Safety of surgical denervation of the common hepatic artery in insulin-resistant dogs.

The objective of this study was to assess the safety of surgical common hepatic artery denervation (CHADN). This procedure has previously been shown to improve glucose tolerance in dogs fed a high-fat high-fructose (HFHF) diet. We assessed the hypoglycemic response of dogs by infusing insulin at a constant rate (1.5 mU/kg/min) for 3 h and monitoring glucose and the counterregulatory hormones (glucagon, catecholamine, and cortisol). After an initial hypoglycemic study, the dogs were randomly assigned to a SHAM surgery (n = 4) or hepatic sympathetic denervation (CHADN, n = 5) and three follow-up studies were performed every month up to 3 months after the surgery. The level of norepinephrine (NE) in the liver and the pancreas was significantly reduced in the CHADN dogs, showing a decrease in sympathetic tone to the splanchnic organs. There was no evidence of any defect of the response to hypoglycemia after the CHADN surgery. Indeed, the extent of hypoglycemia was similar in the SHAM and CHADN groups (~45 mg/dl) for the same amount of circulating insulin (~50 µU/ml) regardless of time or surgery. Moreover the responses of the counterregulatory hormones were similar in extent and pattern during the 3 h of hypoglycemic challenge. Circulating lactate, glycerol, free fatty acids, and beta-hydroxybutyrate were also unaffected by CHADN during fasting conditions or during the hypoglycemia. There were no other notable surgery-induced changes over time in nutrients, minerals, and hormones clinically measured in the dogs nor in the blood pressure and heart rate of the animals. The data suggest that the ablation of the sympathetic nerve connected to the splanchnic bed is not required for a normal counterregulatory response to insulin-induced hypoglycemia and that CHADN could be a safe new therapeutic intervention to improve glycemic control in individuals with metabolic syndrome or type 2 diabetes.

New method for the assessment of perineural invasion from perihilar cholangiocarcinoma.

PURPOSE: Perineural invasion (PN) is often found in perihilar cholangiocarcinoma. New procedure was developed to assess PN around the right hepatic artery (RHA) using dual-energy computed tomography (DECT). METHODS: Thirty patients with perihilar cholangiocarcinoma who underwent DECT before biliary drainage were retrospectively reviewed. Mask images, i.e., the periarterial layer (PAL) around the RHA and superior mesenteric artery (SMA), were made from late arterial phase DECT. The mean CT number of the PAL was measured. RESULTS: Twenty patients with PN around the RHA were classified into the PN (+) group. The remaining 10 patients without PN and other 26 patients with other diseases that are never accompanied with PN were classified into the PN (-) group. The PAL ratio (the CT number of the PAL around the RHA relative to that around the SMA) was calculated. Both the mean CT number of the PAL around the RHA and the PAL ratio were significantly higher in the PN (+) group than in the PN (-) group. According to an ROC analysis, the predictive ability of the PAL ratio was superior. Using the cutoff value of the PAL ratio 1.009, a diagnosis of PN around the RHA was made with approximately 75% accuracy. CONCLUSIONS: Assessment with CT number of the PAL reconstructed from DECT images is an easy and objective method to diagnose PN.

Sympathetic Denervation of the Common Hepatic Artery Lessens Glucose Intolerance in the Fat- and Fructose-Fed Dog.

This study assessed the effectiveness of surgical sympathetic denervation of the common hepatic artery (CHADN) in improving glucose tolerance. CHADN eliminated norepinephrine content in the liver and partially decreased it in the pancreas and the upper gut. We assessed oral glucose tolerance at baseline and after 4 weeks of high-fat high-fructose (HFHF) feeding. Dogs were then randomized to sham surgery (SHAM) (n = 9) or CHADN surgery (n = 11) and retested 2.5 or 3.5 weeks later while still on the HFHF diet. CHADN improved glucose tolerance by ∼60% in part because of enhanced insulin secretion, as indicated by an increase in the insulinogenic index. In a subset of dogs (SHAM, n = 5; CHADN, n = 6), a hyperinsulinemic-hyperglycemic clamp was used to assess whether CHADN could improve hepatic glucose metabolism independent of a change in insulin release. CHADN reduced the diet-induced defect in net hepatic glucose balance by 37%. In another subset of dogs (SHAM, n = 4; CHADN, n = 5) the HFHF diet was continued for 3 months postsurgery and the improvement in glucose tolerance caused by CHADN continued. In conclusion, CHADN has the potential to enhance postprandial glucose clearance in states of diet-induced glucose intolerance.

[Cryosurgery in diffuse hepatic diseases].

Comparative studying, using histological and biomicroscopic methods, of the dosed cryohepatodestruction (CHD), periarterial cryodenervation of hepatic artery (CDHA) and their concomitant application influence on the dynamics of hepatic restoration processes in experimental cirrhosis was performed. The investigations were done on 215 male rats owing body mass 200-280 g in a not changed and pathologically changed liver. There was shown, that CDHA promotes changes in hepatic tissue microhemocirculation, as well as the enhancement of the sinusoidal vessels diameter and relative square of vascular bed. CHD stimulates the reparative processes course in a pathologically changed organ. There was established, that while simultaneous application of two cryosurgical methods, the velocity and grade of restoration processes in cirrhotically-changed liver are enhanced in comparison with such indices changes while separate usage of these two methods.

Heterogeneity in mechanisms underlying vasodilatory responses in small arteries of the rat hepatic mesentery.

We have characterised nerve-mediated vasodilations in small arteries of the rat hepatic mesentery. Stimulation of sympathetic nerves (10 Hz, 10 s) produced a vasodilation which was abolished by the beta-adrenoceptor antagonist, propranolol (2 x 10(-6) M), but was unaffected by NG-nitro-L-arginine methyl ester (L-NAME, 10(-5) M). Stimulation of sensory nerves produced a large vasodilation that was abolished by capsaicin (10(-6) M). This vasodilation was unaffected by L-NAME (10(-5) M), but significantly reduced by the calcitonin gene related peptide (CGRP) antagonist, CGRP8-37 (10(-6) M), or inhibition of adenylate cyclase (SQ22356, 2 x 10(-5) M; 2',5'-dideoxyadenosine, 2 x 10(-4) M). Stimulation of cholinergic nerves produced a small vasodilation which was significantly reduced by scopolamine (10(-6) M). Expression of mRNA for CGRP1 receptors, muscarinic m2, m3 and m5 receptors and neurokinin1 (NK1) and NK3, receptors was detected. Perivascular nerves were immunoreactive for CGRP and substance P. No role was found for substance P, neuronal NO, ATP or adenosine in nerve-mediated responses. L-NAME (10(-5) M) potentiated vasoconstrictions following sympathetic nerve stimulation. This effect was reversed by L-arginine (10(-3) M) and cromakalim (10(-6) M) and mimicked by glybenclamide (10(-5) M), thus implicating KATP channels. Vasodilation in response to sensory nerve stimulation was directly proportional to the level of preconstriction, while vasodilation in response to neurogenic or applied acetylcholine was inhibited at high levels of preconstriction. We hypothesize that, under conditions of intensive vasoconstriction, some endothelial-dependent vasodilations may be less important than vasodilations activated directly through the smooth muscle.

Graft survival is improved by hepatic denervation before organ harvesting.

BACKGROUND: In a recent study, disturbances of hepatic microcirculation at harvesting caused by in situ organ manipulation dramatically reduced survival after a liver transplant. Because hepatic innervation is involved in the regulation of liver hemodynamics, the effect of denervation before harvesting was assessed here. METHODS: The livers were harvested from female Lewis rats (200-230 g) within 25 min. Briefly, after minimal dissection during the first 12 min, the livers were either manipulated gently or left alone for 13 min. Subsequently, an orthotopic liver transplant was performed after 1 hr of storage in cold UW solution. Some donors livers underwent microsurgical denervation before harvesting or rats were given hexamethonium (10 mg/kg, i.v.), a ganglionic blocking agent. RESULTS: In the nonmanipulated group, survival was 100% after the transplant; however, gentle manipulation decreased survival by about 50%. Furthermore, manipulation elevated serum transaminases and bilirubin 6- to 8-fold 8 hr after the transplant and caused necrosis of about 25% of hepatocytes. After organ harvesting, the rate of entry and exit of fluorescein dextran, a dye confined to the vascular space, was decreased 2- to 4-fold, and the maximal increase of surface fluorescence was blunted about 2-fold. Pimonidazole binding, which reflects tissue hypoxia, was increased 2-fold by manipulation. Denervation of the liver before organ harvesting or treatment with hexamethonium prevented the effects of organ manipulation on all parameters studied. CONCLUSION: These data indicate for the first time that hepatic denervation before organ harvesting prevents detrimental effects of brief, gentle manipulation of the liver during harvesting on survival after the transplant. This is consistent with the hypothesis that organ manipulation disturbs the hepatic microcirculation and causes hypoxia at harvesting using mechanisms dependent on innervation.

Mechanisms underlying the neurogenic relaxation in dog isolated hepatic arteries.

In canine hepatic arterial strips responding to nicotine with contraction, prazosin abolished the response or reversed it to a relaxation. Mechanisms underlying the relaxation were analyzed in hepatic and coronary arterial strips denuded of the endothelium and treated with prazosin and indomethacin. In the hepatic arterial strips precontracted with prostaglandin (PG) F2alpha, nicotine-induced relaxations were not influenced by atropine but were inhibited by timolol and abolished by hexamethonium. Treatment with [8-37] calcitonin gene-related peptide ([8-37] CGRP), a selective CGRP1-receptor antagonist, also attenuated the nicotine-induced relaxation, but a vasoactive intestinal polypeptide antagonist was without effect. Combined treatment with timolol and [8-37] CGRP depressed the response to a greater extent than either antagonist alone. The slight relaxation remaining under the combined treatment was abolished by NG-nitro-L-arginine (L-NA) and restored by L-arginine. In coronary arterial strips precontracted with PGF2alpha, nicotine produced a moderate relaxation, which was abolished or markedly inhibited by treatment with hexamethonium or timolol but was unaffected by L-NA. It is concluded that the nicotine-induced relaxation is mediated by norepinephrine, CGRP, and NO released from perivascular nerves in dog hepatic arterial strips; the responses associated with activations of beta-adrenoceptors and CGRP1 receptors are predominant over those to NO. The coronary arterial relaxation seems to be mediated by neurogenic norepinephrine but not by NO.

Evidence for noradrenergic-purinergic cotransmission in the hepatic artery of the rabbit.

1. Transmural electrical field stimulation produced a transient contraction of the isolated hepatic artery of the rabbit that was frequency-dependent up to 64 Hz. A contraction was rarely evoked at a stimulation frequency of less than 8 Hz and never at 4 Hz or less. All contractions were abolished in the presence of tetrodotoxin. 2. Neurogenic contractions were partially inhibited by prazosin. After desensitization of the P2X-purinoceptor with alpha, beta-methylene ATP, contractions in response to electrical stimulation were significantly reduced at all frequencies tested (4-64 Hz). In most cases, contractions were abolished by a combination of both drugs. 3. In vessels treated with 6-hydroxydopamine, no nerve-mediated contractile responses were observed. 4. In arteries from reserpine-treated rabbits, nerve stimulation evoked contractions that were resistant to prazosin. After desentization of the P2X-purinoceptor with alpha,beta-methylene ATP, no neurogenic contractile response remained. 5. The tissue contracted to exogenously applied noradrenaline and alpha,beta-methylene ATP. There was an increase in sensitivity to noradrenaline in 6-hydroxydopamine-treated vessels compared with control vessels, but no difference in potency to alpha,beta-methylene ATP was detected. The potency of noradrenaline and alpha,beta-methylene ATP was not significantly affected by reserpine treatment. 6. In control tissues, fluorescence histochemistry demonstrated the presence of noradrenergic nerve fibres. Noradrenaline-containing nerves were not observed in 6-hydroxydopamine-treated or reserpine-treated vessels. 7. It is concluded that noradrenaline and ATP are cotransmitters in the sympathetic nerves supplying the hepatic artery of the rabbit. In contrast to other vessels, the hepatic artery requires a relatively high frequency of stimulation to evoke contractions and the purinergic component is not frequency-dependent. The significance of this finding in terms of the physiological demands of blood flow to the liver are discussed.

[The surgical treatment of chronic hepatitis and liver cirrhosis at the compensation stage]. / Khirurgicheskoe lechenie khronicheskogo gepatita i tsirroza pecheni v stadii kompensatsii.

The authors have analysed the results of operative treatment of 120 patients with chronic hepatitis and liver cirrhosis at the stage of compensation. Periarterial nervectomy of the common hepatic artery was performed in 30 patients, extraperitonealization of the right hepatic lobe with laser irradiation--in 42, periarterial nervectomy of the common hepatic artery with extraperitonealization of the right hepatic lobe and laser irradiation--in 48. The results of periarterial nervectomy of the common hepatic artery with extraperitonealization of the right hepatic lobe and use of laser irradiation were the best.

Neuroendocrine innervation of the hepatic vessels in the rat and in man.

An extensive array of nerve fibers ramify around the afferent blood vessels of the liver and the extrahepatic and intrahepatic biliary pathways, and are thought to be involved in regulation of blood flow. Although the role of sympathetic innervation is established, little is known about the location or role of regulatory peptidergic innervation in the liver. We examined the anatomic distribution of a wide variety of regulatory peptides and several neural antigens by in situ immunohistochemistry in the rat and in man. A rich peptidergic plexus of nerve fibers and ganglion cells was observed around the arterial vessels in both species, with intense immunoreactivity for neuron-specific enolase, neurofilaments, neuropeptide Y, substance P, and vasoactive intestinal polypeptide. S-100 protein immunoreactivity was seen principally in large nerve bundles, suggesting that the majority of nerves in this area were unmyelinated. In contrast, the portal vessels revealed very little peptidergic innervation. No staining was observed with antibodies directed against insulin, glucagon, gastrin, serotonin, met-enkephalin-Arg-Gly-Leu, cholecystokinin, or growth hormone. These findings indicate the presence of a rich, although selective, peptidergic plexus surrounding afferent hepatic blood vessels. This plexus may play an important role in regulation of hepatic blood flow.

Vasoactive intestinal peptide may participate in the vasodilation of the dog hepatic artery.

The possible direct action of vasoactive intestinal peptide (VIP) on dog hepatic arterial wall or on the noradrenergic innervation of the artery was investigated in vitro. In addition, VIP-containing nerve fibers and terminals were located in the wall of the artery with immunochemical staining. Direct evidence showed that VIP did not affect the release of [3H]norepinephrine but reduced the response of the isolated hepatic artery to electrical field stimulation and exogenous norepinephrine. This suggests that the effect of VIP is postjunctional on the smooth muscle of the artery. VIP-containing nerve fibers and varicosities were observed in the adventitial and medial layer of the arterial wall. These findings strongly support the hypothesis that vasoactive intestinal peptide is a physiological mediator of vasodilation in the hepatic artery.

[Indications for surgery in acute and chronic hepatitis]. / Pokazaniia k operatsii pri ostrom i khronicheskom gepatite.

The author considers that the participation of surgeons in the treatment of patients with acute and chronic hepatitis may be promising. The operation for acute hepatitis is aimed at liquidation of another disease of the patients, that for chronic hepatitic is fulfilled in order to relieve severe manifestations of the disease.

Neuroeffector transmission of the hepatic and pancreatico-duodenal isolated arteries of the dog.

Direct evidence has been obtained that the neurogenic responses of the hepatic and pancreatico-duodenal arteries of the dog are mainly due to norepinephrine released from varicosities and that this effect is mediated via alpha 1-adrenoceptors. In addition, there is a prazosin-resistant response to nerve stimulation that is certainly not mediated via alpha 2-adrenoceptors. These vessels are 10-100 times less sensitive to applied norepinephrine than the great majority of peripheral arteries; however, the pA2 value for prazosin (7.5) is the same as in other systems. The varicose terminal plexus is located deep in the media, as shown by electron microscopic study. Findings indicate that these gastrointestinal arteries are mainly controlled by adrenergic innervation, that their density is as high as that of any other vessel, and that these arteries might be much less influenced by the circulating catecholamines than others. The neuroeffector transmission of hepatic and pancreatico-duodenal arteries is subject to presynaptic modulation. Muscarinic (oxotremorine) and P1 (adenosine) receptor agonists are effective inhibitors of transmission, whereas xylazine surprisingly has no effect.

Lipid metabolism in partially hepatectomized dogs and effect of hepatic periarterial neurectomy.

Lipid metabolism in partially hepatectomized dogs was studied, by observing changes in serum lipids after hepatectomy and biosynthesis of lipids in the slices of the regenerating liver tissue. In addition, the effect of hepatic periarterial neurectomy was evaluated. Serum lipids decreased after partial hepatectomy and did not return to the postoperative level until the first postoperative week, whereas biosynthesis of lipids in the slices of the regenerating liver tissue was considerably augmented in the early postoperative period. This augmentation of lipid synthesis appears to be requirement for regeneration of the liver. When hepatic periarterial neurectomy plus partial hepatectomy was carried out, each lipid and lipoprotein fraction, except for FFA, showed a tendency to recovery earlier from the immediate postoperative decrease and did not show a late postoperative excessive increase. The decrease of alpha-lipoprotein in the immediate postoperative period was augmented and the time of the peak of concentration of pre-beta-lipoprotein was hastened. Therefore, hepatic periarterial neurectomy seems to act in such a manner so as to maintain the homeostasis in lipid metabolism after partial hepatectomy and to activate the regenerative property of the residual liver in the early postoperative period.