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Results for “Enhancer mapping”

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PubMed1995

[Diagnosis of recurrence of cervix carcinoma using dynamic MRI: correlation of pharmacokinetic analysis and histopathology].

PURPOSE: The aim of the study was to evaluate the value of dynamic magnetic resonance imaging (MRI) to classify suspect lesions into benign and malignant in patients previously treated for cancer of the cervix. MATERIALS AND METHODS: Eleven patients with 14 suspect lesions after treatment of cervical carcinoma were examined by dynamic contrast-enhanced MRI. The imaging findings were compared to the giant cross-section specimen as the reference standard. Computed tissue-specific enhancement parameters were obtained (pharmacokinetic mapping) and displayed as color-coded images. The regions of interest were retrospectively defined according to the pharmacokinetic images over the most suspect areas. Therein, the threshold values were determined that achieved the greatest overall accuracy and a low rate of false-positive results. RESULTS: Analysis of the lesions on T2-weighted images revealed sensitivity of 88%, specificity of 40%, and accuracy of 71%. Analysis of the dynamic MR data showed significantly shorter (p < 0.01) and stronger (p < 0.001) contrast media enhancement of malignant (n = 9) than benign lesions (n = 5). CONCLUSION: Pharmacokinetic mapping appears to yield important information for dividing suspect lesions into malignant and benign following treatment of cervical cancer.

Adult↗

PubMed1995

Tumor angiography using high-resolution, three-dimensional magnetic resonance imaging: comparison of gadopentetate dimeglumine and a macromolecular blood-pool contrast agent.

RATIONALE AND OBJECTIVES: We compared the peritumoral vascular definition in rats using either a paramagnetic extracellular or a macromolecular contrast medium in combination with high-resolution magnetic resonance (MR) imaging. METHODS: High-resolution, three-dimensional spoiled gradient-refocused acquisition in a steady state (SPGR) images were acquired from tumor-bearing Fischer-344 rats before, immediately after, and again 40 min after administration of gadopentetate dimeglumine (0.1 mmol Gd/kg; n = 10) and albumin-(Gd-DTPA)30 (0.05 mmol Gd/kg; n = 5). Small peritumoral vessels were analyzed semiquantitatively on maximum intensity projection angiograms using a 4-point scoring system; quantitative analyses included signal-to-background ratios (SBRs) and signal-to-noise ratios. RESULTS: Gadopentetate dimeglumine caused a transient and low-scoring (0.2 +/- 0.1, SBR = 1.9 +/- 0.2) vessel definition but strong rim enhancement (score = 1.4 +/- 0.2). Albumin-(Gd-DTPA)30 produced persistent, high-quality angiograms (score = 2.6 +/- 0.2, SBR = 7.4 +/- 0.2) but minimal rim enhancement (score = 0.3 +/- 0.2). CONCLUSION: Albumin-(Gd-DTPA)30 combined with high-resolution MR imaging produces time-persistent, detailed angiographic definition of peritumoral vessels. Vascular maps obtained with gadopentetate dimeglumine enhancement are not time persistent or of equal quality.

Adenocarcinoma↗

PubMed1995

Glucose, other secretagogues, and nerve growth factor stimulate mitogen-activated protein kinase in the insulin-secreting beta-cell line, INS-1.

The signaling pathways whereby glucose and hormonal secretagogues regulate insulin-secretory function, gene transcription, and proliferation of pancreatic beta-cells are not well defined. We show that in the glucose-responsive beta-cell line INS-1, major secretagogue-stimulated signaling pathways converge to activate 44-kDa mitogen-activated protein (MAP) kinase. Thus, glucose-induced insulin secretion was found to be associated with a small stimulatory effect on 44-kDa MAP kinase, which was synergistically enhanced by increased levels of intracellular cAMP and by the hormonal secretagogues glucagon-like peptide-1 and pituitary adenylate cyclase-activating polypeptide. Activation of 44-kDa MAP kinase by glucose was dependent on Ca2+ influx and may in part be mediated by MEK-1, a MAP kinase kinase. Stimulation of Ca2+ influx by KCl was in itself sufficient to activate 44-kDa MAP kinase and MEK-1. Phorbol ester, an activator of protein kinase C, stimulated 44-kDa MAP kinase by both Ca(2+)-dependent and -independent pathways. Nerve growth factor, independently of changes in cytosolic Ca2+, efficiently stimulated 44-kDa MAP kinase without causing insulin release, indicating that activation of this kinase is not sufficient for secretion. In the presence of glucose, however, nerve growth factor potentiated insulin secretion. In INS-1 cells, activation of 44-kDa MAP kinase was partially correlated with the induction of early response genes junB, nur77, and zif268 but not with stimulation of DNA synthesis. Our findings suggest a role of 44-kDa MAP kinase in mediating some of the pleiotropic actions of secretagogues on the pancreatic beta-cell.

Calcium↗

PubMed2001

Platelet adhesion enhances the glycoprotein VI-dependent procoagulant response: Involvement of p38 MAP kinase and calpain.

In the final stages of activation, platelets express coagulation-promoting activity by 2 simultaneous processes: exposure of aminophospholipids, eg, phosphatidylserine (PS), at the platelet surface, and formation of membrane blebs, which may be shed as microvesicles. Contact with collagen triggers both processes via platelet glycoprotein VI (GPVI). Here, we studied the capacity of 2 GPVI ligands, collagen-related peptide (CRP) and the snake venom protein convulxin (CVX), to elicit the procoagulant platelet response. In platelets in suspension, either ligand induced full aggregation and high Ca(2+) signals but little microvesiculation or PS exposure. However, most of the platelets adhering to immobilized CRP or CVX had exposed PS and formed membrane blebs after a prolonged increase in cytosolic [Ca(2+)](i). Platelets adhering to fibrinogen responded similarly but only when exposed to soluble CRP or CVX. By scanning electron microscopic analysis, the bleb-forming platelets were detected as either round, spongelike structures with associated microparticles or as arrays of vesicular cell fragments. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) elicited by CRP and CVX was enhanced in fibrinogen-adherent platelets compared with that in platelets in suspension. The p38 inhibitor SB203580 and the calpain protease inhibitor calpeptin reduced only the procoagulant bleb formation, having no effect on PS exposure. Inhibition of p38 also downregulated calpain activity. We conclude that the procoagulant response evoked by GPVI stimulation is potentiated by platelet adhesion. The sequential activation of p38 MAPK and calpain appears to regulate procoagulant membrane blebbing but not PS exposure.

Blood Platelets↗

PubMed1996

A 38-kDa host factor interacts with functionally important motifs within the Autographa californica multinucleocapsid nuclear polyhedrosis virus homologous region (hr1) DNA sequence.

We recently demonstrated that the Autographa californica multinucleocapsid nuclear polyhedrosis virus homologous region (hr1) enhances transcription from the viral polyhedrin promoter and also functions as a putative origin of replication (ori). Hr1, carrying five 28-base pair core palindrome units, has also been mapped with respect to its enhancer and ori functions (Habib, S., Pandey, S., Chatterji, U., Burma, S., Ahmad, R., Jain, A., and Hasnain, S. E. (1996) DNA Cell Biol. 15, 737-747). A 38-kDa host factor termed hr1-binding protein (hr1-BP) binds with high specificity and affinity (Kd approximately 6.5 x 10(-11) M) to functionally important motifs within hr1. The core palindrome as well as sequences immediately flanking it are required for this interaction. Divalent cations are not essential, and ionic interactions play only a minor role in complex formation. hr1-BP binds through the minor groove of the double helix to multiple sites within hr1, and binding occurs as a function of the number of modules within hr1. Phosphorylation of hr1-BP is important for host factor-hr1 interaction. Hr1-BP differs in several respects from the other host factor, polyhedrin promoter-binding protein, described previously (Burma, S., Mukherjee, B., Jain, A., Habib, S., and Hasnain, S. E. (1994) J. Biol. Chem. 269, 2750-2757). When hr1-BP was sequestered out, in vivo, by a plasmid carrying hr1 alone, the hr1-mediated enhancement of reporter expression was abolished, demonstrating that the binding of hr1-BP may be crucial for the enhancer activity of the dual function hr1 element.

Base Sequence↗

PubMed2000

Conservation of sigma-core RNA polymerase proximity relationships between the enhancer-independent and enhancer-dependent sigma classes.

Two distinct classes of RNA polymerase sigma factors (sigma) exist in bacteria and are largely unrelated in primary amino acid sequence and their modes of transcription activation. Using tethered iron chelate (Fe-BABE) derivatives of the enhancer-dependent sigma(54), we mapped several sites of proximity to the beta and beta' subunits of the core RNA polymerase. Remarkably, most sites localized to those previously identified as close to the enhancer-independent sigma(70) and sigma(38). This indicates a common use of sets of sequences in core for interacting with the two sigma classes. Some sites chosen in sigma(54) for modification with Fe-BABE were positions, which when mutated, deregulate the sigma(54)-holoenzyme and allow activator-independent initiation and holoenzyme isomerization. We infer that these sites in sigma(54) may be involved in interactions with the core that contribute to maintenance of alternative states of the holoenzyme needed for either the stable closed promoter complex conformation or the isomerized holoenzyme conformation associated with the open promoter complex. One site of sigma(54) proximity to the core is apparently not evident with sigma(70), and may represent a specialized interaction.

Amino Acid Sequence↗

PubMed2003

Enhancement of alpha2-adrenoceptor-mediated vasoconstriction by the thromboxane-mimetic U46619 in the porcine isolated ear artery: role of the ERK-MAP kinase signal transduction cascade.

1. Alpha(2)-adrenoceptor-mediated contractions in porcine blood vessels can be enhanced in the presence of the thromboxane-mimetic U46619, and forskolin. The aim of this study was to determine the role of U46619 in the enhanced contractions, and to determine whether signalling through the ERK-MAP kinase pathway is involved. 2. Responses to the alpha(2)-adrenoceptor agonist UK14304 (1 micro M) were increased from 22+/-3% of the response to 60 mM KCl to 68+/-12% (n=8, mean+/-s.e.m.) in the presence of a low concentration of U46619 (< 20% of the 60 mM KCl response). 3. Both the direct and the U46619-enhanced UK14304 responses were inhibited by 50 microM PD98059, an inhibitor of the ERK-MAP kinase pathway. UK14304-induced contractions were associated with an increase in ERK2 phosphorylation, indicating an increased activity. In the presence of U46619, there was an enhanced phosphorylation of ERK2. U46619 on its own had no effect on ERK phosphorylation. 4. Both the direct and enhanced UK14304 contractions were inhibited in the absence of extracellular calcium. These conditions also prevented the increase in ERK2 phosphorylation. This indicates a role for calcium influx in the enhanced contractions. 5. In conclusion, this study demonstrates that precontraction with the thromboxane-mimetic U46619 enhances alpha(2)-adrenoceptor-mediated vasoconstriction through the enhancement of the ERK-MAP kinase pathway, and influx of extracellular calcium.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2000

Mixing location-relevant and location-irrelevant choice-reaction tasks: influences of location mapping on the Simon effect.

The Simon effect refers to the finding that reaction times are faster when stimulus and response locations correspond than when they do not in tasks where stimulus location is defined as irrelevant. The authors examined the Simon effect for situations in which location-irrelevant trials were intermixed with trials for which stimulus location was relevant. Compatible mapping of the location-relevant trials enhanced the Simon effect relative to an unmixed condition, whereas incompatible mapping reversed the Simon effect. The reversal with incompatible mapping remained evident when task uncertainty was removed by use of a precue and was larger than the reversed effect produced by making incongruent trials more frequent than congruent trials. This result suggests that both attentional biases and task-defined associations contribute to the reversal of the Simon effect.

Choice Behavior↗

PubMed1985

Analysis of the microtubule-binding domain of MAP-2.

We examined the microtubule-binding domain of the microtubule-associated protein (MAP), MAP-2, using rabbit antibodies that specifically bind to the microtubule-binding region ("stub") and the projection portion ("arm") of MAP-2. We found that (a) microtubules decorated with arm antibody look similar to those labeled with whole unfractionated MAP antibody, though microtubules are not labeled with stub antibody; (b) incubation of depolymerized microtubule protein with stub antibody prior to assembly partially inhibits the rate of microtubule elongation, presumably because MAPs that are complexed with antibody cannot bind to microtubules and stabilize elongating polymers; (c) the rate of appearance and amounts of 36- and 40-kD microtubule-binding peptides produced by digestion with chymotrypsin are distinct for MAPs associated with microtubules vs. MAPs free in solution. The enhanced stability of the 40-kD peptide when associated with microtubules suggests that this domain of the protein is closely associated with, or partially buried in, the microtubule surface; (d) MAP-2 is a slender, elongate molecule as determined by unidirectional platinum shadowing (90 +/- 30 nm), which is in approximate agreement with previous observations. Stub antibody labels MAP-2 in the terminal one-quarter of the extended protein, indicating an intrinsic asymmetry in the molecule.

Animals↗

PubMed1997

Differential regulation of FUS3 MAP kinase by tyrosine-specific phosphatases PTP2/PTP3 and dual-specificity phosphatase MSG5 in Saccharomyces cerevisiae.

The Saccharomyces cerevisiae mating pheromone response is mediated by activation of a MAP kinase (Fus3p and Kss1p) signaling pathway. Pheromone stimulation causes cell cycle arrest. Therefore, inactivation of the Fus3p and Kss1p MAP kinases is required during recovery phase for the resumption of cell growth. We have isolated a novel protein tyrosine phosphatase gene, PTP3, as a negative regulator of this pathway. Ptp3p directly dephosphorylates and inactivates Fus3p MAP kinase in vitro. Multicopy PTP3 represses pheromone-induced transcription and promotes recovery. In contrast, disruption of PTP3 in combination with its homolog PTP2 results in constitutive tyrosine phosphorylation, enhanced kinase activity of Fus3p MAP kinase on stimulation, and delayed recovery from the cell cycle arrest. Both tyrosine phosphorylation and kinase activity of Fus3p are further increased by disruption of PTP3 and PTP2 in combination with MSG5, which encodes a dual-specificity phosphatase. Cells deleted for all three of the phosphatases (ptp2delta ptp3delta msg5delta) are hypersensitive to pheromone and exhibit a severe defect in recovery from pheromone-induced growth arrest. Our data indicate that Ptp3p is the major phosphatase responsible for tyrosine dephosphorylation of Fus3p to maintain a low basal activity; it also has important roles, along with Msg5p, in inactivation of Fus3p following pheromone stimulation. These data present the first evidence for a coordinated regulation of MAP kinase function through differential actions of protein tyrosine phosphatases and a dual-specificity phosphatase.

Amino Acid Sequence↗

PubMed2003

Stimulation of the calcitonin gene-related peptide enhancer by mitogen-activated protein kinases and repression by an antimigraine drug in trigeminal ganglia neurons.

Calcitonin gene-related peptide (CGRP) is involved in the underlying pathophysiology of all vascular headaches, including migraines. Elevated levels of CGRP during migraine are restored to normal coincident with headache relief after treatment with the antimigraine drug sumatriptan. We have used primary cultures of trigeminal neurons under conditions simulating migraine pathology and therapy to study the mechanisms controlling the CGRP promoter. Using reporter genes in transient transfection assays, we demonstrate that an 18 bp enhancer containing a helix-loop-helix element is both necessary and sufficient for full promoter activity. NGF treatment and cotransfection with an upstream activator of the extracellular signal-regulated MAP kinases (MAPKs) activated the enhancer. Treatment with sumatriptan repressed NGF- and MAPK-stimulated CGRP promoter activity. Repression was also observed using a synthetic MAPK-responsive reporter gene. Sumatriptan regulation of CGRP gene expression did not couple to a G(i)/G(o) pathway, but rather caused a prolonged increase in intracellular calcium. The importance of the prolonged calcium signal in repression of MAPK activity was demonstrated by using the ionophore ionomycin to mimic sumatriptan action. We propose that activation of MAPK pathways may increase CGRP gene expression during migraine, and that sumatriptan can diametrically oppose that activation via a prolonged elevation of intracellular calcium.

Animals↗

PubMed1998

Signal transduction in human macrophages by gp83 ligand of Trypanosoma cruzi: trypomastigote gp83 ligand up-regulates trypanosome entry through the MAP kinase pathway.

We found that Trypanosoma cruzi trypomastigote cloned surface ligand (gp83 trans-sialidase) signals human macrophages to up-regulate parasite entry by inducing tyrosine phosphorylation of MAP kinase. Preincubation of human macrophages with r-gp83 transsialidase significantly enhanced both the percentage of phagocytosed trypanosomes and the number of trypanosomes per cell in a concentration dependent fashion. Incubation of r.gp83 with macrophages induced tyrosine phosphorylation of several macrophage proteins. This enhancement was inhibited by genistein, a tyrosine kinase inhibitor. The r-trypanosome ligand enhanced tyrosine phosphorylation of ERK1 and this enhancement was specifically inhibited by the inhibitor of MAP kinase phosphorylation, PD 98059, or by genistein. PD 98050 or genistein also inhibited the enhancement of trypomastigote uptake by macrophages induced by the r-ligand. These results indicate that T. cruzi uses a novel mechanism to signal cells in the process of trypanosome entry, via a secreted trypanosome ligand which signals macrophages through the MAP kinase pathway.

Animals↗

PubMed2000

Essential oil of Croton nepetaefolius decreases blood pressure through an action upon vascular smooth muscle: studies in DOCA-salt hypertensive rats.

Experiments tested the hypothesis that hypotensive effects of intravenous (i.v.) treatment with the essential oil of Croton nepetaefolius (EOCN) result from its vasodilatory effects directly upon vascular smooth muscle. In both deoxycorticosterone-acetate (DOCA)-salt hypertensive and uninephrectomised control, conscious rats, i.v. bolus injections of EOCN (1 to 50 mg/kg) decreased mean aortic pressure (MAP) and heart rate (HR) in a dose-related manner. Treatment with DOCA-salt significantly enhanced EOCN-induced decreases in MAP without affecting bradycardia. Likewise, both maximal percent and absolute decreases in MAP elicited by i.v. hexamethonium (30 mg/kg), a ganglion blocker, were significantly greater in DOCA-salt hypertensive than in control rats. In DOCA-salt hypertensive rats, i.v. pretreatment with hexamethonium (30 mg/kg) reduced the bradycardia elicited by EOCN (50 mg/kg) without affecting the enhancement of EOCN-induced hypotension. In isolated thoracic aorta preparations from DOCA-salt hypertensive rats, EOCN (1-300 micrograms/ml) induced a concentration-dependent reduction of phenylephrine-induced contraction. Arteries from DOCA rats showed increased sensitivity to EOCN, as evidenced by the significant decrease in the IC50 for EOCN-induced reduction of phenylephrine-induced contraction (16.4 +/- 3.6 vs. 112.9 +/- 23.4 micrograms/ml in uninephrectomized controls). These results show that i.v. treatment with EOCN dose-dependently decreases blood pressure in conscious DOCA-salt hypertensive rats, and this action is enhanced when compared with uninephrectomized controls. This enhancement appears to be related mainly to an increase in EOCN-induced vascular smooth muscle relaxation rather than to enhanced sympathetic nervous system activity in this hypertensive model. Thus, the hypothesis that EOCN may be a direct vasorelaxant agent is supported by the results of the present study.

Animals↗

PubMed1995

Fibroblast growth factors stimulate protein tyrosine phosphorylation and mitogen-activated protein kinase activity in primary cultures of hippocampal neurons.

Fibroblast growth factors (FGFs) are not only mitogens, but they also promote the differentiation of various cell types. For instance, basic FGF (bFGF) provides a critical trophic support for hippocampal neurons in culture. To elicit their biological effects, FGFs interact with high-affinity receptors that are transmembrane proteins with a cytoplasmic portion containing a tyrosine kinase activity. The tyrosine phosphorylation pattern was examined in primary cultures of hippocampal neurons derived from rat embryos. In these cultures grown for 3 days in the absence of serum, the addition of bFGF causes a rapid increase of tyrosine phosphorylation for various proteins with an optimal level after 5 min of bFGF exposure. Concomitantly, bFGF activates mitogen-activated protein kinase (MAP kinase) activity measured with a selective MAP kinase peptide. The activity increased rapidly after the addition of bFGF and remained elevated even when cultures were treated for 1 h with bFGF. Both acidic and basic FGF were able to enhance protein tyrosine phosphorylation and MAP kinase activity, whereas nerve growth factor and epidermal growth factor did not elicit any of these responses. These data indicate that some of the transduction signals (i.e., tyrosine phosphorylation and activation of MAP kinase) that have been described for the proliferative effect of FGFs are also involved when FGFs act as trophic factors for postmitotic neurons in culture.

Animals↗

PubMed2002

Cardiovascular effects of the essential oil of Mentha x villosa in DOCA-salt-hypertensive rats.

The present study investigated the effects of chronic treatment with deoxycorticosterone-acetate (DOCA)-salt on cardiovascular responses to intravenous (i.v.) injection of the essential oil of Mentha x villosa (EOMV) in conscious rats. In both DOCA-salt-hypertensive and uninephrectomized control, conscious rats, i.v. bolus injections of EOMV (1 to 20 mg/kg body wt.) decreased mean aortic pressure (MAP) and heart rate (HR) in a dose-dependent manner. Treatment with DOCA-salt significantly enhanced EOMV-induced decreases in MAP, without affecting bradycardia. Likewise, both maximal percent and absolute decreases in MAP elicited by i.v. injection of the ganglion blocker, hexamethonium (30 mg/kg body wt.), were significantly greater in DOCA-salt-hypertensive than in control rats. In DOCA-salt-hypertensive rats, i.v. pretreatment with hexamethonium (30 mg/kg body wt.) reduced the bradycardia elicited by EOMV (1 to 20 mg/kg body wt.) without affecting the enhancement of EOMV-induced hypotension. These results show that i.v. treatment with EOMV decreases blood pressure in conscious DOCA-salt-hypertensive rats dose-dependently, and that this action is enhanced when compared with uninephrectomized controls. This enhancement could be related mainly to an increase in EOMV-induced vascular smooth muscle relaxation, rather than to enhanced sympathetic nervous system activity in this hypertensive model.

Animals↗

PubMed2004

Augmentation of serotonin-induced inhibition of neuronal activity in the hippocampus following repeated treatment with methamphetamine.

Electrophysiological studies were performed to determine whether or not hippocampal serotonergic modulation was affected following repeated administration of methamphetamine (MAP). Rats were i.p. administered with MAP (5 mg/kg) or saline once a day for 5 days. Hippocampal slices were prepared at 24 h, 5 and 10 days after the final MAP or saline injection. The population spikes (PS) induced by stimulation of Schaffer collateral/commissural fibers were recorded in the hippocampal CA1 region. Application of serotonin (5-HT) via a bath perfusion system inhibited the PS in a concentration-dependent manner. At 24 h after the final injection, 10-microM 5-HT-induced inhibition of PS was not affected by MAP treatment. However, 5 days after the final injection, the inhibition by 5-HT (10 microM) of PS was significantly augmented in the MAP-treated group. Ten days after the final injection, this augmentation was not statistically significant compared with that of control group. 8-OH-DPAT, a 5-HT1A receptor agonist, inhibited PS, but the inhibition was not enhanced or reduced 5 days after the final MAP treatment. However, the enhancement of PS by RS 67333, a 5-HT4 receptor agonist, was attenuated 5 days after the MAP treatment. It was found that 5-HT-induced inhibition of PS in the hippocampal CA1 region was potentiated 5 days after cessation of MAP, and this effect was suggested to be due to reduction of excitatory 5-HT4 receptor functions.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1988

Dosage-dependent modifiers of polycomb and antennapedia mutations in Drosophila.

Two genes known to control the determination of segmental identity in Drosophila melanogaster are polycomb and antennapedia. To identify additional genes involved in the determination of segmental identity, we have isolated dominant modifers (both suppressors and enhancers) of polycomb and/or antennapedia mutations. Sixty-four such modifier mutations have been recovered and mapped to 18 complementation groups. All of the mutations identify genes necessary for viability of the zygote. Six of the 18 genes that were identified by mutations that interact with polycomb and/or antennapedia have been previously characterized as homoeotic genes [i.e., Sex combs reduced (Scr), Brista (Ba), trithorax (trx), Polycomb (Pc), Polycomblike (Pcl), and Sex comb on midleg (Scm)]. Mutations in several of the additional loci identified here have also been shown to have homoeotic phenotypes.

Animals↗

PubMed2003

High-salt-induced increase in blood pressure: role of capsaicin-sensitive sensory nerves.

OBJECTIVE: To test the hypothesis that sensory afferents are significant functional components in preventing salt-induced increases in blood pressure. DESIGN AND METHODS: Neonatal Wistar rats were subcutaneously injected with 50 mg/kg capsaicin or vehicle on the first and second days of life. After weaning, male rats were divided into three groups and treated for 4 weeks with: control plus normal (0.5%, CON-NS) or high (4%, CON-HS) sodium diet, and capsaicin pretreatment plus HS diet (CAP-HS). Mean arterial pressure (MAP) and its response to bolus injection of calcitonin gene-related peptide (CGRP) and its antagonist, CGRP(8-37), were measured by carotid arterial catheterization. Radioimmunoassay was used to measure CGRP levels in plasma and dorsal root ganglia (DRG). Expression of components of the CGRP receptor, calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 1 (RAMP1), was determined by the use of Western blot analysis. RESULTS: Baseline MAP was increased in CAP-HS compared with CON-HS and CON-NS rats, and it was higher in CON-HS than in CON-NS rats. MAP response to exogenous CGRP was enhanced in CAP-HS and CON-HS than in CON-NS rats, but MAP response to CGRP(8-37) was increased only in CON-HS rats. Plasma CGRP levels were not different among three groups, but CGRP content in DRG was decreased in CAP-HS compared with CON-HS and CON-NS rats. CRLR expression in mesenteric resistance arteries was upregulated in CAP-HS and CON-HS compared with CON-NS rats, but RAMP1 content was not different among these groups. CONCLUSION: Chronic high-salt intake upregulates expression of mesenteric CGRP receptors without altering CGRP levels in plasma and DRG. Increased expression of mesenteric CGRP receptors may play a counter regulatory role in attenuating salt-induced increases in blood pressure.

Animals↗