Hepatic Venous Plasma Research Articles

Clinical investigation of endothelin-1 and nitric oxide in patients with portal hypertension focusing on plasma levels and immunohistological staining of liver tissues

Plasma concentrations of endothelin-1 (ET-1) and nitrite/nitrate of patients with portal hypertension were measured. Sixteen patients with liver cirrhosis (the LC group) and 14 patients with idiopathic portal hypertension (the IPH group) and 12 healthy subjects (normal controls) were included in this study. The peripheral venous plasma concentration of ET-1 was significantly higher in the LC group (6.69±2.44 pg/ml) than in the IPH group (3.07±0.84 pg/ml) and normal controls (1.79±0.36 pg/ml), while the value in the IPH group was also significantly higher than that in normal controls. The peripheral venous plasma concentration of nitrite/nitrate was significantly higher in the LC group (67.7±38.9 μMol/l) than in the IPH group (32.3±24.4 μMol/l) and normal controls (26.1±9.8 μMol/l). Hepatic venous plasma concentrations of ET-1 and nitrite/nitrate were measured in 8 patients from the LC group and 10 patients from the IPH group. The plasma concentration of ET-1 in the hepatic vein was significantly higher than that in the peripheral vein in both the LC and the IPH groups. The plasma concentration of nitrite/nitrate in the hepatic vein was significantly higher than that in the peripheral vein in the LC group. We also investigated the localization of ET-1, endothelin receptor (ET receptor) and nitric oxide synthase (NOS) in the liver tissue of LC patients ( n=10), IPH patients ( n=10) and normal controls ( n=10). The expressions of ET-1, ET A receptors, ET B receptors, and inducive NOS (iNOS) were detected in patients with LC, and the labeling index (LI) was significantly higher than that in patients with IPH and normal controls. The expressions of ET-1, ET A receptors, and ET B receptors were found in patients with IPH, and the LI was significantly higher than that in normal controls. The expression of endothelial NOS (eNOS) was scarce in both LC and IPH patients. From these results, overproduction of ET-1 in the liver was regarded as one of the causes of the high plasma concentration of ET-1 in patients with LC and IPH. One of the causes of the high plasma concentration of nitrite/nitrate in LC was considered to be overproduction of nitric oxide (NO) in the liver. And we suggested that ET-1 is at a relatively higher density than NO in the hepatic sinusoid in LC and IPH.

Hepatic and extra-hepatic stimulation of glutathione release into plasma by norepinephrine in vivo

Studies were conducted to determine the effect of norepinephrine (NE) on reduced glutathione (GSH) and oxidized glutathione (GSSG) export from hepatic and extra-hepatic tissues in vivo. Anesthetized Single Comb White Leghorn (SCWL) males were implanted with cannulae in the carotid artery, hepatic vein (HV) and hepatic portal veins (PV), and the left bile duct. In Experiment 1, GSH and GSSG in hepatic and portal venous plasma and bile were determined prior to, during, and following two 20-min infusions of NE (2 and 10 microg/min per kg BW) into the hepatic PV. The lower NE infusion rate increased hepatic venous GSH (indicative of increased GSH export into liver sinusoids) without affecting systemic or hepatic vascular pressures; however, it had no affect on portal venous GSH. The higher NE infusion rate increased GSH in the HV and hepatic PV (indicative of extra hepatic export of glutathione) as well as systemic pressure, hepatic and portal venous pressures, and the transhepatic pressure gradient. Biliary secretion of GSH and GSSG was unaffected by either rate of NE infusion in Experiment 1. In Experiment 2, pretreatment of birds with phentolamine, an alpha-adrenergic receptor blocker (alpha-block), abolished sinusoidal export GSH as well as the ability of NE to stimulate GSH release from hepatic and extra-hepatic tissue. Although HV and PV pressures were lower in alpha-block birds compared with controls, there were no differences in the transhepatic pressure gradient between groups. Plasma GSSG was below the limits of detection in Experiments 1 and 2. The combined results of Experiments 1 and 2 indicate that hepatic export of GSH was independent of changes in systemic or hepatic vascular pressures or changes in the transhepatic pressure gradient. The results of these studies are the first to demonstrate that export of GSH into plasma in vivo is mediated by an alpha-receptor-mediated mechanism in hepatic and extra-hepatic tissues. The findings may be particularly important with regard to antioxidant homeostasis of animals during periods of stress.

Effects of Dopexamine on Creatinine Clearance, Systemic Inflammation, and Splanchnic Oxygenation in Patients Undergoing Coronary Artery Bypass Grafting

Impairment of splanchnic and peripheral tissue perfusion during cardiopulmonary bypass (CPB) may be responsible for endotoxin-mediated systemic inflammation and acute phase responses. We examined the effects of dopexamine on hemodynamic parameters, creatinine clearance, systemic and splanchnic oxygenation, gastric mucosal pH (pHi), and mixed and hepatic venous plasma levels of endotoxin, interleukin-6 (IL-6), serum amyloid A (SAA), and C-reactive protein (CRP) in 44 patients scheduled for coronary artery bypass grafting. Patients were randomized to receive continuous infusions of 0.5, 1.0, or 2 micro g [centered dot] kg-1 [centered dot] min-1 dopexamine (n = 10 per group) or placebo (n = 14) prior to surgery, intraoperatively, and postoperatively. Dopexamine infusion increased systemic oxygen delivery (P <or=to 0.01). Hepatic venous oxygen saturation did not change, and pHi decreased during and after CPB in all patients (P <or=to 0.01). Postoperative increases in IL-6 were smallest in patients who received 2.0 micro g [centered dot] kg-1 [centered dot] min-1 dopexamine (P <or=to 0.02). SAA and CRP increases during the postoperative period were less pronounced with dopexamine throughout the study. Creatinine clearance was elevated in all dopexamine groups (P <or=to 0.025). This elevation was higher with lower dopexamine doses (P <or=to 0.025). We conclude that dopexamine improves creatinine clearance and reduces systemic inflammation without affecting splanchnic oxygenation. (Anesth Analg 1997;84:950-7)

Metabolic effects of a fat- and carbohydrate-rich meal in rats

To investigate meal-induced changes in hepatic fat and carbohydrate metabolism in rats, hepatic venous, portal venous, and aortal plasma levels of several metabolites as well as changes in hepatic glycogen and lactate content were measured during and after the first nocturnal meal following a 12-h fast. The rats were fed a diet with about 46%, 41%, and 13% of the total energy (≈ 16.5 kJ/g) derived from carbohydrates, fats, and protein, respectively. During the later part of the meal and thereafter, plasma triglyceride level increased in all blood vessels. After a transient initial decrease, portal venous and aortal nonesterified fatty acid (NEFA) levels, net hepatic NEFA uptake, and hepatic β-hydroxybutyrate (BHB) production increased and reached fasting (meal onset) values by 30 min after the meal. Although liver glycogen did not change significantly, the liver released glucose continuously. The liver initially accumulated lactate and maintained a high lactate concentration despite switching from lactate uptake to net release of lactate around 10 min into the meal. Taken together, these data indicate that hepatic glycolysis, gluconeogenesis, and considerable fatty acid oxidation occur concurrently in rat liver during and after a fat- and carbohydrate-rich meal. The findings are relevant to contemporary hypotheses of the metabolic control of eating and, in particular, to hypotheses linking hepatic fatty acid oxidation to postprandial satiety.

Sympathetic discharge to mesenteric organs and the liver. Evidence for substantial mesenteric organ norepinephrine spillover.

This study using sampling of blood from the portal vein, in addition to arterial and hepatic sites, to estimate separately spillovers of norepinephrine from mesenteric organs and the liver in seven patients undergoing upper abdominal surgery. Conventional measurements in arterial and hepatic venous plasma provided a measure of net hepatomesenteric NE spillover (403 pmol/ml) that indicated a 13% contribution of these organs to total body spillover of NE into systemic plasma (3,071+/-518 pmol/min). The net hepatomesenteric spillover of NE into systemic plasma was much lower than the spillover of NE from mesenteric organs into portal venous plasma (1,684+/-418 pmol/min). This and the hepatic spillover of NE into systemic plasma (212+/-72 pmol/min) indicated a considerable combined spillover of NE from hepatomesenteric organs (1,896+/-455 pmol/min). The sum of the latter estimate with the difference between total body and net hepatomesenteric NE spillovers provided an adjusted total body spillover of NE into both systemic and portal venous plasma (4,564+/-902 pmol/min). Mesenteric organs made a 37% contribution, and the liver made a 5% contribution to the adjusted total body spillover of NE. Thus, a substantial proportion of total body sympathetic outflow is directed towards mesenteric organs; this is obscured by efficient hepatic extraction of NE (86+/-6%) when measurements are restricted to arterial and hepatic venous plasma.

Portal hypertensive colopathy in patients with cirrhosis.

Colonic vascular ectasias and colorectal varices have been observed in patients with cirrhosis. However, the pathogenesis of these vascular lesions has not been established. We enrolled 35 cirrhotic patients and 20 normal controls in this study. All received colonoscopic examinations and measurements of plasma glucagon levels. Portal pressure measurements were performed in all the cirrhotic patients. Colonic vascular ectasias occurred more commonly in cirrhotic patients than in controls (17 of 35 versus 0 of 20; p = 0.009) and more commonly in cirrhotic patients with ascites than in those without (15 of 24 versus 2 of 11; p = 0.038). However, the presence of colonic vascular ectasias was not related to the hepatic venous pressure gradient or plasma glucagon levels. Colorectal varices also occurred more commonly in cirrhotic patients than in controls (16 of 35 versus of 1 of 20; p = 0.034), but the hepatic venous pressure gradient, plasma glucagon levels, and severity of cirrhosis were not related to the presence of colorectal varices. Portal hypertension per se and increased plasma glucagon levels may not play an important role in the pathogenesis of colonic vascular ectasias or colorectal varices in patients with cirrhosis.

Hepatomesenteric release and removal of norepinephrine in swine.

Release and removal of norepinephrine (NE) by hepatomesenteric organs in anesthetized swine were examined using measurements of NE in arterial, portal, and hepatic venous plasma. NE spillover from the liver and mesenteric organs increased during splanchnic nerve stimulation, validating these measurements as indexes of sympathetic outflow. Administration of the neuronal uptake-blocking drug desipramine reduced mesenteric NE extraction more than hepatic extraction, suggesting that neuronal uptake was more important for NE removal in mesenteric organs than in the liver. Circulating NE was removed by the liver more efficiently than by mesenteric organs, whereas mesenteric NE spillover (2.46 nmol/min) exceeded liver NE spillover (0.74 nmol/min). Hepatomesenteric NE spillover represented 53% of total body spillover; NE clearance was 42% of total body clearance. Because of efficient hepatic extraction of NE released by mesenteric organs, the sum of mesenteric and hepatic NE spillovers (3.20 pmol/min) exceeded net hepatomesenteric spillover estimated using arterial and hepatic venous measurements alone (1.96 pmol/min). Thus valid assessment of the substantial amounts of NE released by hepatomesenteric organs requires separate examination of mesenteric and hepatic spillovers.

Production and secretion of endothelin by hepatocellular carcinoma.

To clarify whether hepatocellular carcinoma (HCC) may produce and secrete endothelin (ET), we measured plasma levels of ET-1 and big ET-1, a precursor form of ET-1, in 30 patients with HCC. When compared to normal subjects, a substantial number of patients had elevated plasma ET-1 and big ET-1 levels, determined by specific enzyme immunoassays. The mean (+/- SD) plasma concentrations of ET-1 (1.7 +/- 0.9 pmol/L) and big ET-1 (6.1 +/- 4.8 pmol/L) in patients' group were significantly (P < 0.01) higher than those (1.0 +/- 0.3 and 2.0 +/- 0.8 pmol/L, respectively) in control group. There was a significant positive correlation between plasma big ET-1 and alpha-fetoprotein (r = 0.77, P < 0.01). Some of the 29 patients with liver cirrhosis also had modestly elevated plasma big ET-1 levels. The mean (+/- SD) plasma big ET-1 concentration (3.1 +/- 0.9 pmol/L) in patients with liver cirrhosis was significantly (P < 0.01) higher than that in control group, although there was no significant difference between the mean plasma ET-1 levels of both groups. Raised plasma big ET-1 and, less markedly, ET-1 levels in patients with HCC decreased after successful transcatheter arterial embolization concomitantly with a reduction in tumor sizes and a decrease in plasma alpha-fetoprotein levels. In six patients, an arteriovenous difference in ET-1 and big ET-1 levels across the tumor bed with a higher concentration in the venous circulation was found. Reverse-phase high performance liquid chromatography revealed that major portions of immunoreactive ET-1 and big ET-1 in hepatic venous plasma coeluted with synthetic ET-1 and big ET-1, respectively. Immunohistochemistry of HCC tissues from two patients demonstrated HCC cells positive for ET-1 and big ET-1, whereas no ET immunoreactivity was found in adjacent nontumorous hepatocytes. We conclude from these results that ET is produced by and released from a substantial number of HCC, which may stimulate proliferation of carcinoma cells as an autocrine or paracrine growth factor.

Enhancement of unbound clearance of ICG by plasma proteins, demonstrated in human subjects and interpreted without assumption of facilitating structures

The kinetics of hepatic removal of protein-bound substances were studied in nine human subjects with various liver diseases by the use of indocyanine green as a model substance. Intrinsic hepatic clearance of indocyanine green was measured by means of a constant infusion of indocyanine green and concentration measurements of indocyanine green in arterial and hepatic venous plasma samples. During the indocyanine green infusion, 1-1.51 of dextran-70 was given whereby a stable dilution of the plasma protein concentration by a factor of 0.6-0.8 was obtained. In each of the subjects, the intrinsic clearance of indocyanine green increased after the protein dilution (range 11-64%). Elimination of ethanol (not protein bound), similarly assessed, was not significantly changed. The traditional hypothesis that unbound clearance (intrinsic clearance divided by the free fraction of the ligand) is independent of protein concentration was refuted since in each of the subjects the protein dilution was followed by a reduction of the unbound clearance of ICG (P < 0.005, n = 9). We examined whether these observations imply some special mechanism (e.g. a hepatocyte protein receptor) by which the unbound clearance is enhanced by the binding protein(s). The previously developed pseudofacilitation model--describing the effects of ligand-protein diffusion and dissociation in an unstirred plasma layer near the hepatocyte--was extended to the case of a mixture of binding proteins, and parameter-free bounds were derived to predict the response of intrinsic clearance to protein dilution. The observed changes of the intrinsic clearance values did not violate these bounds (P < 0.002, n = 9). Thus no facilitating mechanisms are necessary to account for the observed deviations from the traditional hypothesis.

Intrahypothalamic, but not hippocampal, administration of muscimol suppresses hyperglycemia induced by hippocampal neostigmine in anesthetized rats

We investigated the effects of intrahypothalamic or hippocampal injection of GABA receptor agonists on hyperglycemia induced by hippocampal neostigmine. Prior to the injection of neostigmine (50 nmol) into the hippocampus (HPC), muscimol (0.01-1 nmol) or baclofen (1 nmol) was injected into the bilateral ventromedial hypothalamus (VMH). Muscimol suppressed the hyperglycemia in a dose-dependent manner, but baclofen affected it only minimally. In contrast, neither hippocampal muscimol (1 or 2.5 nmol) nor baclofen (1 nmol) suppressed the hippocampal neostigmine-dependent hyperglycemia. Intrahypothalamic muscimol (1 nmol) also decreased the changes in hepatic venous plasma glucagon and epinephrine significantly. These results indicate that intrahypothalamic muscimol suppresses hyperglycemia caused by cholinergic neurons originating from the HPC, indicating existence of the location specificity.

Effects of adrenergic blockers on central nervous system-mediated hyperglycemia in fed rats

We studied the effect of adrenergic blockade on hepatic venous hyperglycemia and the activation of a hepatic glycogenolytic enzyme, phosphorylase-a, in response to cerebral cholinergic activation. Neostigmine was injected into the third cerebral ventricle of bilaterally adrenodemedullectomized (ADMX) rats, while somatostatin and insulin were administered intravenously. Hepatic venous plasma glucose concentrations and hepatic phosphorylase-a activity were measured. Intracerebroventricular injection of neostigmine (5 × 10 −8 mol) caused increases in hepatic venous glucose concentrations and hepatic phosphorylase-a activity. Both of these changes were prevented by intraperitoneal (IB) pretreatment with phentolamine (5 × 10 −7, 1 × 10 −6 mol) without the intervention of insulin secretion, but not by pretreatment with the α-antagonists antagonist phenoxybenzamine (1 × 10 −6 mol), the β-adrenoreceptor antagonist propranolol (1 × 10 −6 mol), the α 1-antagonists prazosin or bunazosin (1 × 10 −6 mol), the α 2-antagonist yohimbine (1 × 10 −6 mol), or prazosin (5 × 10 −7 mol) plus yohimbine (5 × 10 −7 mol). These results suggest that phentolamine prevented brain-mediated hepatic glycogenolysis by a mechanism that may not be classified pharmacologically as involving either α 1- or α 2-receptors.

Mechanism of intrahippocampal neostigmine-induced hyperglycemia in fed rats.

We previously reported that the injection of neostigmine, an acetylcholine esterase inhibitor, into the dorsal hippocampus produced hepatic venous plasma hyperglycemia associated with an increase of epinephrine and glucagon in anesthetized fed rats. To evaluate the relative contribution of these glucoregulatory hormones and the nervous system to the net hyperglycemic response, we unilaterally injected neostigmine (5 x 10(-8) mol) into the dorsal hippocampus in the following groups of rats: intact rats with bilateral adrenalectomy to eliminate the action of epinephrine, and rats receiving a constant infusion of somatostatin and insulin to prevent the glucagon response and to maintain the basal insulin level. Hepatic venous plasma levels of glucose, immunoreactive glucagon, immunoreactive insulin, epinephrine, and norepinephrine were determined. The area under the glucose curve during the 120-min period following the injection of neostigmine was compared between groups. The areas under the glucose curve for rats receiving somatostatin and insulin, adrenalectomy rats, and adrenalectomy rats receiving somatostatin and insulin were, respectively, 82, 31, and 61% of that for intact rats. The fashion of hippocampal stimulated hyperglycemia with neostigmine was similar to that after injection of neostigmine into the third cerebral ventricle. Therefore, we investigated hyperglycemia in rats with lesions of ventromedial hypothalamus and found that the response to hippocampal neostigmine was significantly inhibited by the hypothalamic lesion. These findings suggest that the glucoregulatory hippocampal activity evoked by neostigmine may be transmitted to peripheral organs via the ventromedial hypothalamus.

Role of brain histamine H 1- and H 2-receptors in neostigmine-induced hyperglycemia in rats

We previously reported that when neostigmine, an inhibitor of acetylcholine esterase, was injected into the third cerebral ventricle, the concentration of hepatic venous plasma glucose was increased via central muscarinic receptors in anesthetized rats. To determine whether brain histamine receptors are involved in cholinergic system transmission with regard to central nervous system (CNS)-mediated glucoregulation, we examined the effects of the H 1 receptor antagonist pyrilamine and the H 2 receptor antagonist ranitidine on neostigmine-induced hyperglycemia in anesthetized rats. The injection of pyrilamine (5×10 −9–5×10 −7 mol) into the third cerebral ventricle suppressed hyperglycemia induced by intraventricular injection of neostigmine (1×10 −9 mol) in a dose-dependent manner. Injection of ranitidine (5×10 −9–5×10 −7 mol) into the third cerebral ventricle did not suppress the hyperglycemia induced by neostigmine, but enhanced it in a dose-dependent manner. These findings suggest that neostigmine-induced CNS-mediated hyperglycemia is transmitted by not only brain cholinergic muscarinic receptors but also in part by histamine H 1 receptors.

Relative contribution of nervous system and hormones to CNS-mediated hyperglycemia is determined by the neurochemical specificity in the brain

To determine whether CNS regulatory pathways are organized so that differential sympathetic outflow patterns occur in response to stress, we injected various doses of neostigmine or bombesin into the third cerebral ventricle of fed rats, and then measured the hepatic venous plasma concentrations of glucose, glucagon, insulin, and epinephrine. The following four groups of rats were studied. Group 1 was intact rats. Group 2 comprised intact rats receiving the constant infusion of a) somatostatin to inhibit the endogenous secretion of insulin and glucagon, and b) insulin to maintain the plasma insulin concentration at basal levels. The infusion was started from −30 minutes and given via a catheter in the femoral vein. Group 3 consisted of rats that underwent bilateral adrenal medullectomy (ADMX) one week before the experiment. Group 4 was ADMX rats administered a constant infusion of somatostatin with insulin through a femoral vein, as above. The administration of 1 × 10 −9 mol neostigmine caused hepatic venous hyperglycemia mediated by three distinct pathways: 1) direct innervation of the liver, 2) a direct action of epinephrine on the liver, and 3) the action of glucagon on the liver. We estimated the relative contribution of these three factors to be about 47, 32, and 21%, respectively. Relative contributions of three factors of the doses of 5 × 10 −9 and 5 × 10 −8 mol neostigmine demonstrated an effect similar to that of 1 × 10 −9 mol neostigmine. Epinephrine was shown to be the only agent involved in the hyperglycemic response to intraventricular bombesin at doses of 1 × 10 −10, 1 × 10 −9, and 1 × 10 −8 mol. Coadministration of atropine with bombesin did not affect the bombesin-induced hyperglycemia. This evidence suggests that the relative contribution of the nervous system and hormones to CNS-mediated hyperglycemia is determined by the type of compound used to stimulate the CNS.

Regional sympathetic activity, severity of liver disease and hemodynamics in patients with cirrhosis

One hundred and eight patients with cirrhosis (23 grade A, 46 grade B and 39 grade C, according to Pugh's classification) underwent hemodynamic studies and plasma catecholamine concentration measurements. Blood samples were withdrawn from the pulmonary artery (n = 108), the hepatic vein (n = 108), the azygos vein (n = 59), the right renal vein (n = 66), the right jugular vein (n = 34) and the femoral vein (n = 33). Plasma noradrenaline concentrations in the pulmonary artery and the hepatic vein were more elevated in grade B (607 +/- 52 and 402 +/- 42 pg/ml, respectively) and C patients (630 +/- 59 and 475 +/- 53 pg/ml, respectively) than in grade A patients (411 +/- 51 and 243 +/- 40 pg/ml, respectively). Plasma noradrenaline concentrations from these two vessels were negatively correlated with indocyanine green clearance. These results indicate that both overall and splanchnic sympathetic activities are dependent on altered hepatic function. Significant correlations were found between the wedged hepatic venous pressure and plasma noradrenaline concentrations from either the pulmonary artery, the hepatic vein or the azygos vein. These correlations indicate that both overall and splanchnic sympathetic activities are dependent on the degree of portal hypertension. Moreover, significant correlations were found between hepatic venous plasma noradrenaline concentrations and systemic hemodynamic values, suggesting that splanchnic sympathetic nervous activity could either play a role in the systemic hyperkinetic syndrome or be a consequence of this hyperkinetic syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

CNS stimulation does not affect hepatic venous glucose concentration in severely diabetic rats

To assess the role of the central nervous system (CNS) in carbohydrate metabolism in diabetes, neostigmine was injected into the third cerebral ventricle in fed rats with streptozotocin (STZ; 80 mg/kg)-induced diabetes under pentobarbital sodium anesthesia. Changes in hepatic venous plasma glucose concentrations were monitored. Neostigmine injection caused no significant changes in the hepatic venous plasma glucose concentration in untreated diabetic rats, whereas the glucose level increased significantly in insulin-treated diabetic rats similarly to the changes in normal control animals. In diabetic rats, the plasma levels of glucagon, epinephrine, and norepinephrine were increased significantly by neostigmine. After various doses (35-80 mg/kg) were given to rats, it was found that the higher the STZ dose, the lower was the hepatic glycogen content and the smaller was the glycemic response to neostigmine. Our results indicate that, in severe diabetes, CNS stimulation with neostigmine fails to increase hepatic glucose output, because glycogen stores are nearly exhausted and gluconeogenesis is already maximal.

Reciprocal changes of plasma glucose and ketone bodies in fasted and acutely diabetic rats after CNS stimulation

To assess the effect of chemical stimulation of the central nervous system (CNS) on ketogenesis, we injected neostigmine (5 × 10 −8mol) into the third cerebral ventricle in normal rats fasted for 48 h and fed rats with diabetes induced by streptozotocin (STZ, 80 mg/kg). The hepatic venous plasma levels of ketone bodies (3-hydroxy-butyrate and acetoacetate), free fatty acids (FFA), and glucose were measured for 120 min after the injection of neostigmine under pentobarbital anesthesia. In the normal rats, plasma glucose levels were significantly increased but neither ketone bodies nor FFA were affected by CNS stimulation with neostigmine. In contrast the plasma levels of ketone bodies and FFA were significantly increased in STZ-diabetic rats, while glucose levels remained unchanged. The intravenous infusion of somatostatin (1.0 μg/kg/min) suppressed the increase in plasma ketone bodies following CNS stimulation in STZ-diabetic rats. These findings suggest that CNS stimulation with neostigmine may accelerate ketogenesis by promoting the lipolysis, which may be induced by glucagon, in fed diabetic rats but not in normal fasted rats.

Relative Contribution of Nervous System and Hormones to Hyperglycemia Induced by Thyrotropin-Releasing Hormone in Fed Rats

In a continuation of our studies on the mechanism of central nervous system induced hyperglycemia in the rat, we evaluated the relative contribution of a direct neural effect on the liver and of certain hormones to the hyperglycemia induced by administration of thyrotropin-releasing hormone (TRH). The findings were compared with those of a previous investigation using neostigmine or 2-deoxy-D-glucose. In the present study TRH was injected into the third cerebral ventricle of rats, and the concentrations of hepatic venous plasma glucose, immunoreactive glucagon, immunoreactive insulin, epinephrine, and norepinephrine, were measured. Four groups of animals were evaluated: (1) intact rats; (2) rats receiving an infusion of somatostatin with insulin via the femoral vein to inhibit glucagon secretion and to maintain the basal insulin level; (3) rats bilaterally adrenalectomized (ADX) to prevent epinephrine secretion, and (4) ADX rats administered an infusion of somatostatin and insulin. Evaluation of the areas under the glucose curves for the rats receiving somatostatin with insulin, ADX rats, and ADX rats receiving somatostatin with insulin showed values 202, 50, and 79% of those observed in intact animals. These observations suggest that TRH-induced hyperglycemia results from at least two effects: a direct neural effect on the liver including a suppressive effect of epinephrine on insulin secretion (contributing about 79% to the total hyperglycemic effect) and a direct effect of epinephrine on the liver (contributing about 21% to the total hyperglycemic effect).(ABSTRACT TRUNCATED AT 250 WORDS)

The Effect of Somatostatin on Insulin and Glucose Levels During Insulin Infusion in Anesthetized Dogs

The purpose of the study was to examine the transhepatic and peripheral effects of somatostatin (SN) infusion on plasma glucose and insulin during insulin (IN) infusion. Hepatic blood flow was measured electromagnetically during intermittent sampling from the portal and hepatic veins, femoral artery, and right external jugular vein. Hepatic blood flow [sum of portal vein (PV) and hepatic artery] was similar during IN or IN + SN infusions. IN concentrations decreased in the portal vein from 374.8 +/- 50.3 to 295.8 +/- 25.9 pM (p less than 0.01) when SN was infused with IN. Hepatic venous plasma IN concentration also decreased from 143.6 +/- 26.6 to 88.3 +/- 10.1 pM (p less than 0.01). Plasma IN concentrations in the femoral artery and jugular vein remained unchanged. Hepatic insulin extraction changed from 64 +/- 4% during IN to 72 +/- 3% during IN + SN (p less than 0.01). Hepatic clearance and total body clearance were unchanged. Peripheral venous glucose with a nadir of 3.82 +/- 0.2 mM during IN alone decreased to a nadir of 3.16 +/- 0.27 mM (p less than 0.01) during IN + SN infusion. Mean portal venous glucose concentrations were 5.0 +/- 0.27 and 3.4 +/- 0.19 mM, respectively (p less than 0.01). In two additional experiments in which endogenous C-peptide concentrations were examined in the portal vein and femoral artery, C-peptide levels were lower during IN + SN compared to IN alone. We conclude that SN used to suppress endogenous insulin secretion increases hepatic insulin extraction, lowers glucose concentrations, and suppresses endogenous C-peptide levels to a greater extent than insulin infusion alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Splanchnic removal of human alpha-atrial natriuretic peptide in humans: Enhancement after food intake

In order to assess the effect of food ingestion on splanchnic disposal of human alpha-atrial natriuretic peptide (ANF), hepatic-intestinal removal of ANF was determined before and after a test meal. Hepatic venous and arterial plasma samples were obtained from six subjects, most of whom had only disorders of minor degree. Hepatic blood flow (HBF) increased significantly after meal ingestion (1.10 ± 0.17 [SEM] to 1.51 ± 0.26 L/min, P < .01). Baseline arterial ANF (10.9 ± 3.1 pmol/L) did not change significantly. In contrast, hepatic venous ANF increased after meal intake (5.7 ± 2.0 to 8.4 ± 1.9 pmol/L, P < .05), and accordingly the splanchnic fractional extraction decreased (0.53 ± 0.09 to 0.35 ± 0.08), although this was not statistically significant. Splanchnic clearance of ANF increased from 347 ± 90 mL/min to a maximal value of 615 ± 158 mL/min ( P < .05). Splanchnic removal of ANF was 3.0 ± 0.5 pmol/min before and increased to a maximum value (7.1 ± 2.2 pmol/min, P < .05) 35 minutes after ingestion of the meal. Our results showed enhanced splanchnic removal of ANF after food intake. This is due to increased hepatic-intestinal clearance of the peptide consequent on increased splanchnic blood flow, rather than altered fractional extraction of ANF.