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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.

Insulin-like growth factor-1 (IGF-1) has many insulin-like activities, including stimulation of glucose uptake in skeletal muscle. However, those with diabetes or chronic liver disease are insulin resistant but show a normal hypoglycemic response to IGF-1. We have previously shown that insulin sensitivity depends on a hepatic parasympathetic reflex release of a hormone from the liver. The hypothesis was tested that insulin action, but not IGF-1 action, is dependent on the hepatic parasympathetic reflex. Glucose disposal in response to three doses of IGF-1 (25, 100, 200 microg/kg) was determined in rats. IGF-1 at 200 microg/kg had similar effect on glucose disposal as did 50 mU/kg of insulin. Interruption of the hepatic parasympathetic reflex either by surgical ablation of the anterior nerve plexus or by atropine (1.0 mg/kg) resulted in insulin, but not IGF-1, resistance. Sixteen hours of fasting resulted in insulin, but not IGF-1, resistance. In conclusion, insulin, but not IGF-1, triggers the hepatic parasympathetic dependent release of a putative hepatic insulin sensitizing substance (HISS) that stimulates glucose uptake in skeletal muscle.

The possible existence of a hepatorenal reflex was evaluated in male Sprague-Dawley rats. Sodium excretion was measured in two groups of six rats each, during the first 4 h following acute ingestion of a known amount of high salt chow (2.0-2.5 mequiv. NaCl). Hourly excretion rates for sodium before surgery were compared with results following 7 days of recovery from either hepatic denervation (n = 6) or sham denervation (n = 6). Before denervation, hourly sodium excretion between the groups was not different. Following surgery for hepatic denervation, sodium excretion was 91% lower than presurgery values for the 1st h (p < 0.02) and 44% lower in the 2nd h (p < 0.04). Sham denervation caused no significant change in sodium excretion when compared with presurgery results. A test for completeness of denervation showed that norepinephrine concentration in liver tissue taken from denervated rats was 5.1 +/- 8 ng/g and that taken from sham rats was 22.8 +/- 1 ng/g (p < 0.001). These data demonstrate that the liver is essential for the normal postprandial excretion of sodium following ingestion of a high salt meal in rats.

This study investigated the glucose response to insulin infused after hepatic denervation. Hepatic denervations were performed on 13 anesthetized cats at different levels: (i) surgical hepatic anterior plexus denervation, (ii) chemical total hepatic denervation by painting phenol on the tissues around the portal vein, bile duct, common hepatic artery, and hepatic ligaments, and (iii) bilateral vagotomy. Sham denervations were performed on 9 animals. Before denervation and after each performance of denervations, insulin (100 mU/kg, i.v.) was infused. Plasma glucose concentrations were analyzed at 15, 30, 45, and 60 min after insulin infusion. Hepatic anterior plexus denervation produced a significant reduction in insulin effectiveness. Phenol denervation and bilateral vagotomy failed to further significantly alter the level of insulin resistance developed by hepatic anterior plexus denervation. These observations demonstrate that the effect of insulin on glucose regulation is markedly reduced in the absence of hepatic anterior plexus innervation, suggesting that hepatic nerve function is necessary for the normal glucose response to insulin. Furthermore, the hepatic nerves of relevance appear to reach the liver primarily, if not exclusively, by the anterior hepatic plexus.

Glucose homeostasis is maintained by complex neuroendocrine control mechanisms, involving three peripheral organs: the liver, pancreas, and adrenal gland, all of which are under control of the autonomic nervous system. During the past decade, abundant results from various studies on neuroendocrine control of glucose have been accumulated. The principal objective of this review is to provide overviews of basic adrenergic mechanisms closely related to glucose control in the three peripheral organs, and then to discuss the integrated glucoregulatory mechanisms in hemorrhage-induced hypotension and insulin-induced hypoglycemia with special reference to sympathoadrenal control mechanisms. The liver is richly innervated by sympathetic and parasympathetic nerves. The functional implication in glucoregulation of sympathetic nerves has been well-documented, while that of parasympathetic nerves remains less understood. More recently, hepatic glucoreceptors have been postulated to be coupled with capsaicin-sensitive afferent nerves, conveying sensory signals of blood glucose concentration to the central nervous system. The pancreas is also richly supplied by the autonomic nervous system. Besides the well documented adrenergic and cholinergic mechanisms, the potential implication of peptidergic neurotransmission by neuropeptide Y and neuromodulation by galanin has recently been postulated in the endocrine secretory function. Presynaptic interactions of these putative peptidergic neurotransmitters with the classic transmitters, noradrenaline and acetylcholine, in the pancreas remain to be clarified. It may be of particular interest that it was vagus nerve stimulation that caused a dominant release of neuropeptide Y over that caused by sympathetic nerve stimulation in the pig pancreas. The adrenal medulla receives its main nerve supply from the greater and lesser splanchnic nerves. Adrenal medullary catecholamine secretion appears to be regulated by three distinct local mechanisms: adrenoceptor-mediated, dihydropyridine-sensitive Ca2+ channel-mediated, and capsaicin-sensitive sensory nerve-mediated mechanisms. In response to hemorrhagic hypotension and insulin-induced hypoglycemia, the sympathoadrenal system is activated resulting in increases of adrenal catecholamine and pancreatic glucagon secretions, both of which are significantly implicated in glucoregulatory mechanisms. An increase in sympathetic nerve activity occurs in the liver during hemorrhagic hypotension and is also likely to occur in the pancreas in response to insulin-induced hypoglycemia. The functional implication of hepatic and central glucoreceptors has been suggested in the increased secretion of glucose counterregulatory hormones, particularly catecholamines and glucagon.

The study was carried out to determine whether the diminished release of norepinephrine (NE) upon sympathetic activation in the presence of sotalol can be attributed to the blockade of beta-adrenoceptors in the liver. NE release from the liver was measured in hepatic venous blood collected during direct hepatic nerve stimulation in anesthetized dogs. The mean basal NE concentration in hepatic venous and aortic blood was 0.046 +/- 0.003 and 0.244 +/- 0.041 ng/mL, respectively. NE release increased significantly as stimulation frequency increased, while aortic NE concentration remained unchanged. The increasing response of NE release upon stimulation in the vehicle control group remained stable during the whole experimental period. In dogs treated with sotalol (5 mg/kg, i.v.), NE release was reduced approximately by 30-43%, and the difference was statistically significant (P less than 0.01) at 8 Hz. (+/-)-Propranolol (2.5 mg/kg, i.v.) tended to diminish it, but the difference was not significant. (-)-Propranolol (0.1 mg/kg, i.v.) did not alter NE release at any frequency tested. The beta-blocking action of these drugs in the liver, as determined by the antagonism against the hepatic arterial vasodilating response to isoproterenol, was most effective with (+/-)-propranolol (100%), followed by (-)-propranolol (90%) and sotalol (70%). The results suggest that the inhibitory effect of sotalol on NE release may be related to a mechanism other than its beta-blocking action in the dog liver.

Sympathetic nerves to the intact liver of the cat were selectively destroyed by injection of 6-hydroxydopamine into the portal vein 1 week prior to the experiment. Glucose output was calculated from the product of the arterial-venous glucose difference and hepatic blood flow. Hepatic blood flow was monitored by an electromagnetic flowmeter using a hepatic venous long-circuit. Stimulation of the parasympathetic nerves isolated from around the common hepatic artery produced a rapid reduction in hepatic glucose output to one-quarter of control levels by 2 min and to zero by 10 min of nerve stimulation. The data show that hepatic glucose balance is readily influenced by the hepatic parasympathetic nerves.

Using a newly described method for obtaining pure, mixed hepatic venous blood samples, it was demonstrated that glucose mobilization from the liver of the anesthetized cat in response to hepatic nerve stimulation is via alpha-adrenergic receptors. Neither the elevation of portal pressure nor the amount of glucose generated by the liver was affected by intraportal administration of 1 mg propranolol/kg (beta blockade). In the presence of alpha-receptor blockade (3 mg phentolamine/kg) the portal venous pressure change was minor and the glucose output actually decreased slightly upon nerve stimulation, a response consistent with our previously demonstrated reduction of glucose output by parasympathetic nerve stimulation. The present responses to nerve stimulation were not due to activation of pancreatic nerves since these nerves were routinely ligated.

Rapid hemorrhage to 50 mmHg (1 mmHg = 133.322 Pa) in the pentobarbital-anesthetized cat leads to severe hyperglycemia which declines only slightly by 90 min of hemorrhage. Insulin levels decline to less than one-half of control levels and remain low throughout, despite the hyperglycemia. Glucagon levels decline at 15 min but are significantly elevated by 90 min. These data confirm that the hepatic glycogenolysis is controlled almost entirely by hepatic sympathetic nerves and adrenal secretions with no role for elevated glucagon levels at the early stages in hemorrhage. Hepatic denervation leads to lesser insulin suppression and greater glucagon elevation at later times (45 and 90 min), suggesting that intact hepatic nerves are required for a normal pancreatic response. Hepatic sympathectomy did not produce these effects. Insulin responses remained normal, but glucagon levels were suppressed throughout the entire experiment in sympathectomized cats. The data suggest that hepatic nerves may modulate insulin and glucagon levels during hemorrhage in an unknown manner.

To investigate the role of the sympathoadrenal system in glucose mobilization by the liver during hemorrhage, catecholamine (CA) output from both adrenal glands was determined in anesthetized dogs. Venous blood draining from both adrenal glands was combined in a Y-tube that was connected to an electromagnetic flow probe to measure total adrenal venous blood flow. Plasma concentrations of norepinephrine (NE), epinephrine (E), dopamine (DA), and glucose (GL) were determined in various vascular regions. Adrenal CA output (nanograms per minute) under basal conditions was 50.2 +/- 13.6, 181.4 +/- 41.9, and 13.7 +/- 4.8 for NE, E, and DA, respectively. These values were found to increase significantly (P less than 0.05) in response to 5 min of hemorrhage, reaching a maximum output (nanograms per minute) of 663.6 +/- 160.6 (NE), 2503.4 +/- 607.8 (E), and 141.7 +/- 43.7 (DA). Aortic CAs (nanograms per millilitre) increased significantly with a predominant increase in E (0.33 +/- 0.08 to 3.75 +/- 1.03, P less than 0.05). In contrast, increases in portal and hepatic venous CAs (nanograms per millilitre) were characterized by a predominant increase in NE (0.30 +/- 0.06 to 0.64 +/- 0.11 and 0.17 +/- 0.02 to 0.31 +/- 0.07, respectively, P less than 0.05). Hepatic venous and aortic GL concentrations also increased significantly during hemorrhage. Among the various correlations between plasma CA and GL concentrations, the strongest correlation was found between hepatic venous NE and hepatic venous GL (r = 0.804, P less than 0.001). Correlation coefficients obtained with aortic NE and E were weaker but significant (r = 0.603 and r = 0.608, respectively, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Bilateral carotid arterial occlusion was used as a means of reflexly activating hepatic sympathetic nerves in cats anesthetized with pentobarbital. The resultant hepatic arterial constriction was used as an index of effective surgical denervation of the liver in situations where the hepatic arterial blood pressure was held constant or was allowed to rise parallel with the systemic blood pressure. Cutting the anterior nerve plexus (around the common hepatic artery) produced a highly variable but incomplete reduction in the constrictor response to carotid occlusion. The remainder of the constrictor effect was abolished only when the posterior plexus and hepatic ligament were also cut. Thus, vascular resistance in the hepatic artery is controlled by both the anterior and posterior hepatic plexuses but the contribution of each plexus varies considerably from animal to animal. This must be considered in any experiments that use, or have used, denervation or stimulation of the hepatic nerves.

Intravenous administration of hypotensive doses (30-200 micrograms/kg) of nifedipine to cats anesthetized with pentobarbital caused an increase in cardiac output accompanied by hepatic venoconstriction. The hepatic venoconstriction and the increase in cardiac output were abolished in animals in which the hepatic sympathetic nerves were cut, the adrenal glands were excluded, and the kidneys were removed. This contrasts with the indirect hepatic venoconstrictor action of isoproterenol which was shown previously not to be abolished by these procedures. Further experiments showed that the hepatic venoconstrictor effect of nifedipine was blocked by removal of the kidneys, but not by removal of the hepatic sympathetic nerves and adrenals. These results support the hypothesis that venoconstriction plays an important role when drugs produce increased cardiac output. In nephrectomized animals, nifedipine had no direct effects on hepatic blood volume and it did not alter the effects of infusions of norepinephrine on hepatic blood volume, which have previously been shown to be mediated through alpha 2-adrenoceptors. However, it did reduce the hepatic venous responses to hepatic sympathetic nerve stimulation by 30%.

Superior mesenteric arterial (SMA) blood flow was measured in pentobarbital-anesthetized cats using a noncannulating electromagnetic flowprobe. The selective adenosine antagonist 8-phenyltheophylline (8-PT) antagonized the dilator effect of infused adenosine but not isoproterenol. The vasodilation in response to reduced arterial perfusion pressure (autoregulation) was blocked by the adenosine receptor blockade, which also reduced the degree of postocclusive (1 min) hyperemia by one-half to two-thirds. The remainder of the hyperemia may have been due partially to adenosine, since exogenous adenosine still produced a small vasodilation (26%), so effects of endogenous adenosine could also still be expected to exert a small effect. Myogenic effects appear unlikely to be the mechanism of the small remaining hyperemia, since venous pressure increments within physiologically relevant ranges did not cause altered SMA conductance, and arterial dilation in response to large decreases in arterial pressure could be blocked by adenosine antagonism. Portal pressure was increased using hepatic nerve stimulation (8 Hz) to raise pressure from 7.0 to 12.4 mmHg (1 mmHg = 133.3 Pa). The small vasoconstriction seen in the SMA was due to the rise in systemic blood pressure, since prevention of a rise in SMA pressure prevented the response and 8-PT blocked the response (previously shown to block arterial pressure-flow autoregulation). An equal rise in PVP imposed by partial occlusion of the portal vein did not lead to changes in SMA vascular conductance. Thus, we conclude that within physiologically relevant ranges of arterial and portal venous pressure, the SMA does not show myogenic responses of the resistance vessels.

Changes in hepatic glucose balance in response to direct stimulation of the hepatic nerves were measured in cats. Simultaneous measurements were made of glucose concentrations entering and leaving the intact liver; this, combined with measured blood flows, allows calculation of hepatic glucose balance. Stimulation of the hepatic sympathetic nerves (8 Hz, 15 V, 1 ms) produced a rapid increase in hepatic glucose output that was statistically significant after 1 min and reached a peak 3--5 min after onset of stimulation, after which time the output declined somewhat. The half time for deactivation of the response was 1.8--2 min. Variability in the responses was largely accounted for by the variable control base lines measured immediately prior to stimulation. Those animals showing the highest basal output showed the least increase in output in response to the nerves. The response to stimulation of the mixed nerve trunk in the presence and absence of atropine (1 mg/kg, intraportal) was similar. Simultaneous activation of hepatic sympathetic and parasympathetic nerves therefore produces a purely sympathetic type of effect on net glucose balance across the liver. It was also shown that changes in net splanchnic output or simply in arterial--hepatic venous glucose differences are an adequate reflection of liver glucose balance under the currently tested responses.

Topical application of 90% phenol around the bile duct, portal vein, and hepatic artery, as well as along each of the three hepatic ligaments was tested for effectiveness of rapid and chronic denervation in cats. Because phenol produces nonselective nerve degeneration, it was assumed that proof of functional sympathectomy was adequate proof of disruption of parasympathetic and afferent nerves as well. Functional sympathetic neurons were evaluated by measuring physiological responses to direct electrical stimulation of the anterior hepatic plexus. Acute or rapid denervation was assessed by the degree of rise in portal blood pressure produced by nerve stimulation. Complete denervation appeared within 20 min and was still present by 80 min postapplication. Chronic denervation was tested by applying the phenol and recovering the cats for 6-14 days. An equal number (n = 6) of sham-denervated cats were compared. Phenol denervation did not alter basal glucose, insulin or glucagon levels, hematocrit, blood pressure, or hepatic glycogen levels. These variables are a good index of stress and metabolic status. Nerve stimulation in the chronic sham group raised portal pressure, arterial pressure, and blood glucose levels, whereas the chronic-denervated group showed no responses. The health of the two groups appeared normal with the sole difference being that the painted tissues were mildly discolored and more adhesions appeared in the phenol-denervated set. Thus phenol is a useful tool for producing hepatic denervation. It is less traumatic, faster, and more certain than surgical denervation. In addition, the hepatic lymphatics can be preserved using the topical application of phenol.

Hepatic blood volume, glucose output, and arterial conductance changes were measured in cats in response to unloading carotid sinus baroreceptors using carotid arterial occlusion or perfusion of carotid arteries in situ. Changes in all three parameters are known to be elicited by direct stimulation of the hepatic sympathetic nerves. The baroreflex did not activate glycogen breakdown, whereas nerve stimulation and hemorrhage did, indicating that not only were hepatic nerves not reflexly activated but glucagon and adrenaline levels in plasma were not significantly elevated. Hemorrhage with carotid pressure held constant produced hyperglycemia within a normal range. Hepatic blood volume responses to hemorrhage and to noradrenaline were normal but carotid baroreflexes caused no blood volume response with the vagus cut or intact and with the adrenals intact. The blood volume response to hemorrhage and to reinfusion of blood were normal when the carotid blood pressure was held steady. Hepatic arterial constriction did occur but was sufficient to exactly offset the rise in blood pressure so that blood flow remained unaltered.

Arterial pressures, portal pressures, and hepatic blood volumes were recorded after hepatic denervation in cats anesthetized with pentobarbital. Bromocryptine (50 micrograms/kg) lowered arterial pressure but did not significantly change portal pressure or hepatic blood volume. However, both portal pressure and hepatic blood volume responses to hepatic nerve stimulation were significantly depressed after bromocryptine especially at low frequencies of stimulation. Responses to intraportal infusions of norepinephrine were significantly impaired only at the highest dose. The inhibitory effect of bromocryptine on the neural responses may, therefore, involve a presynaptic inhibition of norepinephrine release, but the mechanism requires further study. These data provide further support for the hypothesis that drugs which impair hepatic venous responses to sympathetic stimuli cause significant impairment of postural reflexes and orthostatic hypotension during clinical use.

Rapid hemorrhage to 50 mmHg (1 mmHg = 133.322 Pa) mean arterial blood pressure led to a rise in blood glucose levels that reached a level of 500 mg% by 15 min and was then maintained with minor decreases for the full period of hemorrhage (90 min). From changes in hepatic glycogen levels it is estimated that glucose from 3.1 g of glycogen was released per kilogram of body weight over the 90-min period of hemorrhage. Bilateral adrenalectomy or hepatic denervation did not reduce the hyperglycemic response significantly although adrenalectomy tended to produce a lesser response. Removal of the adrenals and the hepatic nerves (surgically or selective hepatic sympathectomy using 6-hydroxydopamine) eliminated all but a very small hyperglycemic response which was of slow onset. Thus, the hyperglycemic response to hemorrhage is controlled by a redundant control system wherein either the adrenals or the hepatic sympathetic nerves can produce the response but elimination of both systems eliminates the response. The minor hyperglycemia that occurred with both systems eliminated shows that other hormonal changes known to occur during hemorrhage play, at most, a minor role in the direct stimulation of glycogenolysis during hemorrhage.

The metabolic role of neurally released noradrenaline (NA) was studied in the liver of anesthetized dogs. Sustained stimulation with various frequencies was directly applied on the anterior plexus of hepatic nerves. Stimulation-induced changes in plasma concentrations of endogenous catecholamines in hepatic venous blood were determined in correlation with concomitant changes in those of glucose (GL). Mean basal values for hepatic venous NA, adrenaline, dopamine, and GL were 0.062, 0.022, 0.032 ng/mL, and 97.9 mg%, respectively. Among these catecholamines, NA was the only one being released significantly during stimulation. While hepatic venous NA increased rapidly during stimulation, being maximum within 3 min, hepatic venous GL increased gradually, reaching a maximum value 5 min after the onset of stimulation. A highly significant correlation (r = 0.90, P less than 0.001) was found between changes in hepatic venous NA and GL concentrations observed during stimulation at various frequencies (2-16 Hz). However, hepatic vasoconstricting responses to stimulation were not correlated with increased hepatic venous GL. An alpha-blockade with phentolamine (2 mg/kg, iv) resulted in diminished release of GL by approximately 50% (P less than 0.05) and reduced hepatic arterial vasoconstriction by approximately 47% (P less than 0.01) upon stimulation (8 Hz, 5 min), even though NA release was markedly enhanced. We conclude that in the dog, NA is the sole catecholamine released within the liver in response to direct hepatic nerve stimulation, and NA thus released mediates the hepatic glycogenolysis via alpha-adrenoceptors.

Intrahepatic blood volume-pressure relationships were studied using plethysmography to measure hepatic blood volume and a hepatic venous long-circuit to control intrahepatic pressure. In cats anesthetized with pentobarbital or with ketamine-chloralose, hemorrhage (to reduce hepatic blood flow to 60% of control) caused marked reductions in hepatic blood volume and intrahepatic pressure but did not significantly change hepatic blood volume-pressure relationships. We were unable to demonstrate an active reflex venous response to hemorrhage in these preparations, although a large passive response occurred. The volume-pressure relationships in innervated livers were different from those in denervated livers: apparent venous compliance was much greater and apparent unstressed volume was zero or negative. Hepatic nerve stimulation in denervated livers caused a marked decrease in hepatic blood volume at low intrahepatic pressures but failed to alter hepatic blood volumes at high intrahepatic pressures (15 mmHg) (1 mmHg = 133.3 Pa). This resulted in large apparent compliances and apparently negative unstressed volumes, as seen in the innervated livers. Thus blood volume-pressure relationships in innervated livers may not give valid measurements of compliance and unstressed volume. A remarkable feature in all these experiments was the linearity of the relationship between hepatic blood volume and intrahepatic pressure. Exudation of fluid begins at higher intrahepatic pressures in innervated compared with denervated livers.