Higher Concentrations Of Neurotensin Research Articles

Neurotensin Changes Propulsive Activity into a Segmental Motor Pattern in the Rat Colon.

Background/AimsNeurotensin is a gut-brain peptide with both inhibitory and excitatory actions on the colonic musculature; our objective was to understand the implications of this for motor patterns occurring in the intact colon of the rat.MethodsThe effects of neurotensin with concentrations ranging from 0.1–100 nM were studied in the intact rat colon in vitro, by investigating spatio-temporal maps created from video recordings of colonic motility before and after neurotensin.ResultsLow concentration of neurotensin (0.1–1 nM) inhibited propagating long distance contractions and rhythmic propagating motor complexes; in its place a slow propagating rhythmic segmental motor pattern developed. The neurotensin receptor 1 antagonist SR-48692 prevented the development of the segmental motor pattern. Higher concentrations of neurotensin (10 nM and 100 nM) were capable of restoring long distance contraction activity and inhibiting the segmental activity. The slow propagating segmental contraction showed a rhythmic contraction—relaxation cycle at the slow wave frequency originating from the interstitial cells of Cajal associated with the myenteric plexus pacemaker. High concentrations given without prior additions of low concentrations did not evoke the segmental motor pattern. These actions occurred when neurotensin was given in the bath solution or intraluminally. The segmental motor pattern evoked by neurotensin was inhibited by the neural conduction blocker lidocaine.ConclusionsNeurotensin (0.1–1 nM) inhibits the dominant propulsive motor patterns of the colon and a distinct motor pattern of rhythmic slow propagating segmental contractions develops. This motor pattern has the hallmarks of haustral boundary contractions.

Neurotensin modulation of acetylcholine, GABA, and aspartate release from rat prefrontal cortex studied in vivo with microdialysis

The effects of the peptide transmitter neurotensin (NT) on the release of acetylcholine (ACh), γ-aminobutyric acid (GABA), glutamate (Glu), aspartate (Asp), and taurine from the prefrontal cortex (PFC) of freely moving rats were studied by transversal microdialysis. Neurotensin (0.2 and 1 μM) administered locally in the PFC produced a concentration-dependent increase in the extracellular levels of ACh, GABA, and Asp, but not of Glu or taurine. The increase produced by 1 μM NT reached a maximum of about 240% for ACh, 370% for GABA, and 380% for Asp. Lower doses of NT (0.05 μM) did not cause a significant change in ACh, GABA, or Asp output in the PFC. Higher concentrations of NT (2 μM) did not induce further increases in the level of neurotransmitters. A high-affinity selective neurotensin receptor (NTR1) antagonist SR 48692 (0.5 μM) perfused locally blocked neurotensin (1 μM)-evoked ACh, GABA, and Asp release. Local infusion of the sodium channel blocker tetrodotoxin (TTX) (1 μM) decreased the release of ACh, had no significant effect on GABA or Asp release, and prevented the 1 μM neurotensin-induced increase in ACh, GABA, and Asp output. Removal of calcium from the Ringer's solution prevented the peptide from having any effects on the neurotransmitters. Thus, in vivo NT plays a modulatory role in the PFC by interacting with cortical neurons releasing GABA and Asp and with ACh-containing neurons projecting to the PFC. The NT effects are of neural origin, as they are TTX-sensitive, and mediated by the NTR1 receptor, as they are antagonized by SR 48692.

Differential effects of neurotensin on dopamine release in the caudal and rostral nucleus accumbens: A combined in vivo electrochemical and electrophysiological study

The time-course of variations in extracellular dopamine concentration following local pressure ejection of 10 −7 to 10 −3 M neurotensin into the ventral tegmental area of the rat was determined in the minute range in the nucleus accumbens by means of differential normal pulse voltammetry associated with carbon fibre electrodes. The effects of neurotensin ejection into the ventral tegmental area were further investigated on the firing activity of the corresponding dopaminergic neurons. The lowest concentration of neurotensin (10 −7 M) enhanced the extracellular dopamine concentration throughout the nucleus accumbens and stimulated the discharge activity of ventral tegmental area dopaminergic neurons. The two highest concentrations of neurotensin (10 −5 M and 10 −3 M) evoked two patterns of responses on the extracellular dopamine concentration and on the discharge activity of dopaminergic neurons. The extracellular dopamine concentration was increased above basal levels in the caudal part of the nucleus accumbens. In the rostral part, the evoked changes exhibited a multiphasic time-course characterized by a decreasing phase below baseline. The firing rate of dopaminergic neurons was either increased or decreased, depending on the neuron being tested. In fact, neurotensin ejection was always followed by an exacerbation of bursting activity, the resulting effect on the mean firing rate being related to the duration of the interburst intervals. Indeed, short interburst intervals permitted an increase in mean firing rate whereas long interburst intervals, indicative of excessive depolarization, led to a decrease in mean firing rate. These results suggest that variations in extracellular dopamine concentration evoked by neurotensin administration into the ventral tegmental area are the result of neurotensin-evoked changes in dopaminergic activity. Moreover, the differential effects evoked by high concentrations of neurotensin could be attributable to two subpopulations of ventral tegmental area dopaminergic neurons which could project differentially to the caudal and the rostral parts of the nucleus accumbens.

Neurotensin Regulates Growth of Human Pancreatic Cancer

The effect of neurotensin (NT) on in vitro-growth of human pancreatic cancer cells (MIA PaCa-2) was examined. Furthermore, the intracellular signal-transduction pathways by which neurotensin regulates growth of MIA PaCa-2 cells were determined. NT is trophic for normal rat pancreas, but the effect of NT on growth of human pancreatic cancer is not known. Effects of NT (10(-12) to 10(-6) mol/l) on growth of MIA PaCa-2 cells were determined by both count of cell numbers and 3H-thymidine incorporation. Action of NT on phosphatidylinositol (PI) hydrolysis, cyclic AMP production, and intracellular calcium level were determined by conventional methods. The effects of 8-bromo-cyclic AMP and prostaglandin E2 on cell growth were determined. Low concentrations of NT (10(-12) to 10(-9) mol/l) stimulated growth in a dose-dependent manner, but higher concentrations of NT (10(-8) to 10(-6) mol/l) did not stimulate growth of MIA PaCa-2 cells. NT (10(-12) to 10(-6) mol/l) stimulated PI hydrolysis and increased intracellular calcium levels in a dose-dependent manner. High concentrations of NT (10(-8) to 10(-6) mol/l) stimulated production of cyclic AMP in a dose-dependent manner. 8-bromo-cyclic AMP inhibited growth of MIA PaCa-2 cells; prostaglandin E2 did not affect growth of MIA PaCa-2 cells. NT stimulates growth of MIA PaCa-2 cells through stimulation of PI hydrolysis and mobilization of calcium. Stimulation of the cyclic AMP pathway by high concentrations of NT abolishes the growth-stimulatory effect of NT that is mediated through PI hydrolysis or calcium mobilization.

Neurotensin: dual effect on the motor activity of rat duodenum

The effects of neurotensin on mechanical activity of rat duodenum were investigated using an isometric-isovolumic preparation. Neurotensin (1 pM to 10 nM) induced a concentration-dependent, tetrodotoxin (TTX)-insensitive fall in both endoluminal pressure and isometric tension. At higher concentrations of neurotensin (1 nM to 1 μM) the relaxation was followed by a concentration-dependent TTX-insensitive contraction, detected only by an increase in endoluminal pressure. Different concentrations of neurotensin were required to desensitize the relaxant and the contractile actions of the neuropeptide. The relaxation was antagonized by apamin, while the contractile response was blocked by nifedipine. Neurotensin, when tested separately on longitudinal and circular muscular strips, caused relaxation of the longitudinal strips. Circular strips showed contractions in response to neurotensin, following an inhibitory phase, if the strips were spontaneously or pharmacologically activated. The results suggest the presence of two sets of neurotensin receptors with a differential localization between the two muscular layers in rat duodenum.

Possible role of plasma neurotensin in regulating the excitatory neural control of the rectum of the fowl.

Effects of neurotensin (NT) applied via the blood vessel on the responses to stimulation of Remak's nerve (RNS) were investigated in the chicken isolated and perfused rectums. NT (5 ng-2 micrograms/ml) produced a concentration-dependent inhibition of the constituent contraction but not relaxation of the responses to RNS. In addition, high concentrations of NT (over 80 ng/ml) produced a contraction of the rectal muscle. Propranolol, a beta-adrenoceptor blocking agent, and guanethidine, an adrenergic neurone blocking agent, were able to reduce the inhibitory effect of NT on the response to RNS while potentiating the contractile effect of NT on the rectal muscle. NT (0.1 and 1 microgram/ml), like norepinephrine, decreased the flow rate of perfusate from the isolated rectum which was perfused at a constant pressure. Guanethidine enhanced norepinephrine-induced vasoconstriction, and phentolamine, an alpha-adrenoceptor blocking agent, plus propranolol was able to abolish it. Either of these prior applications resulted in a small but significant reduction of NT-induced vasoconstriction. These findings suggest that NT in plasma may function as a circulating hormone to exhibit an inhibitory action on the excitatory neural input to the rectum in the chicken, and that catecholamine release from adrenergic nerve terminals by NT may account for some but not all of the activity.

Neurotensin binds with high affinity to small cell lung cancer cells.

Several small cell lung cancer cell lines bound 125I-neurotensin with high affinity. Radiolabeled neurotensin bound with high affinity (Kd = 4 nM) to a single class of sites (2300/cell) using cell line NCI-H209. Binding was time dependent and reversible. Pharmacology studies indicated that the C-terminal of neurotensin was important for the high affinity binding activity. Because high concentrations of neurotensin and its receptors are associated with small cell lung cancer, neurotensin may function as a regulatory peptide in this disease.

Neurotensin: A potent vasoconstrictor in the rat hindquarter

The vasoconstrictor properties of neurotensin (NT) and angiotensin II (AT) were evaluated in isolated, perfused hindquarter, kidney and mesentery of rats. In rat hindquarters, NT (5.4 − 5400 × 10 −9M) and AT (10 − 500 × 10 −9M) elicited dose-dependent vasoconstrictor effects while in the other preparations, only AT was active. Low concentrations of NT produced larger increases of perfusion pressure than AT in the rat hindquarter. Higher concentrations of NT and AT evoked responses of similar magnitude. The vasoconstrictor effects of NT in rat hindquarters were selectively inhibited by [D-Trp 11]-NT, a newly developed NT antagonist. The inhibition appeared to be of the competitive type. In conclusion, the results indicate that NT is a potent vasoconstrictor in the rat perfused hindquarter.