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At least 19 recordsLinked to original sources
PubMed2006

S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt.

Feedback inhibition of the PI3K-Akt pathway by the mammalian target of rapamycin complex 1 (mTORC1) has emerged as an important signaling event in tumor syndromes, cancer, and insulin resistance. Cells lacking the tuberous sclerosis complex (TSC) gene products are a model for this feedback regulation. We find that, despite Akt attenuation, the Akt substrate GSK3 is constitutively phosphorylated in cells and tumors lacking TSC1 or TSC2. In these settings, GSK3 phosphorylation is sensitive to mTORC1 inhibition by rapamycin or amino acid withdrawal, and GSK3 becomes a direct target of S6K1. This aberrant phosphorylation leads to decreased GSK3 activity and phosphorylation of downstream substrates and contributes to the growth-factor-independent proliferation of TSC-deficient cells. We find that GSK3 can also be regulated downstream of mTORC1 in a HepG2 model of cellular insulin resistance. Therefore, we define conditions in which S6K1, rather than Akt, is the predominant GSK3 regulatory kinase.

Animals↗
PubMed2000

Effect of overall feedback inhibition in unbranched biosynthetic pathways.

We have determined the effects of control by overall feedback inhibition on the systemic behavior of unbranched metabolic pathways with an arbitrary pattern of other feedback inhibitions by using a recently developed numerical generalization of Mathematically Controlled Comparisons, a method for comparing the function of alternative molecular designs. This method allows the rigorous determination of the changes in systemic properties that can be exclusively attributed to overall feedback inhibition. Analytical results show that the unbranched pathway can achieve the same steady-state flux, concentrations, and logarithmic gains with respect to changes in substrate, with or without overall feedback inhibition. The analytical approach also shows that control by overall feedback inhibition amplifies the regulation of flux by the demand for end product while attenuating the sensitivity of the concentrations to the same demand. This approach does not provide a clear answer regarding the effect of overall feedback inhibition on the robustness, stability, and transient time of the pathway. However, the generalized numerical method we have used does clarify the answers to these questions. On average, an unbranched pathway with control by overall feedback inhibition is less sensitive to perturbations in the values of the parameters that define the system. The difference in robustness can range from a few percent to fifty percent or more, depending on the length of the pathway and on the metabolite one considers. On average, overall feedback inhibition decreases the stability margins by a minimal amount (typically less than 5%). Finally, and again on average, stable systems with overall feedback inhibition respond faster to fluctuations in the metabolite concentrations. Taken together, these results show that control by overall feedback inhibition confers several functional advantages upon unbranched pathways. These advantages provide a rationale for the prevalence of this control mechanism in unbranched metabolic pathways in vivo.

Biophysical Phenomena↗
PubMed1994

Feedback inhibition in the cat's lateral geniculate nucleus.

Feedback inhibition is generally believed to be a ubiquitous feature of brain circuitry, but few specific instances have been documented. An example in cats is the supposed feedback circuit involving relay cells of the lateral geniculate nucleus and cells of the perigeniculate nucleus (a part of the thalamic reticular nucleus): geniculate relay cells innervate the perigeniculate nucleus, which, in turn, provides an inhibitory, GABAergic projection back to the lateral geniculate nucleus. However, feedback inhibition at the single-cell level requires that a given perigeniculate cell project back onto the same geniculate relay cell that innervates it. We probed for this in an in vitro slice preparation of the cat's lateral geniculate nucleus. We evoked a single action potential in a geniculate cell via a brief, depolarizing pulse delivered through an intracellular recording electrode and looked for any evoked hyperpolarizations. For 6 of the 36 geniculate cells tested, we observed a long-lasting hyperpolarization after the action potential, and much of this was eliminated by application of bicuculline, suggesting synaptically activated inhibitory postsynaptic potentials. We interpreted this to be clear evidence that a given neuron may inhibit itself via circuitry mediating feedback inhibition in the cat's lateral geniculate nucleus.

Animals↗
PubMed2004

Evidence for force-feedback inhibition in chronic stroke.

The presence of force-feedback inhibition was explored during reflex responses in five subjects with known incidence of stroke. Using constant velocity stretches, it was previously found that after movement onset, active reflex force progressively increases with increasing joint angle, at a rate proportional to a fractional exponent of the speed of stretch. However, after the reflex force magnitude exceeds a particular level, it begins rolling off until maintaining a steady-state value. The magnitudes of these force plateaus are correlated with the speed of stretch, such that higher movement speeds result in higher steady-state forces. Based upon these previous studies, we hypothesized that force plateau behavior could be explained by a force-feedback inhibitory pathway. To help facilitate an understanding of this stretch reflex force roll off, a simple model representing the elbow reflex pathways was developed. This model contained two separate feedback pathways, one representing the monosynaptic stretch reflex originating from muscle spindle excitation, and another representing force-feedback inhibition arising from force sensitive receptors. It was found that force-feedback inhibition altered the stretch reflex response, resulting in a force response that followed a sigmoidal shape similar to that observed experimentally. Furthermore, simulated reflex responses were highly dependent on force-feedback gain, where predicted reflex force began plateauing at decreasing levels with increases in this force-feedback gain. The parameters from the model fits indicate that the force threshold for force-sensitive receptors is relatively high, suggesting that the inhibition may arise from muscle free nerve endings rather than Golgi tendon organs. The experimental results coupled with the simulations of elbow reflex responses suggest the possibility that after stroke, the effectiveness of force-feedback inhibition may increase to a level that has functional significance. Practical implications of these findings are discussed in relation to muscle weakness commonly associated with stroke.

Chronic Disease↗
PubMed1997

Decreased hypothalamic-pituitary-adrenal axis sensitivity to cortisol feedback inhibition in human aging.

Aging-related reduction in the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis to glucocorticoid feedback inhibition has been demonstrated in rodents, but aging effects on glucocorticoid feedback inhibition in humans are unclear. This study assessed the influence of aging on the sensitivity of the human HPA axis to feedback inhibition induced by cortisol. Endogenous cortisol feedback inhibition was removed by treatment with metyrapone, which reduces cortisol synthesis by inhibiting 11 beta-hydroxylase. Feedback inhibition was then reintroduced by infusing exogenous cortisol. Sixteen young (26 +/- 1 years old) and 16 older (70 +/- 2 years old) subjects underwent three study conditions in random order. In the two cortisol infusion conditions, oral metyrapone treatment was followed by intravenous infusion of 0.03 mg/kg/h (83 nmol/kg/h) or 0.06 mg/kg/h (166 nmol/kg/h) cortisol for 150 min. Feedback sensitivity was estimated by the latency to and extent of decline of plasma ACTH concentration during and following the cortisol infusion. In a placebo condition, placebo tablets were substituted for metyrapone and normal saline infusion was substituted for cortisol. Blood samples were drawn twice prior to and at 15-min intervals for 4 h following the onset of the infusions, and plasma was assayed for 11-deoxycortisol, cortisol and ACTH. Plasma cortisol suppression and ACTH and 11-deoxycortisol elevations did not differ between age groups after metyrapone. Older subjects exhibited delayed and blunted ACTH responses to infused cortisol. Within older subjects, the ACTH response to the higher dose cortisol infusion was blunted in older women compared to older men. These data provide direct evidence for reduced responsiveness to glucocorticoid feedback inhibition in human aging.

Adrenal Glands↗
PubMed1967

Regulation of glutamine synthetase. II. Patterns of feedback inhibition in microorganisms.

The feedback inhibition of glutamine synthetase was investigated by use of partially purified enzyme preparations from Salmonella typhimurium, Micrococcus sodonensis, Pseudomonas fluorescens, Bacillus cereus, Bacillus licheniformis, Clostridium pasteurianum, Rhodospirillum rubrum, Neurospora crassa, Candida utilis, and Chlorella pyrenoidosa. Inhibition analyses indicated that the enzyme of each organism can be effectively regulated with mixtures of end products from the diverse pathways of glutamine metabolism. When tested individually, tryptophan, histidine, alanine, glycine, glutamine, 5'-adenylate (AMP), cytidine-5'-triphosphate, carbamyl phosphate, and glucosamine-6-phosphate gave limited inhibition. In most cases, the inhibitors were independent in their action, and cumulative degrees of inhibition were obtained with mixtures of these end products. In contrast, with the glutamine synthetases of the two Bacillus species, the simultaneous presence of AMP and histidine (or AMP and glutamine) gave inhibition greater than the sum of the amounts of inhibition caused by either inhibitor alone. Also, alanine and carbamyl phosphate acted synergistically to inhibit the enzyme from N. crassa. The remarkable similarity in the overall patterns of end-product inhibition observed with the enzymes from different sources indicates that these diverse organisms have evolved comparable mechanisms for the regulation of glutamine metabolism. Nevertheless, the enzymes from different sources do differ significantly in their physical and catalytic properties, as was demonstrated by dissimilarities in their purification behaviors, specificity for nucleotide substrate, ability to catalyze the glutamyl transfer reaction, and ability to utilize Mn(++) and Mg(++) as activators for the biosynthetic reaction.

Adenine Nucleotides↗
PubMed2002

Optimization of L-phenylalanine production of Corynebacterium glutamicum under product feedback inhibition by elevated oxygen transfer rate.

Production feedback inhibition both on cell growth and on product formation of phenylalanine fermentation might be alleviated by elevated oxygen supply. Batch fermentations by a high phenylalanine producing strain Corynebacterium glutamicum CCRC 18335 at various initial phenylalanine concentrations (P(0)) ranging from 0 to 20 g/L and different oxygen transfer rate coefficients (K(L)a) ranging from 23 to 76 h(-1) were studied. The fermentation parameters with respect to P(0) were strongly dependent on K(L)a. Cell yield favored higher K(L)a and lower P(0). Product yield with respect to varying phenylalanine concentration was evaluated by the relative oxygen availability (ROA). The optimal ROA for phenylalanine formation was strongly dependent on the product concentration. While P(0) was low, the product inhibition was less significant and the maximum product yield occurred while ROA was at 0.5-0.6. While P(0) was high, the product inhibition was significant and the maximum product yield occurred while ROA was at 0.8-0.9. These results suggest that the product feedback inhibition of phenylalanine fermentation processes can be alleviated by a gradual increase in oxygen supply rate while the increasing product concentration is taken into account. The strategy is demonstrated in a fed-batch culture with elevated oxygen supply. The final phenylalanine concentration was 23.2 g/L, which was 45% better than that of the fed-batch fermentation without elevated oxygen supply. Likewise, the maximum productivity was improved by 42% at 0.37 g/(L x h).

Corynebacterium↗
PubMed2004

Metabotropic glutamate receptors modulate feedback inhibition in a developmentally regulated manner in rat dentate gyrus.

We investigated group II metabotropic glutamate receptor (mGluR) modulation of glutamatergic input onto hilar-border interneurones and its regulation of feedback inhibition in the dentate gyrus. Selective activation of group II mGluRs with (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) depressed mossy fibre (MF)-evoked excitatory drive to these interneurones with significantly greater depression in juvenile than adult rats. During 20 Hz MF stimulus trains, EPSCs became depressed. Depression during the early, but not later part of the train was significantly greater in juvenile than adult rats and was blocked by the mGluR antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495). In dentate granule cells from juvenile rats polysynaptic feedback IPSCs, but not monosynaptic IPSCs, were strongly suppressed by DCG-IV. DCG-IV also suppressed feedback inhibition of perforant path-evoked population spikes. In contrast, in adult animals DCG-IV did not significantly depress feedback inhibition. During 20 Hz stimulus trains in juvenile animals the summation of polysynaptic, but not monosynaptic IPSCs was suppressed by synaptically activated group II mGluRs. Blockade of these mGluRs with LY341495 significantly increased the area and duration of the summated IPSC, causing greater feedback inhibition of granule cell firing. In contrast, in adult animals LY341495 did not alter feedback inhibition following the stimulus train. These findings indicate that group II mGluRs modulate excitatory drive to interneurones in a developmentally regulated manner and thereby modulate feedback inhibition in the dentate gyrus.

Amino Acids↗
PubMed1989

Regulation of the activation of fluorodeoxyuridine by substrate competition and feedback inhibition in 647V cells.

Fluorodeoxyuridine (FdUrd) is a cytotoxic analogue of thymidine which requires activation by thymidine kinase to FdUMP. FdUMP inhibits thymidylate synthetase and, thus, the synthesis of dTTP. 5'-Aminothymidine (5'-AdThd) can antagonize the feedback inhibition exerted by dTTP on thymidine kinase activity and thereby stimulate FdUrd phosphorylation. This provided a novel approach to assess the degree to which end product inhibition regulates the phosphorylation of FdUrd. We used 5'-AdThd to investigate the effects of dThd and IdUrd on the regulation of FdUrd uptake in intact 647V cells, a human bladder cancer cell line. Contributions from catabolic processes were found not to be important in our system. We detected no nucleoside phosphorylase activity in the 647V cells or any effect of 5'-AdThd on the breakdown of 5-fluorodeoxyuridine monophosphate to FdUrd by crude preparations from these cells. Thus, phosphorylation by thymidine kinase determined FdUrd uptake (phosphorylation). In the absence of added nucleosides the rate of FdUrd uptake increased in a time dependent fashion. Diminished feedback inhibition of thymidine kinase appeared to be an important factor, as evidenced by a decrease in intracellular dTTP pools and a time dependent loss in the ability of 5'-AdThd to stimulate FdUrd uptake. Thymidine and iododeoxyuridine inhibited FdUrd phosphorylation (uptake) by two mechanisms: competition for the active site of thymidine kinase and increased feedback inhibition. Increased feedback inhibition was indicated by stimulation of FdUrd uptake by 5'-AdThd. The effects of IdUrd on FdUrd uptake were also time dependent, presumably reflecting accumulation of iododeoxyuridine triphosphate and dTTP pools. FdUrd cytotoxicity was modulated by dThd, IdUrd, and 5'-AdThd in parallel to their perturbation of FdUrd uptake. Individually they reduced the growth inhibitory properties of FdUrd. These results show that the regulation of FdUrd uptake is critically dependent on the presence of dThd and IdUrd and emphasize the potential importance of circulating levels of these nucleosides in mediating FdUrd activation and cytotoxicity.

Cell Line↗
PubMed2006

A role for MAPK in feedback inhibition of Tcrb recombination.

The Tcrb locus is subject to a host of regulatory mechanisms that impart a strict cell and developmental stage-specific order to variable (V), diversity (D), and joining (J) gene segment recombination. The Tcrb locus is also regulated by allelic exclusion mechanisms, which restrict functional rearrangements to a single allele. The production of a functional rearrangement in CD4-CD8- double-negative (DN) thymocytes leads to the assembly of a pre-TCR and initiates signaling cascades that allow for DN to CD4+CD8+ double-positive (DP) differentiation, proliferation, and feedback inhibition of further Vbeta to DJbeta rearrangement. Feedback inhibition is believed to be controlled, in part, by the loss of Vbeta gene segment accessibility during the DN to DP transition. However, the pre-TCR signaling pathways that lead to the inactivation of Vbeta chromatin have not been determined. Because activation of the MAPK pathway is documented to promote DP differentiation in the absence of allelic exclusion, we characterized the properties of Vbeta chromatin within DP thymocytes generated by a constitutively active Raf1 (Raf-CAAX) transgene. Consistent with previous reports, we show that the Raf-CAAX transgene does not inhibit Tcrb recombination in DN thymocytes. Nevertheless, DP thymocytes generated by Raf-CAAX signals display normal down-regulation of Vbeta segment accessibility and normal feedback inhibition of the Vbeta to DJbeta rearrangement. Therefore, our results emphasize the distinct requirements for feedback inhibition in the DN and DP compartments. Although MAPK activation cannot impose feedback in DN thymocytes, it contributes to feedback inhibition through developmental changes that are tightly linked to DN to DP differentiation.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Effects of feedback inhibition on transit time in a linear pathway of Michaelis-Menten-type reactions.

An analysis of the effects of external and internal metabolites on the steady-state behavior of linear pathways comprising a sequence of three Michaelis-Menten-type reactions with and without a simple feedback inhibition (i.e. an interaction of an internal metabolite with the pathway) is performed with respect to the transit time tau by its formulation as rectangular-hyperbolic functions of the flux J, instead of direct expressions in terms of the external metabolite concentrations. For a given concentration of the external metabolite M1 (substrate of the pathway) or M4 (product of the pathway), the flux J has a lower value in the pathway with feedback inhibition than in the pathway without feedback inhibition. With variation in the M1 concentration the transit time tau shows a concave relationship with the flux J which is virtually identical for both pathways, yielding a minimum at a certain value of J. With variation in the M4 concentration the transit time tau monotonously decreases with higher value of J, and for a given value of J the feedback inhibition allows a lower transit time. This effect is enhanced with stronger feedback inhibition, and is in turn greatly reduced with higher values of total concentration and rate constants for the first enzyme in the pathway.

Enzymes↗
PubMed1998

Homogeneous and Spatio-temporal Chaos in Biochemical Reactions With Feedback Inhibition.

A biochemical oscillator involving feedback inhibition can be extended to generate a chaotic attractor. The simple chaotic attractor may be exploited to create signals of higher dimension by passive forcing of other reactions. Diffusively coupled oscillators with negative feedback exhibit regular and irregular patterns in time and space associated with periodic and hyperchaotic attractors, respectively.Copyright 1998 Academic Press

Journal Article↗
PubMed1999

Regulation of phenylalanine biosynthesis. Studies on the mechanism of phenylalanine binding and feedback inhibition in the Escherichia coli P-protein.

Isothermal titration calorimetry (ITC) and site-directed mutagenesis were used to study the interaction of Phe with (a) the Escherichia coli P-protein, a bifunctional chorismate mutase/prephenate dehydratase that is feedback inhibited by Phe, (b) PDT32, a 32 kDa P-protein fragment (residues 101-386) containing the prephenate dehydratase and regulatory domains, and (c) R12, a C-terminal 12 kDa P-protein fragment (residues 286-386) containing the regulatory domain. DeltaH(total) values for PDT32, which included the heats of Phe binding, conformational change, and dimerization, established that in developing a mechanism for end product feedback inhibition, the P-protein has evolved a ligand recognition domain that exhibits Phe-binding enthalpies comparable to those reported for other full-fledged amino acid receptor proteins. Sequence alignments of R12 with other Phe-binding enzymes identified two highly conserved regions, GALV (residues 309-312) and ESRP (residues 329-332). Site-directed mutagenesis and ITC established that changes in the GALV and ESRP regions affected Phe binding and feedback inhibition to different extents. Mutagenesis further showed that C374 was essential for feedback inhibition, but not for Phe binding, while W338 was involved in Phe binding, but not in the Phe-induced conformational change required for feedback inhibition.

Bacterial Proteins↗
PubMed2005

Asp578 in LEU4p is one of the key residues for leucine feedback inhibition release in sake yeast.

We identified a new mutation, Asp578Tyr, in alpha-isopropylmalate synthase (a LEU4 gene product) that releases leucine feedback inhibition and causes hyperproduction of isoamyl alcohol (i-AmOH) in sake yeast. Spontaneous sake yeast mutants that express resistance to 5,5,5-trifluoro-DL-leucine (TFL) were isolated, and a mutant strain, TFL20, was characterized at the genetic and biochemical levels. An enzyme assay for alpha-isopropylmalate synthase showed that strain TFL20 was released from feedback inhibition by L-leucine. Furthermore, DNA sequencing of the LEU4 gene for a haploid of the mutant TFL20 revealed that aspartic acid in position 578 changes to tyrosine. A comparison of the three-dimensional structures of wild-type LEU4p and mutant LEU4D578Yp by the homology modeling method showed that Asp578 is important for leucine feedback inhibition. We conclude that the mutation from Asp to Tyr in 578 is a novel change causing release from leucine feedback inhibition.

2-Isopropylmalate Synthase↗
PubMed1999

Feedback inhibition of rat amiloride-sensitive epithelial sodium channels expressed in Xenopus laevis oocytes.

1. Regulation of the amiloride-sensitive epithelial sodium channel (ENaC) is essential for the control of body sodium homeostasis. The downregulation of the activity of this Na+ channel that occurs when the intracellular Na+ concentration ([Na+]i) is increased is known as feedback inhibition. Although intracellular Na+ is the trigger for this phenomenon, its cellular and molecular mediators are unknown. 2. We used the 'cut-open oocyte' technique to control the composition of the intracellular milieu of Xenopus oocytes expressing rat ENaCs to enable us to test several factors potentially involved in feedback inhibition. 3. The effects of perfusion of the intracellular space were demonstrated by an electromicrographic study and the time course of the intracellular solution exchange was established by observing the effect of intracellular pH: a decrease from pH 7.4 to 6.5 reduced the amiloride-sensitive current by about 40 % within 2 min. 4. Feedback inhibition was observed in non-perfused oocytes when Na+ entry induced a large increase in [Na+]i. Intracellular perfusion prevented feedback regulation even though the [Na+]i was allowed to increase to values above 50 mM. 5. No effects on the amiloride-sensitive current were observed after changes in the concentration of Na+ (from 1 to 50 mM), Ca2+ (from 10 to 1000 nM) or ATP (from nominally free to 1 or 5 mM) in the intracellular perfusate. 6. We conclude that feedback inhibition requires intracellular factors that can be removed by intracellular perfusion. Although a rise in [Na+]i may be the trigger for the feedback inhibition of the ENaC, this effect is not mediated by a direct effect of Na+, Ca2+ or ATP on the ENaC protein.

Adenosine Triphosphate↗
PubMed2001

Feedback inhibition of amidophosphoribosyltransferase regulates the rate of cell growth via purine nucleotide, DNA, and protein syntheses.

To clarify the contributions of amidophosphoribosyltransferase (ATase) and its feedback regulation to the rates of purine de novo synthesis, DNA synthesis, protein synthesis, and cell growth, mutated human ATase (mhATase) resistant to feedback inhibition by purine ribonucleotides was engineered by site-directed mutagenesis and expressed in CHO ade (-)A cells (an ATase-deficient cell line of Chinese hamster ovary fibroblasts) and in transgenic mice (mhATase-Tg mice). In Chinese hamster ovary transfectants with mhATase, the following parameters were examined: ATase activity and its subunit structure, the metabolic rates of de novo and salvage pathways, DNA and protein synthesis rates, and the rate of cell growth. In mhATase-Tg mice, ATase activity in the liver and spleen, the metabolic rate of the de novo pathway in the liver, serum uric acid concentration, urinary excretion of purine derivatives, and T lymphocyte proliferation by phytohemagglutinin were examined. We concluded the following. 1) ATase and its feedback inhibition regulate not only the rate of purine de novo synthesis but also DNA and protein synthesis rates and the rate of cell growth in cultured fibroblasts. 2) Suppression of the de novo pathway by the salvage pathway is mainly due to the feedback inhibition of ATase by purine ribonucleotides produced via the salvage pathway, whereas the suppression of the salvage pathway by the de novo pathway is due to consumption of 5-phosphoribosyl 1-pyrophosphate by the de novo pathway. 3) The feedback inhibition of ATase is more important for the regulation of the de novo pathway than that of 5-phosphoribosyl 1-pyrophosphate synthetase. 4) ATase superactivity leads to hyperuricemia and an increased bromodeoxyuridine incorporation in T lymphocytes stimulated by phytohemagglutinin.

Adenosine Monophosphate↗
PubMed2003

Mutation analysis of the feedback inhibition site of phenylalanine-sensitive 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase of Escherichia coli.

In Escherichia coli, the phenylalanine-sensitive 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase (DAHPS) AroG catalyzes the first committed step in the biosynthesis of aromatic compounds. To investigate the feedback inhibition site of AroG, mutated enzymes prepared with sequence-overlap extension PCR were expressed and purified. The enzymatic activity assay showed that the amino acid replacements at Phe144, Leu175, Leu179, Phe209, Trp215Ala and Val221 completely or partially relieved feedback inhibition of AroG addressed by the phenylalanine. Ile10Ala and Delta(1-15) desensitized feedback inhibition and caused a 70 approximately 90% loss of the specific catalytic activities. These results strongly suggest an involvement of the interior region and the N-terminus of the polypeptide chain of AroG in the formation of the feedback inhibition site of DAHPS.

3-Deoxy-7-Phosphoheptulonate Synthase↗
PubMed1994

Small intestinal capsaicin-sensitive afferents mediate feedback inhibition of gastric emptying in rats.

Functional studies have implied the existence of small intestinal receptive mechanisms for components of chyme to mediate feedback inhibition of gastric function. However, it is not known if the sensors are in the wall of the small intestine or located at another site. The present studies evaluated the localization of receptive mechanisms mediating intestinal feedback inhibition of gastric emptying by functional ablation of intestinal capsaicin-sensitive afferents. Perfusion of the small intestine of conscious rats with hydrochloric acid (0.1 N; total amount 50 meq), glucose (1 M; total amount 90 mg), or a lipid emulsion (Intralipid 10%; total amount 50 mg) inhibited gastric emptying. One to 7 days after perfusion of the intestine with capsaicin (3.6 mumol), feedback inhibition of gastric emptying produced by acid, glucose, or lipid was inhibited 100, 59, and 42%, respectively. We conclude that acid-induced inhibition of gastric emptying is mediated entirely by small intestinal capsaicin-sensitive afferent neurons and that a major portion of the glucose-induced inhibition of gastric emptying is mediated by small intestinal afferents. However, only a minor part of the response to lipid is mediated by this pathway.

Animals↗