESULTS: During air insufflation, mesenteric artery vascular resistance was unchanged, whereas mesenteric arterial blood flow decreased with increasing intraabdominal pressure. Shortly after CO2 insufflation to an intraabdominal pressure of 4 mmHg, mean arterial pressure, mesenteric arterial blood flow, and mesenteric arterial vascular resistance were increased by 21%, 12% and 9%, respectively. Subsequently, with the onset of CO2 resorption in the third minute, mean arterial pressure declined to baseline values and mesenteric arterial vascular resistance declined to 85% of baseline values, whereas mesenteric arterial blood flow continued to increase to a maximum of 24% higher than baseline values. At steady-state conditions during CO2 insufflation, mesenteric arterial blood flow was increased up to an intraabdominal pressure 16 mmHg but decreased at higher intraabdominal pressures. CONCLUSIONS: In contrast to air insufflation, intraabdominal insufflation of CO2 resulted in a moderate splanchnic hyperemia at an intraabdominal pressure < or = 12 mmHg. At higher intraabdominal pressure values, pressure-induced changes became more important than the type of gas used.
BACKGROUND/AIMS: Portal hypertension is characterized by the development of a hyperdynamic splanchnic circulation. To determine whether this process is angiogenesis-dependent, we assessed the effects of SU5416, a specific inhibitor of VEGF receptor-2, in portal hypertensive rats. METHODS: Rats with portal hypertension induced by partial portal vein ligation were treated with SU5416 or vehicle during 5 days. Then, hemodynamic studies were performed using radioactive microspheres. Protein expressions of CD31, VEGF receptor-2 and VEGF were also determined by Western blotting. RESULTS: Treatment of portal hypertensive rats with SU5416 resulted in a significant and marked decrease (by 44%) in portal venous inflow, and increases in splanchnic arteriolar resistance (by 68%) and portal venous resistance (by 93%). In addition, SU5416 administration significantly inhibited the formation of portal-systemic collateral vessels (52% inhibition), as well as the splanchnic CD31 and VEGF receptor-2 protein expressions in portal hypertensive rats, compared with those receiving vehicle. CONCLUSIONS: This study demonstrates that the development of hyperdynamic splanchnic circulation and the formation of portal-systemic collateral vessels in portal hypertensive rats are angiogenesis-dependent processes that can be markedly inhibited by blockade of the VEGF signaling pathway. Therefore, modulation of angiogenesis may represent a potential target in the treatment of portal hypertension.
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Physalaemin has been reported as one of the most potent vasodilator and hypotensive peptides (1-4). In spite of these studies, however, the effect of the peptide on splanchnic circulation is not known precisely. In the present study, the effect of synthetic physalaemin on superior mesenteric arterial blood flow, portal venous blood flow and pancreatic capillary blood flow was investigated in dogs. Dose dependent increases of superior mesenteric arterial blood flow and portal venous blood flow were induced in response to physalaemin (0.1-10.0 ng/kg). Superior mesenteric arterial blood flow and portal venous blood flow attained maximal increases of 77 +/- 8.9% and 70 +/- 8.6%, respectively, at a dose of 5 ng/kg. Physalaemin caused a dose-related decrease in systemic arterial blood pressure. Pancreatic capillary blood flow did not show significant change with the administration of physalaemin. These data suggest that physalaemin may play some physiological roles in the regulation of splanchnic circulation.
Chronic high blood flow and the hyperdynamic circulatory syndrome in portal hypertension are associated with endothelial constitutive nitric oxide (NO) synthase (eNOS) upregulation and increased NO release. In portal vein-ligated (PVL) rats the splanchnic circulation is not yet hyperdynamic on day 3 postoperatively. In vitro perfused superior mesenteric arteries (SMAs) of day 3 PVL and sham rats were challenged with increasing flow rates or the alpha-adrenoreceptor agonist methoxamine (30 and 100 microM) before and after incubation with the NO inhibitor, Nomega-nitro-L-arginine (L-NNA, 10(-4) M). Perfusate NO metabolite (NOx) concentrations were measured by chemiluminescence. PVL rats expressed a significant hyporesponsiveness to increases in flow rate or methoxamine that was overcome by incubation with L-NNA. The PVL vasculature showed significantly higher slopes of NOx production vs. flow-induced shear stress, higher increases in perfusate NOx concentration in response to methoxamine, and higher eNOS protein levels (Western blot) compared with sham rats. In conclusion, eNOS-upregulation and increased NO release by the SMA endothelium occur before the development of the hyperdynamic splanchnic circulation, suggesting a primary role of NO in the pathogenesis of arterial vasodilatation.
Positive pressure ventilation is associated with a reduction and redistribution of cardiac output. Splanchnic blood flow is decreased. Blood supply of the liver is reduced exceeding the fall in cardiac output. As a result oxygen transport to the mesenteric bed and liver is curtailed. There is a concomitant impairment of hepatic venous outflow. These hemodynamic changes may cause functional, structural and metabolic disturbances in organs whose blood supply arises from splanchnic circulation.
A lumped parameter mathematical model to describe the propulsion of blood in the splanchnic circulation was developed by integrating the principles of mechanics and physiology. A set of governing equations by derived by specifically considering the contractility of the portal vein, hepatic vein, liver sinusoids, and of the draining lymphatics. These equations were then simulated on a computer. The present simulation results substantiate previous experimental observations that hepatic venous pressure leads to portal hypertension and increased liver interstitial fluid volume.
OBJECTIVE: To investigate the influence of increased intra-abdominal pressure during pneumoperitoneum on splanchnic circulation. DESIGN: Open study. SETTING: University hospital, Sweden. SUBJECTS: Five otherwise healthy patients (mean age of 34 years), undergoing laparoscopic cholecystectomy. INTERVENTIONS: Arterial and hepatic vein catheterization and simultaneous arterial and hepatic vein blood gas sampling in the awake state, during anaesthesia, after the establishment of pneumoperitoneum (intra-abdominal pressure level 11-13 mmHg) and after 30 and 60 minutes of pneumoperitoneum. MAIN OUTCOME MEASURES: Hepatic blood flow was estimated by the continuous infusion method and used as a measure of splanchnic blood flow. Splanchnic oxygen consumption was calculated according to the Fick principle. RESULTS AND CONCLUSION: Splanchnic blood flow and splanchnic oxygen consumption were not affected by pneumoperitoneum at this level of intra-abdominal pressure.
BACKGROUND: We tested the hypothesis that some of the maintenance of resting, regional hepato-splanchnic perfusion that is mediated by endogenous adenosine (ADO) during sepsis is interdependent with nitric oxide (NO). MATERIALS AND METHODS: Twenty-four hours after sepsis/sham induction, rats were divided into two groups. Group 1 received a 10-min infusion of the ADO antagonist 8-sulfophenyltheophylline (8-SPT; 0.9 mg/kg x min), followed by 10 min of 8-SPT plus L-NAME (0.5 mg/kg x min). Group 2 received L-NAME first followed by 8-SPT in the presence of L-NAME (all groups: n = 6-10). Hemodynamic and regional hepato-splanchnic blood flow measurements were made prior to infusions, 10 min after initiation of each single agent infusion, and again after double agent infusion. RESULTS: Twenty-four hours after sepsis hepato-splanchnic blood flow was significantly elevated, compared to nonseptic rats. Both ADO receptor blockade alone and NOS inhibition alone decreased total hepato-splanchnic blood flow to nonseptic values. Decreases in small intestinal and cecal blood flow accounted for the majority of this decrease, but decreased hepatic arterial perfusion contributed as well. No further alterations were seen when 8-SPT was infused in the presence of L-NAME, nor when L-NAME was infused in the presence of 8-SPT. CONCLUSIONS: These data indicate that there is significant interdependence of endogenous NO and ADO in maintaining resting small bowel, cecal, and hepatic arterial perfusion during sepsis. The lack of responses in other regions of the hepato-splanchnic circulation demonstrate regional specificity of this ADO-NO interdependence.
BACKGROUND: Liver cirrhosis increases portal vein pressure and alters the splanchnic circulation. With Doppler sonography, we investigated the hemodynamic changes in the portal vein, superior mesenteric artery, hepatic and splenic arteries and spleen size in a group of patients with end-stage liver disease before and after orthotopic liver transplantation (OLT). METHODS: Ten patients (seven male, three female; mean age = 48.8 +/- 7.6 years) who underwent OLT for liver cirrhosis mainly associated with hepatitis C virus infection completed the study. The control group consisted of 10 patients matched by sex and age who had no gastroenterologic or vascular diseases. All patients underwent duplex Doppler sonography (Toshiba SSA 270A with a 3.5-MHz probe) after 24 h of fasting (baseline) and then 6 and 12 months after OLT. The following parameters, expressed as the mean of three measurements, were evaluated: portal flow velocity (PFV), pulsatility index of the superior mesenteric artery (MAPI), resistance indexes of the hepatic (HARI) and splenic (SARI) arteries, and longitudinal diameter of the spleen (LDS). RESULTS: PFV in the pre-OLT phase was significantly lower in the patients than in the controls ( p < 0.0001); it progressively and significantly increased over baseline levels at 6 and 12 months ( p < 0.0001), approaching control values. LDS in the pre-OLT phase was significantly higher than in controls ( p < 0.0001); after OLT, it decreased significantly compared with baseline values ( p < 0.005). The MAPI of patients in the pre-OLT phase was lower than that in controls ( p < 0.0001); post-OLT, it progressively increased and reached values that were significantly above baseline at 12 months ( p < 0.005). In the pre-OLT phase, the HARI and SARI were significantly higher than in controls ( p < 0.04); 6 and 12 months after OLT, those values were significantly below baseline values ( p < 0.001), and there was no significant difference from control values. CONCLUSION: These data show that many of the hemodynamic parameters typical of decompensated cirrhosis improve progressively within 12 months after transplantation.
On-line recording of the sequential changes in systemic, pulmonary, mesenteric, hepatic and renal circulations during onset of endotoxaemia and at 24 h of established hyperdynamic sepsis were evaluated in seven chronically instrumented and sedated sheep receiving a continuous intravenous infusion of Escherichia coli endotoxin (20 ng min-1 kg-1). A transient and significant (P < 0.05) pulmonary arterial vaso-constriction was noted after 13 +/- 4 min, and was followed immediately by a simultaneous significant decrease of coeliac trunk, superior mesenteric artery, and portal vein blood flow to below 50% of baseline values. The superior mesenteric artery and portal vein blood flows partially recovered pre-endotoxin levels to 69 and 75% of baseline, respectively, after 70 min of endotoxin infusion. In contrast, the coeliac trunk blood flow remained reduced for a more prolonged period of time, but then completely recovered baseline values at 100 min. The response of the hepatic artery was biphasic, and consisted of a transient (5-10 min) vasoconstriction at 40 min followed by transitory increase of hepatic artery blood flow reaching a maximum of 921% of baseline values at 102 min. Contrasting with the early changes observed in mesenteric vascular resistances mostly unrelated to systemic haemodynamics, the response of the renal vasculature appeared to be more dependent on changes of renal perfusion pressure. A follow-up at 24 h revealed that the continuous intravenous infusion of endotoxin reproduced some of the most characteristic features of human sepsis with increased cardiac output and decreased vascular resistances of all vascular beds. We conclude that hepatic artery blood flow is selectively and considerably increased in early endotoxaemia in sheep independently of changes in portal vein blood flow, suggesting a disregulation of the physiologic hepatic arterial buffer response, most probably secondary to an increased liver oxygen demand required for phagocytosis, transport, and digestion of the the sudden overload of bacterial endotoxins.
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We have analysed the adjustment of blood flow and vascular conductance in the abundantly supplied splanchnic circulation to a generally released pressor reaction. Pressor responses were induced by 2-min periods of standardized, sustained handgrip in seven healthy students. The effects of handgrip tests were followed both in the fasting state and after the consumption of a substantial, mixed meal. In the first of the two sessions, changes in superior mesenteric artery blood flow were recorded and concomitant changes in local vascular conductance derived. In the other session, pressor released cardiac output changes were recorded and changes in total peripheral vascular conductance derived. Both types of flow changes were recorded using ultrasound Doppler technique. Typically, blood flow in the superior mesenteric artery increased two- to threefold after a meal. Handgrip contractions induced an initial rapid increase in heart rate, cardiac output and total peripheral conductance, followed by a gradual decline in total peripheral conductance and stroke volume and a gradual increase in heart rate and mean arterial pressure for the rest of the period. At the end of 2-min pressor periods, total peripheral conductance was only about 10% below the pre-handgrip level, whereas vascular conductance locally in the area of the superior mesenteric artery decreased by some 30%. Thus, it appears that the splanchnic vascular bed contributes markedly to the compound pressor response. Handgrips caused significantly less reduction in local vascular conductance in the post-prandial than in the pre-prandial state, indicating that blood flow to the digesting gastrointestinal tract retains a relatively high priority also in a pressor situation.
Postural hypotension results from sympathetic failure to cause superior peripheral vasoconstriction. The importance of the splanchnic circulation was studied by measuring mesenteric artery blood flow with duplex Doppler scanning. Nine normal and 9 Type 1 diabetic controls were compared to 8 Type 1 patients with autonomic neuropathy whose pressure fell 40-113 mmHg (range) on tilting. Measurements were made supine and after vertical tilt, fasting without insulin and after a 550 kcal meal. Superior mesenteric artery diameter decreased on tilting in normal controls but not in diabetic control or neuropathy groups (supine vs tilted: controls. 6.3 +/- 0.9 to 5 +/- 0.9 mm, p = 0.004, diabetic controls: 6.0 +/- 0.6 to 6.0 +/- 1.0 mm, and neuropathy group: 6.4 +/- 0.9 to 5.6 +/- 0.9 mm), but proportional blood flow changes were similar in all subjects (controls: 407 +/- 154 to 255 +/- 67 ml min-1 (-31%, p = 0.03), diabetic controls: 379 +/- 140 to 306 +/- 149 ml min-1 (-8%, p = 0.28), neuropathy group: 639 +/- 371 to 435 +/- 142 ml min-1 (-23%, p = 0.10). Postprandially supine superior mesenteric artery flow increased in all subjects but this did not affect the degree of systolic blood pressure drop on tilting (fasting vs postprandial blood flow: controls: 407 +/- 154 to 775 +/- 400 ml min-1 (p = 0.04), diabetic controls: 379 +/- 140 to 691 +/- 262 ml min-1 (p = 0.01), neuropathy group: 639 +/- 371 to 943 +/- 468 ml min-1 (p < 0.06)). The similarity of superior mesenteric artery responses to tilting in the three groups, and the lack of exacerbation of postural hypotension in the presence of postprandial hyperaemia indicates that control of splanchnic blood flow is less important in the aetiology of diabetic autonomic postural hypotension than previously thought.
Acute liver failure is associated with mortality of around 50%. The aim of the present studies was to examine the circulatory and metabolic state of the splanchnic region in acute liver failure. This had not been studied previously and it could be expected that improved understanding of the pathophysiology of acute liver failure could lead to improved therapy. Hepatic plasma flow was estimated in patients with acute liver failure after development of hepatic encephalopathy grade III, by the use of liver vein catheterization and continuous infusion of sorbitol. The method was evaluated against the prerequisites of Fick's principle. Hepatic plasma flow could be estimated with sorbitol but not in all patients and the standard error of the estimated hepatic blood flow was higher than in other patient groups. In 20 patients with acute liver failure, mean hepatic blood flow was increased. At the same time, the systemic and the peripheral hemodynamics were examined. The ratio hepatic blood flow/cardiac output was increased in many patients. Lower extremity blood flow was within normal limits. Thus, low systemic vascular resistance index in acute liver failure was likely to be a consequence of vasodilatation in the muscular resistance vessels and, in particular, in the splanchnic resistance vessels. Intervention with high-volume plasmapheresis changed systemic and splanchnic hemodynamics differently, suggesting that the splanchnic vasodilatation in liver failure may by caused by a specific mechanism different from the one that leads to peripheral vasodilatation. Infusion of dopamine increased mean arterial pressure, cardiac output, and hepatic blood flow in acute liver failure. The splanchnic exchange of substrates for oxidative metabolism was examined. Splanchnic oxygen consumption was increased. The ratio splanchnic oxygen consumption/systemic oxygen consumption indicated that 1/3 of the oxygen used in the whole body in acute liver failure was used in the splanchnic region. The splanchnic metabolism of fuel substrates was abnormal. Lactate and pyruvate was released and there were no detectable gradients of free fatty acids or of the sum of amino acids. There was a small release of ketone bodies. The data suggested that the energy needs of the failing liver was covered by intracellular fat. The hypothesis of splanchnic tissue hypoxia was examined from different approaches. The normal hepatic venous oxygen saturation, the splanchnic release of both lactate and pyruvate, and a normal hepatic venous pyruvate/lactate ratio in the presence of low acetoacetate/hydroxybutyrate ratio rather indicated high substrate turnover than splanchnic tissue hypoxia. Amino acid and ammonia metabolism was examined. It was observed that arterial ammonia concentration measured after institution of mechanical ventilation was associated with cerebral herniation 1-5 days later. The background for hyperammonemia was that ammonia was released from the splanchnic circulation. The data implied that glutamine was deamidated in the gut and alanine and ammonia was released into the portal vein as during normal circumstances. Then due to severely decreased hepatic function the liver was unable to remove ammonia and alanine as it normally would. Further, the data implied that urea synthesis was impaired. Exchange of ammonia in muscle tissue was studied in 7 patients with acute liver failure and muscle tissue seems to play a major role in ammonia detoxification in acute liver failure. Treatment with high-volume plasmapheresis decreased arterial ammonia, which was likely due to increased urea production or stimulation of glutamine synthesis in muscle tissue. These findings add to our understanding of the pathophysiology and have implications for the management of acute liver failure.