Postprandial hypotension: microneurographic analysis and treatment with vasopressin

To clarify the mechanism of postprandial hypotension (PPH), we made microneurographic analyses of patients with PPH and 10 healthy controls by recording multi-unit vasoconstrictive impulses of muscle sympathetic nerve activity (MSNA) directly from the tibial nerve fascicles during a glucose tolerance test. Oral intake of 75 grams glucose in 225 ml of water produced significant and prolonged hypotension in all patients and an increase in MSNA in all healthy subjects. Insulin and glucose responses were not significantly correlated with arterial blood pressure reduction. PPH was prevented by an infusion of vasopressin (0.3 U/min) given before glucose intake. These results suggest that PPH is caused by the lack of sympathetic compensation for the systemic hypotensive stress of splanchnic blood pooling that occurs after food ingestion, and that prior treatment with vasopressin reduces the portal venous flow by constricting the splanchnic vessels in patients with PPH.     

Release of tissue-type plasminogen activator (t-PA) in the splanchnic circulation of the anaesthetised pig during high sympathetic tone

Background

There is a substantial local release of tissue-type plasminogen activator (t-PA) in the splanchnic vascular bed, and this release is increased at high sympathetic tone. Coronary t-PA release is also significant, and this release increases during cardiac nerve stimulation and during reperfusion after 10 min of local myocardial ischemia. However, by repeated cycles of myocardial ischemia/reperfusion coronary t-PA release progressively declines.

Objectives

Accordingly, we hypothesised that splanchnic t-PA release might decrease after an initial peak during maintained and long-lasting sympathetic stimulation.

Methods

In 6 anaesthetised pigs sympathetic tone was augmented by bleeding (20-25 mL/kg over 30 minutes). During the subsequent 2 hours period portal vein (draining the splanchnic vasular bed) - and arterial blood samples were drawn every 20 min and portal vein blood flow was recorded continuously in order to estimate t-PA release in the splanchnic vascular bed.

Results

Relatively stable haemodynamic conditions were obtained after bleeding with mean arterial blood pressure at 50 to 65 mmHg and a portal vein flow at about the 50% of baseline value. Net splanchnic t-PA release rose to a peak 40 min after bleeding, but subsequently declined towards baseline values. Arterial t-PA activity rose after the bleeding period and to a peak value at end of the observation period.

Conclusions

Net splanchnic t-PA release increased only transiently during the period with increased sympathetic stimulation, whereas the arterial t-PA level remained elevated. During a strong and longlasting sympathetic stimulation the lack of a continuously augmented splanchnic t-PA release might increase the risk for intravenous splanchnic thrombosis.     

Central nervous control of hepatic circulation.

This study was undertaken to assess the role of the hypothalamus and medulla oblongata in regulation of liver circulation in anesthetized dogs. Blood pressure, flow in hepatic artery and portal vein, and shifts of blood volume in the liver were recorded. Stimulation of the anterior hypothalamus produced changes in arterial pressure which were followed by passive changes in hepatic arterial blood flow; changes in hepatic artery resistance were rather small. Stimulation of the medial and posterior hypothalamus increased hepatic arterial resistance by 65-170%. Liver portal blood flow during stimulation of most of the hypothalamic sites decreased, hepatic portal pressure rose and vascular portal venous resistance increased 2.5-3 times. Three areas only (sympatho-inhibitory area, paraventricular and lateral hypothalamic nuclei) when stimulated produced dilatation of hepatic portal and splanchnic vascular beds, thus increasing portal blood flow. All cases of stimulation led to the decrease of blood volume in the liver by 10-36%. Stimulation of medullary structures (n. tractus solitarii, reticular nn.) caused similar changes in hepatic circulation, however the amplitude of reaction was 1.5-6 times smaller than upon hypothalamic stimulation. Central impulses to the hepatic vessels are transmitted by sympathetic adrenergic nerve fibers through vascular alpha-adrenoreceptors. It is concluded that the hypothalamic level of the central nervous system, unlike the bulbar one, exerts considerable, differentiated, well coordinated and to some extent specific influences on hepatic circulation.     

Effect of food intake on cardiovascular control in patients with impaired autonomic function

Food intake results in a variety of responses, with the autonomic nervous system playing an important role in maintaining cardiovascular homeostasis. In patients with autonomic failure, who have severe sympathetic impairment, food substantially lowers blood pressure even in the supine position. This is related to a marked increase in splanchnic blood flow, without compensatory changes in the rest of the circulation. Of the food components, glucose causes similar effects to food, while an isosmotic, isocaloric load of the inert carbohydrate, xylose, causes only a small fall in blood pressure. Lipid causes a small, short-lived fall in blood pressure and protein causes minimal change. Insulin appears to contribute to the fall in blood pressure, as bolus injections of insulin (even before ensuing hypoglycaemia), or insulin infusions (with an euglycaemic clamp), when given intravenously lower blood pressure. Other vasodilatatory gut peptides released by food may also play a role. The somatostatin analogue, Octreotide (SMS 201-995), which inhibits the release of a range of peptides, prevents both glucose and food-induced hypotension. Studies of the mechanisms responsible for post-prandial hypotension in autonomic failure continue to provide insight into the relationship between food intake and the hormonal, peptidergic and neural responses which affect the cardiovascular system.     

Reflex control of renal nerve activity originating from the osmoreceptors in the hepato-portal region.

The reflex effects of hepatic osmoreceptors on the renal sympathetic nerve activity (RNA) were studied in 30 pentobarbital anesthetized, vagotomized and sino-aortic baroreceptor denervated (SAD + VD) rabbits. The changes in mean arterial pressure (MAP), heart rate (HR), and RNA were examined when 9% NaCl, 6.5% LiCl or 50% glucose solution was infused into the hepatic portal vein at a rate of 0.15 ml/kg/min for 10 min. Infusion of 9% NaCl solution into the hepatic portal vein increased the plasma osmolality by 10.8 +/- 1.0 mOsmol/kg from the control level in the blood of the hepatic portal vein and by 2.8 +/- 2.0 mOsmol/kg from the control level in the systemic blood. MAP was significantly elevated by 10.2 +/- 5.0 mmHg but HR did not change with hepatic portal infusion of 9% NaCl solution. Intraportal infusion of 9% NaCl solution significantly decreased the RNA by 28.6-34.2% from the control level, 6.5% LiCl solution by 28.6 +/- 4.7%, and 50% glucose solution by 26.2 +/- 3.0%. Femoral arterial infusion of hypertonic NaCl solution, however, did not evoke any significant change in RNA in SAD + VD rabbits. These findings suggest that increases in osmolality and NaCl concentration in the systemic circulation do not result in a decrease of RNA. Furthermore, after section of the anterior and posterior plexus of the hepatic nerve, hepatic portal infusion of hypertonic NaCl solution elicited no change in RNA. The present data indicate that an increase in osmolality in the hepatic portal venous blood results in a reflex decrease of RNA. This reflex may be important for restoration of a postprandial increase in osmolality.     

Vasopressin effect and pathophysiological analysis on postprandial hypotension

In order to clarify the effect of arginine vasopressin (AVP) on postprandial hypotension (PPH) in patients with multiple system atrophy, a loading test of 75 g glucose in 225 ml water was performed during infusion of AVP (0.3 U/min). AVP (0.3 U/min) infusion prior to the loading was significantly effective for PPH in all patients: PPH following to oral intake of glucose was completely prevented. We conclude that infusion of AVP maintained circulating systemic blood volumes by reduced portal venous flow (after a reduction of portal venous inflow) as a result of vasoconstrictive effect of AVP on the splanchnic vessels in patients with PPH.     

Autonomic modulation of insulin levels in foetal sheep

The autonomic nervous system plays an important part in metabolic and circulatory adaptation of the foetus to changes in its intrauterine environment and after delivery. Foetal and neonatal glucose metabolism and insulin secretion are influenced by changes in humoral catecholamine levels as they may occur during asphyxia. To assess the role of neuronal and humoral sympathetic activity in foetal endocrine pancreatic regulation, chronically catheterized foetal sheep near term were chemically sympathectomized with 6-hydroxydopamine. Experiments were carried out in unanaesthetized foetal sheepin utero in the absence of uterine contractions. Insulin and glucose levels, blood gases, acid-base status and catecholamines were measured before, during and after a 2 min occlusion of uterine blood flow caused by mechanical constriction of the maternal aorta. Pancreatic blood flow was determined using radioactive labelled microspheres. During normoxaemia, insulin levels, pancreatic blood flow and glucose transport to the organ in sympathectomized foetuses were elevated compared with intact animals, whereas glucose concentrations did not show any significant differences. After the onset of asphyxia humoral catecholamine levels rose significantly in both groups. Insulin concentrations in the plasma of both intact and symphathectomized foetuses were no longer different indicating both indirect (blood flow and humoral catecholamine related) and direct (neurally mediated) sympathetic effects on pancreatic beta cells.     

Brain processing of duodenal and portal glucose sensing

Peripheral and central glucose sensing play a major role in the regulation of food intake. Peripheral sensing occurs at duodenal and portal levels, although the importance of these sensing sites is still controversial. The present study aimed to compare the respective influence of these sensing pathways on the eating patterns; plasma concentrations of glucose, insulin and glucagon‐like peptide‐1 (GLP‐1); and brain activity in juvenile pigs. In Experiment 1, we characterised the changes in the microstructure as a result of a 30‐min meal in eight conscious animals after duodenal or portal glucose infusion in comparison with saline infusion. In Experiment 2, glucose, insulin and GLP‐1 plasma concentrations were measured during 2 h after duodenal or portal glucose infusions in four anaesthetised animals. In Experiment 3, single photon emission computed tomography brain imaging was performed in five anaesthetised animals receiving duodenal or portal glucose or saline infusions. Both duodenal and portal glucose decreased the amount of food consumed, as well as the ingestion speed, although this effect appeared earlier with the portal infusion. Significant differences of glucose and GLP‐1 plasma concentrations between treatments were found at the moment of brain imaging. Both duodenal and portal glucose infusions activated the dorsolateral prefrontal cortex and primary somatosensory cortex. Only duodenal glucose infusion was able to induce activation of the prepyriform area, orbitofrontal cortex, caudate and putamen, as well as deactivation of the anterior prefrontal cortex and anterior entorhinal cortex, whereas only portal glucose infusion induced a significant activation of the insular cortex. We demonstrated that duodenal and portal glucose infusions led to the modulation of brain areas that are known to regulate eating behaviour, which probably explains the decrease of food intake after both stimulations. These stimulation pathways induced specific systemic and central responses, suggesting that different brain processing matrices are involved.     

Hepatic portal injection of glucose elevates efferent sympathetic discharges of interscapular brown adipose tissue

Efferent sympathetic discharges of interscapular brown adipose tissue were recorded after three different concentrations of glucose (138, 277, and 416 mM) and 154 mM NaCl were injected into the portal vein or into the right jugular vein. When injected into the portal vein there was a significant increase in the discharge in response to both concentrations of glucose (277 and 416 mM), whereas only 416 mM glucose solution could cause an increase in the discharge when injected into the right jugular vein. There was no appreciable change in the discharge following the NaCl injections into the portal and jugular veins, and the portal glucose responses in the discharge were abolished by transection of the hepatic branch of the vagus nerve. Since stimulated sympathetic activity has been shown to elevate thermogenesis of the adipose tissue, these findings suggest that vagal glucose signals derived from the portal vein may be involved in the regulation of heat production of this tissue.     

Cerebral carbohydrate metabolism during severe ischemia in fetal sheep

The effect of cephalic hypotension on brain metabolism was studied in 10 unanesthetized, normoxic (PaO2 greater than 17 mm Hg), late-gestation fetal lambs. Perfusion pressure (cephalic arterial minus sagittal venous pressure) was 40 +/- 1 mm Hg (SEM) during control and was reduced to 10 +/- 1 by occlusion of the Grachio-cephalic artery. Cerebral blood flow was measured with microspheres, and arterial and sagittal vein blood samples were analyzed for oxygen content, glucose, and lactate. During the occlusion, oxygen consumption decreased from 125 +/- 8 to 95 +/- 4 (p less than 0.05) (all values mumol 100 g-1 min-1), and glucose uptake increased from 20 +/- 3 to 25 +/- 1 (p less than 0.05). During the control period, there was no net lactate flux; during the occlusion, lactate excretion was 5.7 +/- 1.4 (p less than 0.005). The control glucose and oxygen uptakes demonstrated a normal 6:1 molar ratio; however, during the occlusion, 9.4 mumol 100 g-1 glucose min-1 were taken up in excess of expected aerobic glucose metabolism. If all of this glucose were anaerobically metabolized to lactate, three times the measured efflux would be produced. The transport properties of the fetal blood-brain barrier may be important factors in perinatal brain injury.     

Effects of hypothalamic lesion on pancreatic autonomic nerve activity in the rat

The effects of hypothalamic lesions and intravenous glucose infusion on the efferent activity of vagal and splanchnic nerves to the pancreas were studied in anesthetized rats. Lesions of the ventromedial hypothalamic (VMH), the dorsomedial hypothalamic (DMH) and the paraventricular (PVN) nuclei increased vagal and reduced splanchnic nerve activity. Lesion of the lateral hypothalamic area (LHA) decreased pancreatic vagal nerve activity, and produced either increased or decreased activity of pancreatic splanchnic nerve. Intravenous glucose infusion increased activity of the vagal nerve and reduced that of the splanchnic nerve. These glucose responses were influenced by hypothalamic lesions only slightly or not at all. The findings suggest that hypothalamic modulation of pancreatic hormone secretion involves both the parasympathetic and sympathetic nervous systems, and provide evidence that not only the VMH and the LHA but also the DMH and the PVN are involved in this mechanism.     

Afferent connections to cardiovascular sites in the amygdala: a horseradish peroxidase study in the cat

Either the left or right cervical vagus was electrically stimulated in anesthetized rats before and after selective transection of either the coeliac, gastric and hepatic abdominal branches in order to evaluate the contribution of these branches to vagal controlled insulin secretion. Changes of insulin secretion were estimated on the basis of insulin concentration in venous plasma, sampled by indwelling jugular catheters. Plasma glucose concentration in overnight food-deprived rats was clamped between 130 and 160 mg/dl by means of continuous i.v. glucose infusion, and surgical stress-induced sympathetic activity was blocked by concomitant i.v. infusion of phentolamine and propranolol. Before transection of any abdominal branch, both right and left cervical vagal stimulation induced a 3- to 4-fold increase of plasma insulin concentration and significant increases of plasma glucose concentration, while the heart rate decreased rapidly and significantly. The right cervical vagal stimulation-induced insulin response (integrated incremental area) was significantly decreased by either bilateral coeliac (-37%) or bilateral gastric (-57%), but not by hepatic (-5%) vagotomy. The left cervical vagal stimulation-induced insulin response was significantly decreased (-41%) by hepatic vagotomy. The concomitant rises of plasma glucose concentration may have contributed more than 50% to the vagal stimulation-induced insulin responses. However, calculating the purely neural components revealed that the right cervical vagal stimulation-induced insulin response was still decreased by coeliac (-48%) or gastric (-84%) and not decreased (+24%) by hepatic vagotomy, and the left cervical vagal stimulation-induced insulin response was decreased (-52%) by hepatic branch vagotomy. We conclude that cervical vagal stimulation-induced insulin-secreting activity reaches the pancreas via all 3 abdominal divisions of the vagus nerve, and suggest that pancreatic beta-cells are innervated through all 3 abdominal divisions.     

Effect of synthetic neuromedin-N, a novel neurotensin-like peptide, on exocrine pancreatic secretion and splanchnic blood flow in dogs

Neuromedin-N, a novel neurotensin-like peptide, has recently been identified from porcine spinal cord by using a bioassay for a stimulatory effect on guinea pig ileum. The amino acid sequence of the peptide has been determined to be Lys-Ile-Pro-Tyr-Ile-Leu, which is quite homologous to the COOH-terminal sequence of neurotensin. In this study, the effect of neuromedin-N on pancreas and splanchnic blood flow was investigated in eight dogs. Intravenous injections of graded doses of synthetic neuromedin-N caused a dose-dependent decrease of systemic arterial pressure and a dose-dependent increase in both portal and superior mesenteric arterial blood flow, which were measured with transit time ultrasonic flow meter. Volume and protein output of the pancreatic juice were also increased significantly by Neuromedin-N. Pancreatic capillary blood flow measured with laser Doppler flowmetry was increased in a dose-related manner. The present study first demonstrated that neuromedin-N retains a potent stimulatory effect on the pancreas and splanchnic circulation, indicating that this peptide is one of the biological active forms of neurotensin-like peptide in mammals. This study also leads to the suggestion that this peptide possesses physiological significance as a novel neuropeptide.     

Superior mesenteric artery dilatation alone does not account for glucose-induced hypotension in human sympathetic denervation

Haemodynamic and hormonal effects of two oral isovolaemic, isoosmotic solutions of 0.5 g/kg and 1.0 g/kg glucose were studied in 10 humans with sympathetic denervation due to primary autonomic failure (AF). Measurements were made supine for 60 min, and also after 5 min 45 head-up tilt, before and 60 min after glucose. There was a similar fall in blood pressure (BP) after each dose, after 0.5 g/kg from 160+/-12 / 87+/-6 to 143+/-13 / 76+/-6 mm Hg, P < 0.05 and after 1.0 g/kg from 160+/-13 / 90+/-6 to 136+/-9 / 76+/-5 mm Hg, P < 0.05. Heart rate, cardiac index and forearm muscle blood flow did not change after either dose. After 0.5 g/kg, superior mesenteric artery blood flow was unchanged but rose significantly after 1.0 g/kg, from 243 (169-395) to 722 (227-982) ml/min, P < 0.05, 15 min after ingestion. BP fell further on tilt 60 min after each dose, but there was no difference between doses. Plasma glucose was higher after 1.0 g/kg but plasma insulin was similar after each dose. Thus, in AF with sympathetic denervation there was no dose-related effect of glucose on supine or postural hypotension. Supine hypotension after glucose was not attributable solely to increased splanchnic blood flow; other factors, including dilatation in other vascular beds may have contributed.     

The effect of intraportal and intravenous glucose infusion and an intravenous glucose tolerance test on insulin and glucagon levels in conscious cats with normal and chronically phenol-denervated livers

Cats were prepared with chronically implanted catheters in the portal and femoral vein for administration of glucose. A femoral arterial catheter was used for blood sampling. After at least 5 days following the implantations, cats received an infusion of 3 mg/kg/min into the portal vein and the insulin and glucagon responses were compared with a similar infusion into the femoral vein. The hypothesis predicted that glucose receptors in the liver would result in greater pancreatic hormonal responses than would be seen with the femoral infusions of glucose. This did not occur. There was no statistically significant difference between the rise in insulin and the decrease in glucagon elicited by the glucose infusion into the two alternate infusion sites. A sham-denervated series showed similar responses. A group of cats that underwent hepatic denervation using topical phenol application to the hepatic plexus near the hilum of the liver was tested. The responses of the denervated group were similar to those for the control and sham-operated groups, confirming that hepatic glucose receptors do not serve as an afferent limb of a hepato-pancreatic reflex controlling insulin and glucagon release in conscious cats. In all experiments, a bolus of glucose (500 mg) was injected i.v. to represent a tolerance test. The responses of blood glucose levels, pancreatic insulin and glucagon and recovery from the stimulus were similar in all groups which suggests that hepatic nerves are not essential for a normal hepatic response to intravenously infused glucose. It is suggested, however, that hepatic nerves may be important in producing normal hepatic responses to oral glucose loads.     

Baroreceptor reflex effect on sympathetic nerve activity in stroke-prone spontaneously hypertensive rats

To elucidate the relationship between responses in sympathetic outflow to incremental changes in blood pressure, we performed baroreflex activation experiments in conscious, stroke-prone, spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats. We gave incremental bolus injections of nitroprusside and methoxamine and measured mean blood pressure (MAP), heart rate, and splanchnic nerve activity (SpNA). Change in heart rate per change in blood pressure was greater in WKY rats than in SHRSP indicating the decrease in baroreceptor sensitivity displayed in the latter strain. In contrast, change in SpNA per change in blood pressure was greater in SHRSP than in WKY rats. These findings suggest that sympathetic outflow in SHRSP is more reactive to blood pressure changes than in WKY rats. The discordance in heart rate and SpNA changes supports the notion that central neural integration of autonomic function in SHRSP is impaired.     

Effects of neuropeptide Y on insulin and glucagon secretion in the pig.

Neuropeptide Y (NPY)-nerves occur in the pancreas. We therefore infused synthetic porcine NPY directly into the pancreatic artery in anaesthetized pigs to study its direct in vivo influence on pancreatic blood flow and on insulin and glucagon secretion. NPY was given both under basal, normoglycemic conditions, and during an ongoing intravenous infusion of glucose, which raised plasma glucose levels to 20 mM. NPY was infused at 0.5 (n = 2), 5 (n = 3), 35 (n = 7), or 175 (n = 5) pmol/min. We found that NPY at 5, 35, and 175 pmol/min inhibited glucagon secretion. Furthermore, at 35 and 175 pmol/min, NPY also reduced pancreatic blood flow. In contrast, only at 175 pmol/min, NPY inhibited basal and glucose-stimulated insulin secretion. We conclude that in the pig NPY might participate in the regulation of glucagon secretion (as an inhibitor) and of pancreatic blood flow (as a vasoconstrictor). In contrast, NPY does not seem to be involved in the regulation of insulin secretion.     

Nervous regulation of insulin release by the intestinal vagal glucoreceptors

In anesthetized cats and rats, it is demonstrated that glucose perfusion of the small intestine produces a rapid increase of insulin secretion (IRI) which precedes glycemia variation. This mechanism involves the autonomic nervous system and originates from intestinal glucoreceptors, the existence of which was recently reported. The nervous pathways are described in this study:(1) the afferent pathway is represented by vagal fibers coming from the intestinal glucoreceptors; (2) the efferent pathway involves both sympathetic fibers (splanchnic nerves) and chiefly parasympathetic fibers (vagal nerves). These results are established after surgical suppression of afferent and efferent vagal fibers, and pharmacological exclusion of parasympathetic or sympathetic fibers. The role of this nervous regulation of insulin secretion is discussed with special reference to other already known mechanisms.     

Effect of synthetic chicken and porcine vasoactive intestinal peptide on pancreatic blood flow in dogs

Studies were conducted in dogs to determine the effect of synthetic chicken and porcine vasoactive intestinal peptide on blood flow and exocrine secretion of the pancreas and on systemic arterial pressure. The stimulatory effect of synthetic chicken vasoactive intestinal peptide on blood flow and exocrine secretion of the pancreas was almost similar to that observed after synthetic porcine vasoactive intestinal peptide stimulation, whereas, synthetic chicken vasoactive intestinal peptide retained only approximately two thirds of the potency of synthetic porcine vasoactive intestinal peptide in its effect on lowering systemic arterial pressure. This study suggests that an increase in exocrine pancreatic secretion may be related to an increase in pancreatic blood flow in response to vasoactive intestinal peptide. This study leads us to speculate that total amounts of splanchnic organ blood flow increased in response to porcine vasoactive intestinal peptide are much more greater than those after chicken vasoactive intestinal peptide stimulation, although we cannot exclude the possibility that porcine vasoactive intestinal peptide may be much more potent in its effect on vasodilations in peripheral systemic vessels in comparison with chicken vasoactive intestinal peptide.     

Power spectral analysis of the baroreflex in neonatal swine

The baroreflex was observed in neonatal swine as young as 4 h of age. Bolus injections of Na nitroprusside (NP) and phenylephrine (PE), induced changes in blood pressure and elicited changes in both heart rate and in cervical sympathetic and splanchnic discharge; changes in sympathetic discharge were reflected in altered power spectral magnitude. Measures of heart rate showed that the magnitude of the PE-induced decreases was positively correlated with increasing postnatal age. The results indicate that the baroreflex, as indicated by changes in sympathetic discharge and heart rate, is present in early neonatal swine.