Liver Denervation Research Articles

Divergent splanchnic sympathetic efferent nerve pathways regulate interleukin-10 and tumour necrosis factor-α responses to endotoxaemia.

The efferent branches of the splanchnic sympathetic nerves that enhance interleukin-10 (IL-10) and suppress tumour necrosis factor-α (TNF) levels in the reflex response to systemic immune challenge were investigated in anaesthetized, ventilated rats. Plasma levels of TNF and IL-10 were measured 90min after intravenous lipopolysaccharide (LPS, 60µg/kg). Splanchnic nerve section, ganglionic blockade with pentolinium tartrate or β2 adrenoreceptor antagonism with ICI 118551 all blocked IL-10 responses. Restoring plasma adrenaline after splanchnic denervation rescued IL-10 responses. TNF responses were disinhibited by splanchnic denervation or pentolinium treatment, but not by ICI 118551. Splanchnic nerve branches were cut individually or in combination in vagotomized rats, ruling out any vagal influence on results. Distal splanchnic denervation, sparing the adrenal nerves, disinhibited TNF but did not reduce IL-10 responses. Selective adrenal denervation depressed IL-10 but did not disinhibit TNF responses. Selective denervation of either spleen or liver did not affect IL-10 or TNF responses, but combined splenic and adrenal denervation did so. Finally, combined section of the cervical and lumbar sympathetic nerves did not affect cytokine responses to LPS. Together, these results show that the endogenous anti-inflammatory reflex is mediated by sympathetic efferent fibres that run in the splanchnic, but not other sympathetic nerves, nor the vagus. Within the splanchnic nerves, divergent pathways control these two cytokine responses: neurally driven adrenaline, acting via β2 adrenoreceptors, regulates IL-10, while TNF is restrained by sympathetic nerves to abdominal organs including the spleen, where non-β2 adrenoreceptor mechanisms are dominant. KEY POINTS: An endogenous neural reflex, mediated by the splanchnic, but not other sympathetic nerves, moderates the cytokine response to systemic inflammatory challenge. This reflex suppresses the pro-inflammatory cytokine tumour necrosis factor-α (TNF), while enhancing levels of the anti-inflammatory cytokine interleukin-10 (IL-10). The reflex enhancement of IL-10 depends on the splanchnic nerve supply to the adrenal gland and on β2 adrenoreceptors, consistent with mediation by circulating adrenaline. After splanchnic nerve section it can be rescued by restoring circulating adrenaline. The reflex suppression of TNF depends on splanchnic nerve branches that innervate abdominal tissues including, but not restricted to, spleen: it is not blocked by adrenal denervation or β2 adrenoreceptor antagonism. Distinct sympathetic efferent pathways are thus responsible for pro- and anti-inflammatory cytokine components of the reflex regulating inflammation.

Morphometric analysis of the human common hepatic artery reveals a rich and accessible target for sympathetic liver denervation

This study quantified the distribution of nerves and adjacent anatomies surrounding human common hepatic artery (CHA) as guidance for catheter based denervation. CHA collected from cadaveric human donors (n = 20) were histologically evaluated and periarterial dimensions and distributions of nerves, lymph nodes, pancreas and blood vessels quantified by digital morphometry. Nerve abundance decreased significantly with distance from the aortic ostium (P < 0.0001) and was higher in the Superior/Inferior compared to the Anterior/Posterior quadrants (P = 0.014). In each locational group, nerves were absent from the artery wall, and starting 0.5–1.0 mm from the lumen exhibited a first order dependence on radial distance, fully defined by the median distance. Median subject-averaged nerve distance to the lumen was 2.75 mm, ranging from 2.1–3.1 mm in different arterial segments and quadrants and 2.0–3.5 mm in individuals. Inter-individual variance was high, with certain individuals exhibiting 50th and 75th nerve distances of, respectively, 3.5 and 6.5 mm The pancreas rarely approached within 4 mm of the lumen proximally and 2.5 mm more distally. The data indicate that the CHA is a rich and accessible target for sympathetic denervation regardless of sex and diabetes, with efficacy and safety most optimally balanced proximally.

Hepatic Sympathetic Denervation Reduces Hepatic Steatosis and Blunts Liver Lipid Acquisition Pathways in Diet‐Induced Obese Mice

Non‐alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is directly associated with obesity and a significant contributor to chronic metabolic and cardiovascular diseases. We recently demonstrated that diet‐induced NAFLD is accompanied by robust elevations in hepatic sympathetic nerve activity (SNA), and that pharmacological or surgical reductions in hepatic SNA reduces hepatic steatosis in obese mice. However, the underlying molecular mechanisms through which liver SNA contributes to NAFLD remain unknown. We hypothesized that liver SNA contributes to hepatic steatosis via influences on both liver acquisition and disposal pathways. Starting at 6 wks of age, male C57B1/6 mice were fed a high fat diet (HFD, 60% fat) or remained on normal chow (NC, 5% fat) for 10 wks. Liver selective sympathetic denervation was then performed by applying 10% phenol to the hepatic nerve bundle, whereas saline served as a sham surgery. Seven days after surgery, histological examination (Oil Red O) confirmed widespread and severe lipid accumulation in the liver of HFD mice relative to NC counterparts (0.6±0.4% vs 38±7% stained area, NC Sham vs HFD Sham, p&lt;0.05), which was reduced following liver denervation (16±5% stained area, HFD Denervation, p&lt;0.05 vs HFD sham). Western blot analysis revealed that hepatic carnitine palmitoyltransferase 1a (CPT1a), as an indicator of mitochondria b‐oxidation, and acyl‐coenzyme A oxidase 1 (ACOX1), as a marker of peroxisomal b‐oxidation, were elevated following HFD feeding (CPT1a: 1.0±0.0 vs 1.5±0.1; ACOX1: 1.0±0.1 vs 1.2±0.1 fold NC, NC Sham vs HFD Sham, p&lt;0.05 for both). Liver denervation did not affect hepatic CPT1a and ACOX1 expression in either diet group (e.g. CPT1a fold NC: NC Denervation 0.9±0.1; HFD Denervation 1.4±0.2, p&gt;0.05 vs respective Sham). In addition, liver denervation did not alter microsomal triglyceride transfer protein, an endoplasmic reticulum protein involved in the processing of VLDL in either diet group. Real time PCR analysis showed robust obesity‐associated elevations in liver fatty acid transport protein 5, suggestive of increased liver FFA uptake, which was reduced by 30% following removal of liver SNA (2.9±1.1 vs 9.7±1.0 fold NC, NC Sham vs HFD Sham, p&lt;0.05; 6.9±0.8 fold NC, HFD Denervation, p=0.2). Liver immunohistochemistry also indicated that the FFA transport protein cluster of differentiation 36 (CD36) was upregulated following HFD feeding and reduced in obese mice following removal of hepatic SNA (Figure). Lastly, HFD feeding resulted in an upregulation of mRNA indicators of triglyceride synthesis, (e.g. acyl‐CoA diacylglycerol acyltransferase 2: 1.0±0.2 vs 2.6±0.2 fold NC, NC Sham vs HFD Sham, p&lt;0.05), which were reduced by liver denervation in HFD animals (1.4±0.2 fold NC, HFD Denervation, p&lt;0.05 vs HFD sham). Collectively, these findings indicate that removal of the liver sympathetic nerves appears to beneficially alter hepatic triglyceride storage during HFD feeding by influencing lipid acquisition pathways, with less of an effect on triglyceride disposal mechanisms. These data also reinforce the idea that targeting hepatic sympathetic overactivity may be a novel therapeutic strategy to treat NAFLD.Support or Funding InformationHL116776This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Experimental Liver Autotransplantation With Novel Scheme of Veno-venous Bypass as a Model of Liver Denervation and Delymphatization

The impact of denervation and delymphatization (DD) on liver tissue remains a topic of major interest in liver transplantation, as the organ or its part continues to function well. Various chemical and/or surgical interventions have been developed to achieve in situ liver denervation and delymphatization, but it is evident that DD can be achieved only through “ectomia”, ie, complete isolation of the organ from adjacent and connected structures. This Study describes a liver DD model based on a technique of autotransplantation (replantation), maximally preventing ischemia in the transplanted (replanted) graft and dyscirculatory complications in the recipient. Experiments were performed on eight male mongrel dogs. Venous reservoir and roller pumps were used in a forced nontraditional bypass scheme. Autotransplantation was performed by step-by-step dissection of the suprahepatic, infrahepatic, and portal structures, leading to DD, with subsequent recovery of the blood vessel and bile duct. DD was achieved successfully with stable hemodynamic parameters during all surgery periods. All animals survived. This model of liver autotransplantation lead to DD of the organ. It was characterized by hemodynamic stability of the liver as well as of the whole body at every stage of the surgery, proffering liver DD for experimental studies.

Hemodynamic response to propranolol in patients with recurrent hepatitis C virus-related cirrhosis after liver transplantation: A case-control study

Cirrhosis recurrence is frequent after orthotopic liver transplantation for hepatitis C virus (HCV). Because transplantation causes liver denervation, we hypothesized that the response to propranolol might differ in transplant patients versus nontransplant patients with cirrhosis and portal hypertension. Twenty-one patients with cirrhosis recurrence after orthotopic liver transplantation with portal hypertension were compared to 20 nontransplant patients with cirrhosis, HCV, and portal hypertension, and they were matched by sex, age, presence of varices, and Child-Pugh score. The patients underwent systemic and hepatic hemodynamic measurements at the baseline and 20 minutes after intravenous propranolol (0.15 mg/kg). At the baseline, the transplant patients with cirrhosis had a lower hepatic venous pressure gradient (HVPG) than the nontransplant patients with cirrhosis (14.8 ± 2.9 versus 17.3 ± 4.4 mm Hg, P = 0.03) but a higher mean arterial pressure (MAP; 100.3 ± 12.3 versus 91.8 ± 11.6 mm Hg, P = 0.04) and higher systemic vascular resistance (2253 ± 573 versus 1883 ± 525 dyn/second/cm(-5) , P = 0.03). There were no differences in the cardiac index (CI). Propranolol significantly decreased HVPG to similar extents in transplant patients and nontransplant patients with cirrhosis (-14.1% ± 8.0% versus -16.9% ± 9.5%, P > 0.99). MAP tended to increase in transplant patients with cirrhosis, whereas it slightly decreased in nontransplant patients (5.1% ± 14.2% versus -4.8% ± 6.4%, P = 0.007); however, the reduction in CI was less marked in transplant patients with cirrhosis (-18.6% ± 7.6% versus -26.9% ± 9.0%, P = 0.005). In conclusion, patients with HCV-related cirrhosis and portal hypertension after orthotopic liver transplantation have lower baseline HVPG values but similar HVPG responses to propranolol infusions in comparison with nontransplant patients with cirrhosis. In contrast to nontransplant patients, propranolol increases the systemic vascular resistance and arterial pressure in transplant patients with cirrhosis and attenuates the fall in CI.

Liver denervation increases the levels of serum triglyceride and cholesterol via increases in the rate of VLDL secretion

Intra-hepatic metabolism of lipids is subject to hormonal, metabolic and neural regulation, but little is known about the latter. Catecholamines stimulate the output of glucose and inhibit the release of very low density lipoproteins (VLDL) from the liver. To investigate the effects and involved mechanism of liver denervation on the levels of serum and liver lipids. Two groups of male rats were taken as control and cases and the liver was denerved chemically by 90% phenol in the case group. On the fourth day of the operation, blood samples were taken and the liver homogenized for lipid and glycogen analyses. Cholesterol, triglyceride, HDLc and glucose were measured enzymatically. Total phospholipids were analyzed by the measuring of liberated inorganic phosphate in organic phase. Glycogen was extracted by ethanol and analyzed by phenol/sulphuric acid reagent. In a separate experiment, the rate of triglyceride secretion was measured in vivo by using tyloxapol and compared in two groups. The serum concentrations of triglyceride (73.7 ± 6.3 vs. 45.8 ± 1.6 mg/dL, P ≤ 0.003) and cholesterol (87.7 ± 3.7 vs. 67.4 ± 2.2mg/dL, P ≤ 0.001) were significantly higher in the denerved compared with the control group. The serum glucose showed a significant decrease (170.5 ± 5.4 vs. 140.6 ± 10.7 mg/dL, P ≤ 0.04) in the denerved group while HDLc had no significant difference between the two groups. Denerved rats compared to the control rats had the higher levels of hepatic glycogen (201.1 ± 20.6 vs. 100.7 ± 19.9 mg/g liver, P ≤ 0.02). The contents of liver triglyceride, cholesterol and total phospholipids did not differ significantly between two groups. The mean rate of triglyceride secretion from the liver increased in the denerved group (276.1 ± 16.1 vs. 230.6 ± 7.7 mg/dL.h, P ≤ 0.03). Liver denervation increases the levels of serum triglyceride and cholesterol via increases in the rate of VLDL secretion. Liver innervation plays a role on the regulation of metabolism of lipids and carbohydrates.

Role of the autonomic nervous system in rat liver regeneration.

To study the regulatory role of autonomic nervous system in rat regenerating liver, surgical operations of rat partial hepatectomy (PH) and its operation control (OC), sympathectomy combining partial hepatectomy (SPH), vagotomy combining partial hepatectomy (VPH), and total liver denervation combining partial hepatectomy (TDPH) were performed, then expression profiles of regenerating livers at 2 h after operation were detected using Rat Genome 230 2.0 array. It was shown that the expressions of 97 genes in OC, 230 genes in PH, 253 genes in SPH, 187 genes in VPH, and 177 genes in TDPH were significantly changed in biology. The relevance analysis showed that in SPH, genes involved in stimulus response, immunity response, amino acids and K(+) transport, amino acid catabolism, cell adhesion, cell proliferation mediated by JAK-STAT, Ca(+), and platelet-derived growth factor receptor, cell growth and differentiation through JAK-STAT were up-regulated, while the genes involved in chromatin assembly and disassembly, and cell apoptosis mediated by MAPK were down-regulated. In VPH, the genes associated with chromosome modification-related transcription factor, oxygen transport, and cell apoptosis mediated by MAPK pathway were up-regulated, but the genes associated with amino acid catabolism, histone acetylation-related transcription factor, and cell differentiation mediated by Wnt pathway were down-regulated. In TDPH, the genes related to immunity response, growth and development of regenerating liver, cell growth by MAPK pathway were up-regulated. Our data suggested that splanchnic and vagal nerves could regulate the expressions of liver regeneration-related genes.

Caffeine-induced natriuresis and diuresis via blockade of hepatic adenosine-mediated sensory nerves and a hepatorenal reflex

The hepatorenal reflex, activated by intrahepatic adenosine, is involved in the regulation of urine production in healthy rats and renal pathogenesis secondary to liver injury. Hepatic adenosine A1 receptors regulate the hepatorenal reflex. The aim of the present study was to evaluate whether caffeine mediates renal natriuresis and diuresis in healthy and diseased liver through this mechanism. Rats were anesthetized and instrumented to monitor systemic, hepatic, and renal circulation and urine production. Intrahepatic (intraportal but not intravenous) caffeine (5 mg·kg-1) increased urine flow (~82%) in healthy rats. This effect was abolished by liver denervation. Intraportal infusion of adenosine decreased urine production, and this response was abolished by intraportal but not intravenous caffeine. Liver injury was induced by intraperitoneal injection of thioacetamide (500 mg·kg-1), and functional assessment was performed 24 h later. Liver injury was associated with lower (~30%) glomerular filtration rate, lower (~18%) renal arterial blood flow, and lower urine production. Intraportal but not intravenous caffeine improved basal urine production and renal ability to increase urine production in response to saline overload. The liver-dependent diuretic effect of caffeine is consistent with the hypothesis for the adenosine-mediated mechanism of hepatorenal syndrome.

HISS, not insulin, causes vasodilation in response to administered insulin

Meal-induced sensitization to the dynamic actions of insulin results from the peripheral actions of a hormone released by the liver (hepatic insulin sensitizing substance or HISS). Absence of meal-induced insulin sensitization results in the pathologies associated with cardiometabolic risk. Using three protocols that have previously demonstrated HISS metabolic action, we tested the hypothesis that HISS accounts for the vasodilation that has been associated with insulin. The dynamic metabolic actions of insulin and HISS were determined using a euglycemic clamp in response to a bolus of 100 mU/kg insulin in pentobarbital-anesthetized Sprague-Dawley rats. Hindlimb blood flow was measured with an ultrasound flow probe on the aorta above the bifurcation of the iliac arteries. Fed rats showed tightly coupled metabolic and vascular responses, which were completed by 35 min after insulin administration. Blocking HISS release, with the use of atropine or hepatic surgical denervation, eliminated the HISS-dependent metabolic and vascular responses to insulin administration. Physiological suppression of HISS release occurs with fasting. In 24-h fasted rats, HISS metabolic and vascular actions were absent, and atropine had no effect on either action. Fed rats with liver denervation did not release HISS, but intraportal venous infusion of acetylcholine, to mimic the permissive parasympathetic nerve signal, restored the ability of insulin to cause HISS release and restored both the metabolic and vascular actions. These studies report vascular actions of HISS for the first time and demonstrate that HISS, not insulin action, results in the peripheral vasodilation generally attributed to insulin.

Central and Peripheral Effects of Thyroid Hormone Signalling in the Control of Energy Metabolism

Increasing evidence points towards a role for thyroid hormone signalling in the central nervous system with respect to the development of symptoms of thyroid disease, in addition to the well-known peripheral effects of thyroid hormone. Thyroid hormone affects target tissues directly via thyroid hormone receptors, but also indirectly through effects on the integration of the sympathetic signal in target tissues. The present review discusses these pathways and the evidence for a third pathway, that is effects of thyroid hormone on the pre-autonomic neurones in the central nervous system. The pre-autonomic neurones reside in the hypothalamus in brain nuclei such as the paraventricular nucleus of the hypothalamus where thyroid hormone receptor isoforms are expressed. Recent data from studies in transgenic mice implicate a role for thyroid hormone receptor alpha 1 in the modulation of sympathetic signalling to target tissues, thereby affecting both glucose and lipid metabolism. Focal stimulation of hypothalamic nuclei expressing thyroid hormone receptors and selective liver denervation experiments in rats have provided further evidence indicating that the metabolic changes observed during hyperthyroidism are not only a result of increased thyroid hormone signalling in the periphery, but also, at least in part, result from altered signalling in thyroid hormone sensitive neurones.

Hepatic denervation impairs the assembly and secretion of VLDL‐TAG

VLDL secretion is a regulated process that depends on the availability of lipids, apoB and MTP. Our aim was to investigate the effect of liver denervation upon the secretion of VLDL and the expression of proteins involved in this process. Denervation was achieved by applying a 85% phenol solution onto the portal tract, while control animals were treated with 9% NaCl. VLDL secretion was evaluated by the Tyloxapol method. The hepatic concentration of TAG and cholesterol, and the plasma concentration of TAG, cholesterol, VLDL-TAG, VLDL-cholesterol and HDL-cholesterol were measured, as well as mRNA expression of proteins involved in the process of VLDL assembly. Hepatic acinar distribution of MTP and apoB was evaluated by immunohistochemistry. Denervation increased plasma concentration of cholesterol (125.3 +/- 10.1 vs. 67.1 +/- 4.9 mg dL(-1)) and VLDL-cholesterol (61.6 +/- 5.6 vs. 29.4 +/- 3.3 mg dL(-1)), but HDL-cholesterol was unchanged (45.5 +/- 6.1 vs. 36.9 +/- 3.9 mg dL(-1)). Secretion of VLDL-TAG (47.5 +/- 23.8 vs. 148.5 +/- 27.4 mg dL h(-1)) and mRNA expression of CPT I and apoB were reduced (p < 0.01) in the denervated animals. MTP and apoB acinar distribution was not altered in the denervated animals, but the intensity of the reaction was reduced in relation to controls.

Distinct effects of surgical denervation on hepatic perfusion, bowel ischemia, and oxidative stress in brain dead and living donor porcine models

The liver function and perfusion following brain death is mainly influenced by the sympathetic nerves and hormones. We examined the specific influence of surgical liver denervation on systemic and hepatic perfusion parameters, bowel ischemia and oxidative stress in hemodynamically stable BD and control (living donor [LD]) pigs. Brain death was induced in 8 pigs via saline infusion into the balloon of an epidural Tieman-catheter (1 mL/15 minutes) and compared to the control group (n = 6) over 4 hours. At 2 hours postoperatively, complete liver denervation was initiated. We analyzed systemic cardiocirculatory parameters (mean arterial pressure, aortic flow, bowel ischemia (endotoxin, and endotoxin-neutralizing capacity) and oxidative stress (total glutathione in erythrocytes [tGSH(E)]) and compared them to local/hepatic perfusion parameters (hepatic artery and portal venous flow, liver blood flow index, and microperfusion), local bowel ischemia (intramucosal pH [pHi] of stomach [pHi(S)]/colon[pHi(C)]), and liver oxidative stress (glutathione [rGSH(L), GSSG(L)]). Following brain death, the parameters including mean arterial pressure, aortic flow, pHi, endotoxin, and tGSH(E) showed no significant changes at 2 hours. Portal venous flow and microperfusion were decreased significantly and hepatic arterial buffer response was ineffective. Hepatic oxidative stress was increased in BD animals (decrease rGSH(L), increase GSSG(L)). Surgical denervation/manipulation increased portal venous flow significantly, hepatic arterial buffer response became effective, and stomach pHi decreased (BD and LD groups). Hepatic oxidative stress was reduced in the BD group (increase rGSH(L)/GSSG(L); P < 0.001) while it was increased in the LD group (decrease rGSH(L)/GSSG(L); P < 0.001). In conclusion, denervation reduces hepatic oxidative stress in BD only in contrast to the LD. The reciprocal effect of denervation depends on the state of neural activation and postulates a potential benefit of surgical denervation before organ harvesting in brain death.

Intrahepatic adenosine-mediated activation of hepatorenal reflex is via A1 receptors in rats

Previous studies have shown that intrahepatic adenosine is involved in activation of the hepatorenal reflex that regulates renal sodium and water excretion. The present study aims to determine which subtype of adenosine receptors is implicated in the process. Mean arterial pressure, portal venous pressure and flow, and renal arterial flow were monitored in pentobarbital anesthetized rats. Urine was collected from the bladder. Intraportal administration of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist, increased urine flow by 24%, 89%, and 143% at the dose of 0.01, 0.03, and 0.1 mg x kg(-1), respectively; in contrast, DPCPX, when administered intravenously at the same doses, only increased urine flow by 0%, 18%, and 36%. The increases in urine flow induced by intraportal administration of DPCPX were abolished in rats with liver denervation. Intrahepatic infusion of adenosine significantly decreased urine flow and this response was abolished by intraportal administration of DPCPX. Neither intraportal nor intravenous administration of 3,7-dimethyl-1-propargylxanthine, a selective adenosine A2 receptor antagonist, showed significant influence on urine flow. Systemic arterial pressure, renal blood flow and glomerular filtration rate were unaltered by the administration of any of the drugs. In conclusion, intrahepatic adenosine A1 receptors are responsible for the adenosine-mediated hepatorenal reflex that regulates renal water and sodium excretion.

Contribution of hepatic adenosine A1 receptors to renal dysfunction associated with acute liver injury in rats†

Acute liver injury is associated with renal insufficiency, whose mechanism may be related to activation of the hepatorenal reflex. We previously showed that intrahepatic adenosine is involved in activation of the hepatorenal reflex to restrict urine production in both healthy rats and in rats with cirrhosis. The aim of the present study was to test the hypothesis that activation of intrahepatic adenosine receptors is involved in the pathogenesis of the renal insufficiency seen in acute liver injury. Acute liver injury was induced by intraperitoneal injection of thioacetamide (TAA, 500 mg/kg) in rats. The animals were instrumented 24 hours later to monitor systemic, hepatic, and renal circulation and urine production. Severe liver injury developed following TAA insult, which was associated with renal insufficiency, as demonstrated by decreased (approximately 25%) renal arterial blood flow, a lower (approximately 30%) glomerular filtration rate, and decreased urine production. Further, the increase in urine production following volume expansion challenge was inhibited. Intraportal, but not intravenous, administration of a nonselective adenosine receptor antagonist, 8-phenyltheophylline, improved urine production. To specify receptor subtype, the effects of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an adenosine A(1) receptor antagonist) and 3,7-dimethyl-1-propargylxanthine (DMPX, an adenosine A(2) receptor antagonist) were compared. Intraportal but not intravenous administration of DPCPX greatly improved impaired renal function induced by acute liver injury, and this beneficial effect was blunted in rats with liver denervation. In contrast, neither intraportal nor intravenous administration of DMPX showed significant improvement in renal function. In conclusion, an activated hepatorenal reflex, triggered by intrahepatic adenosine A(1) receptors, contributed to the pathogenesis of the water and sodium retention associated with acute liver injury.

Liver denervation affects hepatocyte mitochondrial fatty acid transport capacity.

The effect of liver denervation on the activity of hepatic carnitine palmitoyltransferase (CPT) system, which catalyses the transfer of long-chain fatty acids into the mitochondria, was studied in rats. Noradrenaline content in phenol-denervated liver (D) was reduced by 87%. CPT I and II activities (measured by radioassay after detergent separation of the enzymes) were decreased (p < 0.001) in D (2.6 +/- 0.1 and 0.68 +/- 0.2 nmol min(-1) mg(-1) protein, respectively) as compared with controls (4.7 +/- 0.3 and 2.5 +/- 0.2 nmol min(-1) mg(-1) protein, for CPT I and II, respectively). A less intense immunoreactive band for denervated liver CPT II was obtained after Western blotting. Concomitantly, long-chain fatty acid incorporation (p < 0.001), evaluated after administration of [14C]-oleate and total fat content (p < 0.001) were increased in D in relation to controls, while incorporation of exogenous [14C]-oleate into secreted VLDL, was decreased (p < 0.01). The effect of sympathetic denervation on CPT activity was different from that evoked by adrenodemedullation, which caused an augmentation of CPT activity (p < 0.01), when compared with the liver of intact rats. The effects of denervation and adrenodemedullation on the other parameters of lipid metabolism studied, were similar. The results strongly suggest a role of liver sympathetic innervation in the regulation of liver lipid metabolism.

Effect of Dopamine Infusion on Hemodynamics after Hepatic Denervation

Background. The effects of dopamine (DA) on systemic hemodynamics are better understood than its effects on hepatic hemodynamics, especially after liver denervation occurring during liver transplantation. Therefore, a porcine model was used to study DA's effects on hemodynamics after hepatic denervation.Materials and methods. Fifteen pigs underwent laparotomy for catheter and flow probe placement. The experimental group (n = 7) also underwent hepatic denervation. After 1 week, all pigs underwent DA infusion at increasing doses (3–30 mcg/kg/min) while measuring hepatic parameters [portal vein flow (PVF), hepatic artery flow (HAF), total hepatic blood flow (THBF = HAF + PVF), portal and hepatic vein pressures] and systemic parameters [heart rate (HR), mean arterial pressure (MAP)].Results. There was a significant increase in HAF from baseline to the 30 mcg/kg/min DA infusion rate (within-subjects P < 0.01), but the differences between the two groups were not significant. PVF and THBF showed large effects (increases) with denervation, but the increase in flow with DA infusion was not present after denervation. Perihepatic pressures were unchanged by denervation or DA. Heart rate differed significantly between the control and denervated animals at baseline, 3, 6, 12 (all P < 0.05), and 30 mcg/kg/min DA (P = 0.10). Control vs denervation MAP at baseline was 100 ± 4 vs 98 ± 4 Torr and at 30 mcg/kg/min it was 110 ± 3 vs 101 ± 5 mm Hg.Conclusions. Hepatic flows tended to be higher after denervation. HAF showed similar increases with DA in both control and denervation groups. Increases in PVF and THBF with DA infusion were not present after denervation. HR was significantly decreased and MAP tended to be lower after denervation. The HR and MAP response to DA was similar in both groups. Therefore, both denervation and DA infusion have an effect on systemic and hepatic hemodynamics.

Meal Patterns Prior to and Following Liver Transplantation in Rats

Bellinger, L. L., R. Fabia and B. S. Husberg. Meal patterns prior to and following liver transplantation in rats. Physiol Behav 62(3) 525–529, 1997.—Afferent nerves of the liver have been suggested to have a major influence on feeding behavior. Nevertheless, total liver denervations (TLD) in rats, that were verified by histofluorescence technique, did not change short or long term meal patterns. However, these studies have been criticized that the TLD procedures may have missed some liver innervation. In the present study meal patterns were conducted prior to and following liver transplantation in rats using a transplant procedure with arterialization. The transplanted rats recovered their pre-operative body weight in 7.5 ± 0.6 days and meal pattern analysis was conducted two days later. In comparison with pre-surgery there was no differences in 24 h food intake (gms); dark phase: intake (gms), meal size (gms), meal duration (min), inter-meal interval (min), and frequency; and light phase: intake (gms), meal size (gms), meal duration (min), inter-meal interval (min), and frequency. These data, like earlier work in TLD rats showing that the animals consumed normal meals (when offered a variety of diets), starting with the first meal post-surgery, question the importance of liver afferents in the control of feeding behavior.

Insulin resistance caused by hepatic cholinergic interruption and reversed by acetylcholine administration.

The role of hepatic parasympathetic nerves in insulin effectiveness was evaluated in fed anesthetized rats. Insulin sensitivity was assessed using a modified euglycemic clamp to quantitate the amount of glucose required to maintain euglycemia over 60 min after administration of insulin (50 mU/kg). With normal innervation, intraportal infusions of acetylcholine (ACh, 2.5 micrograms.kg-1.min-1) did not alter insulin sensitivity, but intraportal venous atropine (3 mg/kg) reduced insulin sensitivity (49.4 +/- 5.8%, P < 0.001, n = 7). Liver denervation resulted in reduction of insulin responsiveness by 70.8 +/- 5.8% (P < 0.001, n = 8), which was fully (96.8 +/- 12.5%) reversed by ACh. ACh into the portal vein reversed insulin resistance produced by denervation, but intravenous ACh was without effect, thus showing that the liver was the site of ACh action. Regression analysis suggests that some component of insulin response is not dependent on hepatic cholinergic nerve effects but that virtually all of the variability in response to insulin in normal fed rats tested under these conditions could be accounted for by variability in the hepatic parasympathetic-dependent insulin sensitivity. These data suggest a major role for hepatic parasympathetic nerves in regulation of whole body clearance of glucose in response to insulin.

Effect of parasympathetic denervation of liver and pancreas on glucose kinetics in man

The study aim was to investigate the role of the parasympathetic nervous system in the control of glucose tolerance in man. Glucose kinetics were determined during an oral glucose tolerance test (OGTT) in six subjects with truncal vagotomies and six control subjects. Basal plasma glucose levels in the two groups were equal; however, 20 to 40 minutes after the OGTT, glucose was higher in vagotomized compared with control subjects ( P < .02). There were no differences in insulin levels between the subjects. Glucagon decreased after the OGTT in the controls, whereas in the vagotomized subjects it increased transiently and did not decrease beyond basal levels. There was no difference in basal hepatic glucose production, but suppression was greater in controls in the first 10 minutes ( P < .01). Gut-derived glucose appearance increased faster and to a higher level (56.0 ± 8 v 29.7 ± 2.9 μmol/kg/min, P < .02) in vagotomized subjects. There were no differences in the metabolic clearance rate of glucose between the two groups. It is concluded that parasympathetic innervation of the pancreas is essential for suppression of glucagon secretion during hyperglycemia. However, abnormal glucose tolerance in vagotomized subjects is primarily due to rapid gut glucose absorption, with the denervated parasympathetic system playing only a minor role.

Liver denervation attenuates the hypophagia produced by an imbalanced amino acid diet

We observed previously that totally liver denervated (TLD) rats consumed more of an imbalanced amino acid diet (IAAD) than sham-operated controls (CON). For the present study rats were either CON, TLD, had only the hepatic-vagal branch cut (HVX), or had all nerves on the hepatic artery and portal vein removed (HAPV) ( n = 10−11). The rats were prefed a purified basal diet for 9 days then switched to an isoleucine IAAD for 7 days. On days 2–5 all experimental groups consumed more ( p < 0.05) of the IAAD than the CON; they also showed less ( p < 0.01) weight loss on days 3–7. This experiment showed that either total or partial liver denervations enhanced the intake of an IAAD compared to CON. However, when one considers the anatomical arrangement of the nerves and the surgery technique employed the vital neural pathway may involve the hepatic vagal branch.