Biomedical subjects
Publications and source records attributed to S Rosell.
The physiological significance of neurotensin, with respect to gut motility in man, may be to mediate postprandial, fat-induced changes in the motility pattern of the gastrointestinal tract. There is strong experimental evidence that this effect of neurotensin is endocrine-mediated. The role of neurotensin as a paracrine hormone, neurotransmitter or neurocrine hormone remains to be determined.
The effects of intrajejunal and intravenous infusion of fat (100 ml Intralipid 20%) on pentagastrin-stimulated gastric acid secretion and on the concentrations of plasma neurotensin-like immunoreactivity (p-NTLI) were studied in eight healthy subjects. Gastric acid secretion was studied for a 1.5-h period at 15-min intervals after fat administration. Acid secretion was reduced by 58% and 36%, respectively, after intrajejunal and intravenous administration. The concentration of p-NTLI rose significantly from 29 to 177 pmol/l at 45 min after intrajejunal administration but did not change after intravenous infusion. The results indicate that large volumes of fat inhibit gastric acid secretion by a neurotensin-independent postabsorptive mechanism and by an intestinal mechanism that may in part be mediated by neurotensin.
The concentration of neurotensin-like immunoreactivity in plasma (p-NTLI) increases after the ingestion of food, and fat seems to be the most important nutrient. It is essential to characterize the NT species that are responsible for this postprandial rise of p-NTLI. After an overnight fast, two male and two female subjects therefore ingested 300 ml of cream (containing 40% (w/w) milk fat). Unextracted plasma samples were subjected to column chromatography and the eluates were analysed using four NT antisera having different specificities. The concentration of chromatographically identified NT(1-13) in peripheral plasma increased significantly from 3 pM in the fasting state to 26 pM 30 min after the ingestion of fat. The concentration of NT(1-8), which is probably a metabolite of NT(1-13), also increased markedly. No significant increase of smaller COOH-terminal sequences of NT was found. The results show that the plasma concentration of NT(1-13) may increase about tenfold following the ingestion of fat. This is further support for the hypothesis that NT(1-13) may function as a hormone.
Exposure of rats to smoke from one cigarette caused local oedema due to a marked increased in vascular permeability from the epiglottis down to bronchioli, as indicated by extravasation of Evans blue in the airway mucosa. The cigarette smoke-induced extravasation of Evans blue was still present after removal of the tar and nicotine content of the smoke, suggesting that chemical irritants in the vapour phase were the main mediators of the vascular permeability response. Local or systemic pretreatment with capsaicin or [D-Arg1, D-Pro2, D-Trp7,9, Leu11] SP, a substance P antagonist, abolished or significantly reduced the airway oedema induced by cigarette smoke or vagal nerve stimulation. No reduction of the cigarette smoke or vagally induced tracheal oedema was seen upon pretreatment with mepyramine plus cimetidine, fentanyl, disodiumchromoglycate, methylprednisolone or terbutaline. The results thus indicate that the cigarette smoke or vagally induced tracheal oedema is most likely to be due to substance P release from local capsaicin-sensitive afferent neurons in the airway mucosa. Local administration of substance P antagonists may be considered as a pharmacological means of inhibiting local mucosal oedema in the airways caused by airway irritants such as cigarette smoke.
Electrical stimulation of the cervical vagus nerve in anesthetized guinea pigs induced a rapid increase in respiratory insufflation pressure, suggesting increased airway resistance. After intravenous administration of a substance P (SP) antagonist, [D-Arg(1),D-Pro(2),D-Trp(7,9),Leu(11)]SP, the insufflation pressure response to vagal stimulation was reduced by 78% while the cardiovascular effects were unchanged. Histamine receptor-blocking agents were used to inhibit the effects of histamine release induced by the SP-antagonist. [D-Arg(1),D-Pro(2),D-Trp(7,9),Leu(11)]SP also reduced the increase in insufflation pressure caused by intravenous SP or capsaicin. The long-lasting noncholinergic contraction of the main and hilus bronchi induced by field stimulation in vitro, as well as the contractile effects of SP and capsaicin, were also blocked by the SP antagonist. The cholinergic contractions and the noncholinergic tracheal relaxation on field stimulation in vitro were, however, not blocked by the antagonist. Vagal stimulation in vivo also increased vascular permeability in the respiratory tract and esophagus, causing a subepithelial edema as indicated by Evans blue extravasation. Previous treatment with [D-Arg(1),D-Pro(2),D-Trp(7,9),Leu(11)]SP inhibited the permeability increase induced by both vagus nerve stimulation and exogenous SP. SP release from vagal sensory nerves was indirectly shown by reduction in the bronchial levels of SP after nerve stimulation in vivo. The data suggest that a major portion of the vagally or capsaicin-induced increase in smooth muscle tone is caused by SP release from sensory neurons. In addition, activation of vagal SP-containing sensory nerves induces local edema. Tracheobronchial afferent SP-containing C fibers may thus exert local control of smooth muscle tone and vascular permeability in normal and pathophysiological conditions.
The effect of intraduodenal administration of various types of lipids on the concentration of p-NTLI has been studied on anesthetized rats. Oleic acid, sodium oleate, triolein, linoleic acid, linolenic acid, arachidonic acid, butyric acid, liquid paraffin, phosphatidyl choline (lecithin) and saline were administered. Oleic acid, triolein, linoleic acid and linolenic acid significantly increased the integrated response of p-NTLI. The maximal concentration of p-NTLI was reached 40 min after administration of oleic acid. However after instillation of triolein, the maximal concentration was reached at 100 min which was significantly later. The results indicate that the response of p-NTLI following administration of fat into the duodenum of rats is a specific event caused by fatty acids rather than by lipophilic substances in general. Of the substances tested 18-carbon fatty acids were the most effective in increasing the concentration of p-NTLI. Shorter- or longer-chain fatty acids were less effective. The degree of unsaturation, i.e. the presence of one or more double bounds is also of importance. Triglycerides seem to be hydrolysed to fatty acids before they may bring about an increase in the concentration of p-NTLI. The charge of lipids seems to be critical since the sodium salt of oleic acid had limited effects. Arachidonic acid did not change the integrated response of p-NTLI indicating that products of cyclooxygenase and lipoxygenase pathways are not involved in the fatty acid induced release of NTLI.
The purpose of this study was to evaluate the pharmacological properties of a substance P (SP) analogue [D-Arg, D-Pro, D-Trp, Leu]SP as an SP antagonist. This analogue, blocked the SP-induced contractions of the isolated guinea-pig ileum and the rat urinary bladder and it exhibited no spasmogenic activity on these preparations. The affinity constant (pA2) for [D-Arg, D-Pro, D-Trp, Leu]SP versus SP was 6.31 on the guinea-pig ileum preparation and 5.30 on the rat urinary bladder preparation. The slopes of the regression lines of the Schild plots were close to unity. These data indicate that [D-Arg, D-Pro, D-Trp, Leu]SP blocks SP receptors in a simple competitive manner and suggest that there are at least two subpopulations of SP receptors. The contractions caused by the closely related tachykinins eledoisin and physalaemin were also blocked by the SP analogue. However, the slopes of the regression lines were significantly different from unity. Moreover, when tested on the hamster urinary bladder, which contracts at low concentrations of eledoisin but is rather insensitive to physalaemin and SP, [D-Arg, D-Pro, D-Trp, Leu]SP did not block the contractile actions of eledoisin or of physalaemin and SP. Compared to SP eledoisin and physalaemin may bind to SP receptors in a different manner. Eledoisin also seems to interact with receptors different from the SP receptors.
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Electrical stimulation of the feline vagal or splanchnic nerves after hexamethonium blockade of nicotinic ganglionic transmission produces gastric contractions, suggesting antidromic activation of thin afferents. The present experiments were performed to examine whether substance P is involved as a transmitter in such gastric responses. Cats were anesthetized with chloralose, laparotomized and the adrenals were ligated. The left greater splanchnic nerve, proximal to the celiac ganglion, and the left or right cervical vagal nerve were dissected, cut and placed on electrodes for peripheral stimulation. Gastric motility was monitored with a balloon. Hexamethonium was administered i.v. as well as i.a. to the stomach. Nerve stimulations produced powerful gastric contractions, which were antagonized by large doses (approximately 0.8 mumol) of substance P administered i.a. to the stomach. Similarly, the gastric contractions elicited by vagal or splanchnic nerve stimulations were reduced to at least 60% of control by the specific substance P antagonist (D-Pro2, D-Trp7,9)-SP administered i.a. (0.4-1.3 mumol). The present results support the concept that substance P is associated with gastric excitatory motor responses, possibly elicited by antidromic activation of thin afferent nerve fibres.
Ten analogs of substance P (SP) were designed and synthesized. The agonist and antagonist activities against SP were assayed on the isolated guinea pig ileum. The prime designs were changes of the important Met11 to include Leu11, Thr11, D-Leu11 and D-Ala11. Step-wise designs of changing D-Arg1 and D-Pro2 to the corresponding L-configurations resulted in decreasing antagonist activity. Changing Leu11 to D-Leu11 and D-Ala11 reduced antagonist activity. [D-Arg1,D-Pro2,D-Trp7,D-Trp9,Leu11]-SP is the most potent antagonist of this group of analogs, and required a 100-fold increase in the concentration of SP to give 50% of the maximal response caused by SP.
Nine of 34 (26%) consecutive patients with different endocrine gastrointestinal tumors had increased levels of plasma neurotensinlike immunoreactivity in the fasting state. This was the case in 6 of 18 (33%) patients with endocrine pancreatic tumors and in 3 of 16 (19%) patients with gut tumors. Only 1 of 13 patients with midgut tumors had increased plasma-neurotensinlike immunoreactivity, despite the fact that most of the normal neurotensin-containing cells are located in the midgut. In 3 of 4 cases the concentration of plasma-neurotensinlike immunoreactivity decreased after streptozotocin or surgical treatment. In 1 patient, increasing levels of plasma-neurotensinlike immunoreactivity were found several months before the onset of clinical symptoms or signs of relapse after surgical treatment. Neurotensin was found in extracts of primary tumors and metastases. Plasma-neurotensinlike immunoreactivity in patients with "neurotensinomas" represents more than one molecular form, including neurotensin(1-13) and neurotensin(1-8). Neurotensin(1-8) in plasma may be a degradation product of neurotensin(1-13) released from the tumor tissue. We have not been able to relate any specific symptoms to elevated plasma-neurotensinlike immunoreactivity.
Ingestion of fat causes a pronounced decrease in lower esophageal sphincter (LES) pressure. This may be due in part to effects of neurotensin (NT), which is released postprandially after the ingestion of fat. The aim of the present investigation was to establish whether the LES pressure decreases at physiological plasma concentrations of NT(1-13). In addition, we have compared the effects and metabolism of NT(1-13) and (Gln4)NT(1-13). The experiments were performed in 3 healthy male volunteers who had fasted for at least 11 hours prior to the study. NT(1-13) or (Gln4)NT(1-13) were infused intravenously at a dose of 12 pmoles X kg-1 X min-1. LES pressure was monitored by a continuous pull-through method with a perfused catheter. The concentrations of chromatographically identified tridecapeptides were determined using NH2 and COOH-terminal directed antisera. Already one min after the start of the infusions the LES pressure had decreased by 43% of the control value. At that time the plasma concentration of the neurotensin tridecapeptide was about 15 pM. NT(1-13) and (Gln4)NT(1-13) had similar half-lives in plasma (2.5 min). NT(1-8) and (Gln4)NT(1-8) were found to be the main metabolites of NT(1-13) and (Gln4)NT(1-13) respectively. The results indicate that the increase in the plasma concentration of NT(1-13) seen after the ingestion of food is sufficient for neurotensin to function as a hormone of the endocrine type. NT(1-13) and (Gln4)NT(1-13) have the same effects on LES pressure in humans and show the same pharmacokinetic characteristics.
Current thinking concerning the possible role off neurotensin in disease is reviewed. The type of approach used in this article is to summarize the results of studies concerning release of neurotensin-like immunoreactivity and to describe the effects of neurotensin which may be of physiological significance such as changes in gastrointestinal motility from a fasting to a fed type in gastric acid secretion and vasoconstriction in adipose tissue. The possible involvement of neurotensin in motility disturbances, duodenal ulcer and obesity has also been discussed. In addition, studies concerning the role of neurotensin in endocrine tumours are presented.
Substance P (SP) and the C-terminal sequences octa- and penta-SP produced dose-dependent vasopressor responses, and the action was associated with mild tachycardia. The vasopressor effect of SP was counteracted by the SP antagonist [D-Pro2,D-Phe7,D-Trp9]SP given intracisternally, suggesting that central SP receptors were involved. Experiments with different sodium contents in the vehicle and with naloxone pretreatment indicate that central naloxone-sensitive opiate receptors may exist, capable of modulating the effects of SP receptor activation.
Substance P is widely distributed in the nervous system. In brain and spinal cord it may act as a transmitter, for example at the central branches of primary sensory neurons. It may also be released from the sensory nerve endings and is thought to be involved in antidromic vasodilatation and in synaptic transmission in autonomic ganglia. In some central neurons substance P is stored together with 5-hydroxytryptamine and thyrotropin-releasing hormone. These neurons project to the ventral horn of the spinal cord, amongst other places. In another system substance P coexists with a cholecystokinin-like peptide. These neurons are localized in the periaqueductal central grey matter and also project to the spinal cord. Finally, injection of a substance P antagonist into the ventral mesencephalon causes marked morphological changes in neurons that contain dopamine, substance P and gamma-aminobutyric acid (GABA).
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