Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the functions of chromogranin A (CGA), the major soluble component of secretory granules in both adrenal medullary chromaffin cells and many other endocrine cell types appears to be that of a prohormone. CGA is the precursor of several peptides including pancreastatin, a 49-residue peptide, and a 20-residue peptide, chromostatin, which have been identified as biologically active peptides. Chromostatin produces a dose-dependent inhibition (ID50 of 5 nM) of the secretagogue-evoked catecholamine secretion from chromaffin cells. Here we report that chromostatin potently inhibits L-type calcium currents recorded with the nystatin-perforated patch technique in cultured chromaffin cells. This inhibitory effect of chromostatin on calcium currents was not observed in experiments using the classical patch-clamp whole-cell approach which induces the leakage of cytoplasmic components. Using 125I-chromostatin, we show that chromostatin exhibits a fully reversible and saturable binding to the plasma membrane of cultured chromaffin cells. Analysis of binding experiments at equilibrium indicates the existence of one class of binding sites with a Bmax of 2.7 pmol/mg of chromaffin cell proteins and an apparent Kd of 6.5 nM. This high affinity is in good correlation with the half-maximal concentration (ID50 5 nM) of chromostatin inhibiting catecholamine secretion from chromaffin cells. Specificity of the chromostatin binding was further assessed by displacement experiments with unlabeled CGA-related or -unrelated peptides. We found an excellent quantitative correlation between the affinities of the various peptides determined by binding assays and their functional potency tested on catecholamine secretion: bovine chromostatin greater than human chromostatin greater than CGA much greater than rat chromostatin, pancreastatin, CAP-14, substance P, and Leu-enkephalin. Cross-linking experiments reveal that chromostatin associates specifically with an 80-kDa plasma membrane protein. These results together with the patch-clamp experiments support the idea that chromaffin cells possess specific chromostatin receptors and that activation of such receptors leads to the inhibition of L-type voltage-sensitive calcium channels through an intracellular second messenger pathway.
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PMID:Chromostatin receptors control calcium channel activity in adrenal chromaffin cells. 130 44

To test whether endogenous sensory neuropeptide release results in airway hyperresponsiveness to exogenous bronchoconstrictor stimuli, male Camm-Hartley guinea pigs were exposed either to capsaicin aerosol for 10 min (CAP-AER) or to saline aerosol (SAL-AER) as a control condition. The following day, animals were anesthetized, tracheostomized, and beta-adrenergically blocked with propranolol, and their bronchoconstrictor responses to intravenously administered acetylcholine (ACh), neurokinin A (NKA), or capsaicin were measured. The bronchoconstriction induced by isocapnic dry gas hyperpnea also was assessed. Compared with the SAL-AER control group, the CAP-AER-treated animals exhibited augmented bronchoconstrictor responses to ACh and NKA. In contrast, the SAL-AER and CAP-AER groups had equivalent bronchoconstrictor responses to dry gas hyperpnea and to intravenously administered capsaicin. CAP-AER treatment caused neutrophilic airway inflammation, as reflected in increased numbers of neutrophils in bronchoalveolar lavage fluid obtained from CAP-AER-treated animals. Ablation of airway c-fiber neuron function (by chronic pretreatment with capsaicin prior to capsaicin aerosol inhalation) eliminated the ACh hyperresponsiveness observed in the CAP-AER-treated animals, demonstrating that sensory nerve products play a key role in the development of this nonspecific hyperresponsiveness. Our results demonstrate that sensory nerve stimulation with capsaicin aerosol leads to nonspecific bronchoconstrictor hyperresponsiveness and cellular airway inflammation, and thus disclose another potentially important role of sensory nerves in regulating airway function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endogenous sensory neuropeptide release enhances nonspecific airway responsiveness in guinea pigs. 844 18

A transurethral prostatic resection for prostatism in a 73 year old man showed a cluster of richly capillarised clear cells originally thought to be indicative of invasive carcinoma. Immunohistochemical studies were carried out on this tissue specimen and three similar cases using a variety of antibodies--Neuron specific enolase, PGP 9.5, chromogranin, synaptophysin, serotonin, somatostatin, substance P, calcitonin, calcitonin gene related peptide, met-enkephalin, VIP, neurofilament, CAM 5.2, S100 protein, prostatic specific antigen and prostatic acid phosphatase. The cellular foci were shown to be composed of paraganglionic cells. The cell clusters were well defined and predominantly comprised clear cells with scanty, fine eosinophilic cytoplasmic granules in three cases. The cell nuclei were round to oval, moderately pleomorphic, with evenly dispersed dense chromatin. It is concluded that the presence of minute foci of paraganglial cells in the bladder wall and prostate gland may be misinterpreted as malignant because of their close association with nerves and their relative rarity. Immunohistochemical staining with neuroendocrine markers should dispel any doubt about their identity.
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PMID:Paraganglial cells of urinary bladder and prostate: potential diagnostic problem. 169 Feb 21

The major neuronal populations of the primate cerebral cortex can be classified immunocytochemically according to their transmitters and in terms of the differential expression of certain other molecules such as neuropeptides, calcium-binding proteins and protein kinases. We have been able to chart the time course of developmental expression of these molecules and to show that gene expression for many of them is regulated in adult and infant animals by afferent activity entering the cortex. In the visual cortex of adult monkeys, levels of immunocytochemically detectable gamma aminobutyric acid (GABA), of its synthesizing enzyme glutamic acid decarboxylase (GAD) and of the tachykinins are greatly reduced in deprived ocular dominance columns within 24 h of blocking impulse activity in the optic nerve by intraocular injection of tetrodotoxin (TTX). Conversely, levels of immunocytochemically detectable calcium-calmodulin-dependent protein kinase (CAMII kinase) are increased in deprived eye dominance columns. These effects are quickly reversible on restoration of binocular vision, and experiments involving in situ hybridization and S1 nuclease protection assays show that the changes are associated with parallel changes in mRNA levels for preprotachykinin and CAM II kinase, but not for GAD, which appears to be regulated by post-transcriptional mechanisms. Experiments in the primate somatic sensory cortex suggest comparable activity-dependent effects on gene expression there also. It is proposed that effects of this type underlie the establishment of cortical maps during development and their activity-dependent mutability in adulthood.
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PMID:The role of afferent activity in the maintenance of primate neocorticalfunction. 217 67

Nonanoyl vanillylamide (nonivamide NVA) was compared with trans-8-methyl-N-vanillyl-nonenamide (capsaicin, CAP) with regard to their pharmacokinetic properties, their potency in stimulating primary afferent neurons and depleting them of substance P and somatostatin in rats. Following the injection of 50 mg kg-1 the time course of the presence of NVA in brain and blood was similar to that of CAP. The concentration of NVA in brain was higher than in blood; the reverse was true for CAP. The ability of NVA and CAP to stimulate afferent neurons was measured by the reflex depressor response following i.v. injection and by the number of wiping movements following instillation of the substances into the eye. In both tests, the potency of NVA was about half of that of CAP. Treatment of newborn rats by s.c. injections of 50 mg kg-1 NVA or CAP seemed to cause a larger depletion of substance P and somatostatin in the sciatic nerve and the spinal cord than treatment of adult rats. Depletion by CAP was generally larger than that by NVA although depletion experiments are hardly suitable for quantification. The depletion of substance P by CAP and NVA could be correlated with the extent to which ocular chemosensitivity and neurogenic plasma extravasations were attenuated. The methods used are discussed in view of their possible use in screening further capsaicin analogues.
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PMID:Comparison of nonivamide and capsaicin with regard to their pharmacokinetics and effects on sensory neurons. 620 5

CAM 4515 and CAM 4750 are new nonpeptide tachykinin NK1 receptor antagonists with different lipophilicities. Two separate, simple, and sensitive HPLC methods for the quantitation of these two compounds in plasma and the evaluation of their oral bioavailability in rats were developed and validated. Extraction of CAM 4515 from plasma involved protein precipitation with acetonitrile, while that for CAM 4750 involved a one-step liquid-liquid extraction with methylene chloride. The analytes in extracts were chromatographed on a C18 column using two different separation buffers, 47% 0.02 M sodium citrate (pH 3.5)-53% acetonitrile for CAM 4515 and 59% 0.02 M potassium phosphate dibasic (pH 7.0)-41% acetonitrile for CAM 4750, and both compounds were detected by fluorescence (excitation 278 nm; emission 342 nm). Stability profiles of both drugs at -20 degrees C or room temperature in plasma and in reconstituted buffers were good. The limit of quantitation for both drugs was 5 ng ml-1 with good linearity from 5 to 1000 ng ml-1 using 100-200 microliters of plasma. Excellent precision (relative standard deviation < 8.3%) and accuracy (relative error +/- 9.2%) were observed for both CAM 4515 and CAM 4750. Oral bioavailability studies were conducted for each compound in rats receiving a p.o. dose of 20 mg kg-1 and an i.v. dose of 5 mg kg-1. The absolute oral bioavailability of CAM 4750 (80%) was estimated to be 40-fold greater than that of CAM 4515 (2%). The experimental results suggest that incorporation of a pyridine group into the structural backbone may greatly improve bioavailability.
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PMID:Development of HPLC plasma assays for CAM 4515 and CAM 4750, two new nonpeptide tachykinin antagonists, and application to bioavailability studies. 888 18

CAM 5500 and CAM 5187 are new nonpeptide tachykinin NK3 receptor antagonists with different lipophilicity and solubility. We have developed and validated two separate, simple HPLC methods for quantitation of these two compounds in plasma to support oral pharmacokinetic/bioavailability studies in rats. The two compounds in plasma were extracted on cyano SPE cartridges with different washing schemes to optimize extraction efficiency and chromatographic specificity. The analytes and internal standard in the resulting extracts were chromatographed on a C18 HPLC column, using mobile phases containing different phosphate buffer strengths and acetonitrile concentrations. Both compounds were detected using UV, Peak area ratios were proportional over the concentration range of 50-3000 ng ml-1 for CAM 5500, and 100-1500 ng ml-1 for CAM 5187. Stability profiles of both drugs and internal standard in rat plasma at 37 degrees C and in injection solvent at ambient temperature were good. Assay precision, based on quality controls, was < 5.6% and 13.4% (%RSD) for CAM 5500 and CAM 5187, respectively. Similarly, assay accuracy for both compounds was within +/- 7.1% and +/- 6.0% (%RE), respectively. The HPLC methods were successfully applied to assay samples from two oral bioavailability studies. Oral bioavailability studies were conducted for each compound in rats receiving a PO dose of 20 mg kg-1 or an i.v. dose of 5 mg kg-1. Despite their difference in lipophilicity and solubility, the absolute oral bioavailability of CAM 5500 (5.3 +/- 4.8%) is similar to that of CAM 5187 (8.8% +/-3.2%).
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PMID:Development and application of sensitive HPLC assays for NK3 antagonists in rat plasma. 957 34

The effects of permanent disruption of neuropeptide transmission on the induction (i.e., sensitization) and elicitation (i.e., challenge) phases of contact hypersensitivity (CHS) are described. BALB/c mice were chemically denervated of neuropeptide (i.e., tachykinin) containing sensory C fibers by an acute injection of capsaicin (50 mg/kg) on postnatal day (PND) 2 to 3. As young adults (PND 45-60), these mice and their control littermates were sensitized by topical application of 0.1% 2,4-dinitrofluorobenzene (DNFB) or vehicle. Treatment groups generated from this exposure regimen consisted of untreated, controls (O/O), denervated, controls (CAP/O), untreated, sensitized (O/DNFB), and denervated, sensitized (CAP/DNFB). The elicitation phase of CHS was evaluated in these animals by measuring ear thickness in response to a DNFB challenge. In DNFB-sensitized groups, ear thickness was significantly increased over controls but was additionally increased 2.4-fold in CAP/DNFB compared to O/DNFB mice. The induction phase of CHS was next assessed in young adult mice by measuring lymph node cell (LNC) proliferation. For this, mice were sensitized for 3 consecutive days before their draining, auricular nodes were removed. The LNC were dissociated and cultured for 24 h with tritiated thymidine to assess LNC proliferation. As expected, significantly higher numbers of LNC occurred in both DNFB-sensitized groups (CAP/DNFB, O/DNFB) compared to the unsensitized, controls (CAP/O, O/O). However, LNC proliferation in CAP/DNFB was significantly higher than O/DNFB animals. Flow cytometry on similarly exposed mice failed to demonstrate any significant difference in the population of CD4CD8 or CD3CD45R LNC cells from neuropeptide-denervated (CAP/O, CAP/DNFB) mice or their respective treatment mates (O/O, O/DNFB), suggesting that alterations in T or B cell populations did not underlie these changes. Finally, cytokine release from the LNC from these treatment groups was examined. For this, the auricular lymph nodes were removed from animals, 2 to 4 h after the animals were administered a single application of a sensitizing concentration (0.1%) of DNFB or acetone vehicle. LNC, dissociated from these nodes, were cultured for 24 h. The nutrient media was removed from these cultured cells and examined for the release of proinflammatory cytokines, interleukin (IL)-1beta, IL-2 and tumor necrosis factor (TNF)alpha, by ELISA. There were no significant increases in IL-2. However, IL-1beta release was significantly increased in CAP/DNFB mice over O/DNFB by 18-fold and by over 30-fold compare to O/O controls. Levels of TNFalpha were significantly increased in both O/DNFB and CAP/DNFB mice over the nonsensitized controls (O/O, CAP/O). CAP/DNFB values were approximately double that of O/DNFB. There was no significant difference in IL-1beta or TNFalpha release between the nonsensitized controls (O/O, CAP/O). Collectively, these data indicate that neuropeptide denervation by neonatal administration of capsaicin alters both the induction and elicitation phases CHS and may modify sensitivity to chemically induced CHS.
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PMID:Neuropeptide denervation alters both the elicitation and induction phases of contact hypersensitivity in mice. 987 94

Bronchopulmonary C fibers defend the lungs against injury from inhaled agents by a central nervous system reflex consisting of apnea, cough, bronchoconstriction, hypotension, and bradycardia. Glutamate is the putative neurotransmitter at the first central synapses in the nucleus of the solitary tract (NTS), but substance P, also released in the NTS, may modulate the transmission. To test the hypothesis that substance P in the NTS augments bronchopulmonary C fiber input and hence reflex output, we stimulated the C fibers with left atrial capsaicin (LA CAP) injections and compared the changes in phrenic nerve discharge, tracheal pressure (TP), arterial blood pressure (ABP), and heart rate (HR) in guinea pigs before and after substance P injections (200 microM, 25 nl) in the NTS. Substance P significantly augmented LA CAP-evoked increases in expiratory time by 10-fold and increases in TP and decreases in ABP and HR by threefold, effects prevented by neurokinin-1 (NK1) receptor antagonism. Thus substance P acting at NTS NK1 receptors can exaggerate bronchopulmonary C fiber reflex output. Because substance P synthesis in vagal airway C fibers may be enhanced in pathological conditions such as allergic asthma, the findings may help explain some of the associated respiratory symptoms including cough and bronchoconstriction.
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PMID:Substance P in the nucleus of the solitary tract augments bronchopulmonary C fiber reflex output. 1100 86

Our previous studies have shown that the activation of the transient receptor potential vanilloid type 1 (TRPV1) expressed in the renal pelvis leads to an increase in ipsilateral afferent renal nerve activity (ARNA) and contralateral renal excretory function, but the molecular mechanisms of TRPV1 action are largely unknown. This study tests the hypothesis that activation of receptors of neurokinin 1 (NK1) or calcitonin gene-related peptide (CGRP) by endogenously released substance P (SP) or CGRP following TRPV1 activation, respectively, governs TRPV1-induced increases in ARNA and renal excretory function. Capsaicin (CAP; 0.04, 0.4, and 4 nM), a selective TRPV1 agonist, administered into the renal pelvis dose-dependently increased ARNA. CAP (4 nM)-induced increases in ipsilateral ARNA or contralateral urine flow rate (Uflow) and urinary sodium excretion (UNa) were abolished by capsazepine (CAPZ), a selective TRPV1 antagonist, or 2-[1-imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenyl-4-perhydroisoindolone (3aR,7aR) (RP67580) or cis-2-(diphenylmethyl)-N-[(2-iodophenyl)-methyl]-1 azabicyclo[2.2.2]octan-3-amine (L703,606), selective NK1 antagonists, but not by CGRP8-37, a selective CGRP receptor antagonist. Both SP (7.4 nM) and CGRP (0.13 muM) increased ARNA, Uflow, or UNa, and increases in these parameters induced by CGRP but not SP were abolished by CAPZ. CAP at 4 nM perfused into the renal pelvis caused the release of SP and CGRP, which was blocked by CAPZ but not by RP67580, L703,606, or CGRP8-37. Immunofluorescence results showed that NK1 receptors were expressed in sensory neurons in dorsal root ganglion and sensory nerve fibers innervating the renal pelvis. Taken together, our data indicate that NK1 activation induced by SP release upon TRPV1 activation governs TRPV1 function and that a TRPV1-dependent mechanism is operant in CGRP action.
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PMID:Interdependent regulation of afferent renal nerve activity and renal function: role of transient receptor potential vanilloid type 1, neurokinin 1, and calcitonin gene-related peptide receptors. 1836 71


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