UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The possible role of the ventral tegmental area (VTA) and its dopaminergic projections in cardiovascular regulation is reviewed. 2. Our own work has shown that stimulation of the VTA by local microinjection of the substance P analogue DiMe-C7 caused an increase in blood pressure. The mechanism of the pressor response was an interaction of central dopaminergic activation, most likely at the level of the baroreflex, with the circulatory actions of vasopressin. 3. These findings are important for a possible role of the mesolimbic dopamine system in cardiovascular homeostasis. Several studies reviewed here show that neuronal activity of the VTA and its mesolimbic projections is altered by changes in blood pressure, salt and electrolyte balance, stress and food and water intake. 4. The VTA and mesolimbic dopamine system, while playing a widely accepted role in locomotor activity, cognition and reward mechanisms, may also be involved in the integration of sensory and behavioural information with cardiovascular homeostasis.
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PMID:Role of the mesolimbic dopamine system in cardiovascular homeostasis. Stimulation of the ventral tegmental area modulates the effect of vasopressin on blood pressure in conscious rats. 975 Sep 53

Capsaicin depolarizes primary afferent C-fibers releasing substance P (SP) whose N-terminal metabolites appear to play a role in the development of antinociception. Because some effects of SP(1-7) are similar to those of zinc, we tested the hypothesis that zinc in the extracellular area plays a role in capsaicin-induced antinociception, as measured using the abdominal stretch (writhing) assay. Decreases in zinc were achieved by intrathecal (i.t.) injection of membrane-impermeable compounds: ethylenediaminetetraacetic acid disodium-calcium salt (Ca++ EDTA), a calcium-saturated chelator of divalent cations, or dipicolinic acid, a zinc chelator. Ten nanomoles of Ca++ EDTA had no effect on writhing at either 90 min or 24 h after injection, yet pretreatment with Ca++ EDTA prevented the development of antinociception 24 h after i.t. injection of either 2. 8 nmol of capsaicin or 10 nmol of SP(1-7). One nanomole of dipicolinic acid injected i.t. also blocked capsaicin- and SP(1-7)-induced antinociception. When injected 24 h after SP(1-7), Ca++ EDTA failed to reverse antinociception. Acute antinociception produced 30 min after injection of SP(1-7) was also blocked when Ca++ EDTA was injected 24 h, but not 60 min, before SP(1-7). Thus, the optimal time of Ca++ EDTA-induced hyperalgesia (90 min), described previously, did not correspond to that of its inhibitory effect on antinociception (24 h). In contrast, we found that the previously described antinociception after an i.t. injection of zinc (90 min) is greatly attenuated by 24 h. Thus, zinc appears to be necessary, but may not be sufficient, for the long-term antinociceptive effect of capsaicin, acting downstream from the action of substance P N-terminal metabolites.
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PMID:Chelation of zinc in the extracellular area of the spinal cord, using ethylenediaminetetraacetic acid disodium-calcium salt or dipicolinic acid, inhibits the antinociceptive effect of capsaicin in adult mice. 991 86

Severe human scorpion envenoming is characterised by instability of several physiological systems and death. These manifestations are explained by the ability of the venom toxins to activate sodium channels in nerve terminals with the subsequent release of neurotransmitters, specially acetylcholine and noradrenaline. However, there is evidence to suggest that other neurotransmitters are also released. We now have sought evidence for a role of the substance P receptor, the tachykinin NK1 receptor, in mediating part of the contractile actions of Tityus serrulatus venom on the isolated guinea pig ileum. Scorpion venom induced a significant elevation of baseline tension with frequent and periodic superimposed contractions on the elevated baseline. Pretreatment with atropine partially blocked the elevation in baseline and in the number of superimposed contractions. These responses were also partially inhibited by the tachykinin NK1 receptor antagonist, CP96,345 (the dihydrochloride salt of (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)methyl)-1-az abicycol[2.2.2]octan-3-amine), but not by its inactive enantiomer, CP96,344 (the 2R-3R enantiomer of CP96,345). Pretreatment with the combination of atropine and CP96,345 completely inhibited the effects of the venom. Moreover, pretreatment with the combined drugs abolished the effects of toxin gamma, a toxin purified from the venom. Finally, another tachykinin NK1 receptor antagonist, RP67,580 ((3aR, 7ar)-7,7-diphenyl-2-[1-imino-2-(2-methoxy-phenyl)ethyl]perhydro isoindol-4-one), significantly inhibited the venom-induced contractions. These results demonstrate an important role for NK1 receptors in mediating part of the contractile effects of the venom on guinea pig ileum. The release of neuropeptides may play an important role in the systemic manifestations of severe envenoming.
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PMID:Pharmacological evidence that neuropeptides mediate part of the actions of scorpion venom on the guinea pig ileum. 1019 59

In cases of severe human scorpion envenoming, lung injury is a common finding and frequently the cause of death. In the rat, two distinct mechanisms account for oedema following the intravenous injection of the venom -- acute left ventricular failure resulting from a massive release of catecholamines and an increase in pulmonary vascular permeability. In the present work, we investigated the effects of a tachykinin NK1 receptor antagonist (CP96,345, the dihydrochloride salt of (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)methyl)-1-az abicycol[2.2.2]octan-3-amine) and its 2 R-3 R inactive enantiomer (CP96,344) on the acute lung injury induced by the i.v. injection of Tityus serrulatus venom in rats. Lung injury was assessed by evaluating the extravasation of Evans blue dye in the bronchoalveolar lavage fluid and in the lung of venom-treated and control animals. The effects of the platelet-activating factor (PAF) receptor antagonist WEB2170 (2-methyl-1-phenylimidazol[4,5c]pyridine) were evaluated for comparison. The i.v. injection of the venom induced the extravasation of Evans blue in the bronchoalveolar lavage fluid and into the left lung. Pretreament with the tachykinin NK1 receptor antagonist CP96,345, but not CP96,344, inhibited Evans blue dye extravasation in the bronchoalveolar lavage fluid and in the lung by 96% and 86%, respectively. The PAF receptor antagonist WEB2170 inhibited the increase in vascular permeability in the bronchoalveolar lavage fluid by 60% and had no effect on the extravasation to the lung parenchyma of venom-injected animals. In addition to abrogating lung injury, pretreatment of rats with CP96,345, but not CP96,344 or WEB2170, decreased by 70% the mortality induced by the venom. This is the first study to show the relevance of the tachykinin NK1 receptor in mediating lung injury and mortality in animals injected with the neurotoxic T. serrulatus venom. Blockade of the tachykinin NK1 receptor may represent an important strategy in the treatment of patients with signs of severe envenoming and clearly deserves further studies.
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PMID:Effects of tachykinin NK1 or PAF receptor blockade on the lung injury induced by scorpion venom in rats. 1044 90

The effects of lateral ventricular injections of succinyl-[Asp6, N-Me-Phe8]-substance P (SENK; 25, 100, 200 ng), a tachykinin NK3 receptor agonist, and [Sar9, Met(O2)11]-substance P (Sar Met; 100, 200 ng), an NK1 receptor agonist, on normal (gastric fistula closed) and sham drinking (gastric fistula open) of hypertonic NaCl by sodium-deficient rats were compared. Intraventricular injections of Sar Met had no effect on NaCl intake in either condition. Injections of 100 ng and 200 ng SENK caused an equal suppression of NaCl intake in the 2 fistula conditions. The latency to drink was not affected, but the initial lick rate was significantly lower and decayed more rapidly after 100 ng SENK than after saline or 25 ng SENK. The results show that (a) the tachykinin subtypes are not equally involved in the control of need-induced salt intake; (b) negative feedback from the stomach and distal gastrointestinal tract is not required for intraventricular injections of SENK to suppress sodium appetite; (c) the activation of NK3 receptors decreases the oral excitatory influence of hypertonic NaCl in sodium-deficient rats.
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PMID:Differential effects of intraventricular injections of tachykinin NK1 and NK3 receptor agonists on normal and sham drinking of NaCl by sodium-deficient rats. 1049 85

Chronic administration of the mineralocorticoid deoxycorticosterone acetate (DOCA) induces a steady and robust increase in salt appetite and plasma Na(+) over the course of treatment. Interestingly, salt appetite behavior persists in rats even with elevated plasma Na(+) levels. Since there is evidence that the pathways normally associated with salt and water homeostasis are relatively unaffected in the DOCA-treated rat, we hypothesized that other regulatory systems may be hyperactive giving rise to this dysfunctional condition. The mesolimbic dopaminergic system has long been associated with orienting and reward-seeking behaviors such as those observed in reproduction, drug abuse, and appetite. Furthermore, we have previously shown that chronic DOCA administration results in an increase in mRNA levels of the endogenous opiate enkephalin in male rats given 24-hour access to tap water and 2% NaCl (two-bottle choice). Thus, in the present study, we tested the hypothesis that the mesolimbic dopaminergic system is dysfunctionally sensitized to the presence of a salt stimulus in DOCA-treated animals. Four groups of rats were injected with DOCA (5 mg/rat/day, 11 days) and one with vehicle (all were given access to water but access to salt was regulated). Two DOCA groups were given 2 h of 2% NaCl access/day and on the last day, one group was not given access (2hX). One of the two remaining DOCA groups was given 24-hour access to salt (24h) and the other no access at all (24hX). Consistent with our hypothesis, in the shell of the nucleus accumbens (AcbSh) we found relatively higher enkephalin- and tachykinin-mRNA abundance in the 2h vs. 2hX and dynorphin-mRNA in the 24h vs. 24hX groups. In addition, there were decreases in dopamine transporter binding in the AcbSh and decreases in tyrosine hydroxylase immunoreactivity throughout the striatum in the 24h vs. 24hX group. Furthermore, rats denied access to salt (2hX and 24hX) had higher cholecystokinin-mRNA levels in the ventral tegmental area compared to the 2h and 24h groups, respectively. These results suggest that basal ganglia structures associated with reward and goal-seeking behavior may be activated to elicit salt craving behavior in the DOCA-induced salt-appetitive rat.
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PMID:Salt appetite in salt-replete rats: involvement of mesolimbic structures in deoxycorticosterone-induced salt craving behavior. 1087

Neurokinin B (NKB) is one member of an evolutionarily conserved family of neuropeptides, the tachykinins. Preferential binding of NKB to endogenous NK(3) receptors affects a variety of biological and physiological processes, including endocrine secretions, sensory transmission, and fluid and electrolyte homeostasis. In light of its widespread biological actions, immunohistochemical detection of the c-Fos protein product was used to study the distribution of neuronal activation in the rat brain caused by intraventricular (icv) injections of the selective NK(3) receptor agonist (succinyl-[Asp(6), N-Me-Phe(8)] substance P [6-11]), senktide. Quantitative analysis revealed that treatment with isotonic saline or 200 ng senktide resulted in the differential expression of Fos-like immunoreactivity (FLI) throughout the brain. Senktide induced the highest number of FLI neurons in the lateral septum, bed nucleus of the stria terminalis, amygdala, paraventricular nucleus of the hypothalamus, median preoptic nucleus, organum vasculosum of the lamina terminalis, supraoptic nucleus, periaqueductal gray, and medial nucleus of the solitary tract compared to isotonic saline controls. Additional regions that contained elevated FLI following icv injection of senktide, relative to saline injection, included the cerebral cortex, lateral hypothalamic nucleus, suprachiasmatic nucleus, ventral tegmental area, substantia nigra, inferior colliculus, locus coeruleus, zona incerta, and arcuate nucleus. Our data indicate that activation of NK(3) receptors induces the expression of FLI within circumscribed regions of the rat brain. This pattern of neuronal activation overlaps with nuclei known to regulate homeostatic processes, such as endocrine secretion, cardiovascular function, salt intake, and nociception.
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PMID:Distribution of Fos-like immunoreactivity within the rat brain following intraventricular injection of the selective NK(3) receptor agonist senktide. 1099 47

Tryptase, a serine protease synthesized by and stored in mast cells, is implicated as an important mediator in the pathogenesis of airway inflammation. In this study, tryptase was evaluated for its ability to induce microvascular leakage into the airways of guinea pigs. Dose- and time-dependent increases in airway microvascular leakage were produced by intratracheal tryptase (0.3-3 microg). Intratracheal tryptase (3-30 microg) had no effect on airway tone as measured by pulmonary insufflation pressure. Tryptase-induced airway microvascular leakage was partially blocked by the tachykinin NK1 receptor antagonist CP 99994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] and an inhibitor of leukotriene formation SCH 37224 (1-(1,2-dihydro-4-hydroxy-2-oxo-1-phenyl-1,8-naphthyridin-2-yl)pyrrolidinium, hydroxide inner salt). Neither CP 99994 nor SCH 37224 inhibited tryptase proteolytic activity in-vitro. Pretreatment of guinea pigs with histamine H1 receptor antagonists or a tachykinin NK2 receptor antagonist had no affect on the airway microvascular leakage induced by tryptase. It is speculated that tryptase may be important in the pathogenesis of airway inflammation, particularly in disorders that involve increased airway microvascular leakage such as asthma.
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PMID:Tryptase-induced airway microvascular leakage in guinea pigs: involvement of tachykinins and leukotrienes. 1142 50

Calcitonin gene-related peptide (CGRP) and substance P are known to play a counterregulatory role in acquired models of salt-dependent hypertension. In contrast, neuronal production of these peptides is decreased in the spontaneously hypertensive rat, which may contribute to the elevated blood pressure. To determine the role played by CGRP and substance P in Dahl-salt hypertension, 4- to 6-week-old male salt-resistant (DR) and salt-sensitive (DS) rats were divided into 4 groups (n=5/group) and pair-fed low-salt (0.2% NaCl) (DR/LS and DS/LS) and high-salt (8% NaCl) diets (DR/HS and DS/HS) for 3 weeks. After 3 weeks, all the rats had venous (for drug administration) and arterial (for blood pressure monitoring) catheters surgically implanted and were studied in the conscious and unrestrained state. Mean arterial pressure was significantly higher in the DS/HS rats animals (185.8+/-1.6 mm Hg, P<0.001). Intravenous administration of CGRP and SP receptor antagonists was without effect in any of the groups studied. CGRP and SP mRNA content from dorsal root ganglia were not significantly different between the groups. Whereas immunoreactive CGRP was decreased in the DS groups (DS/HS, 9.4+/-0.4 pg/microgram protein; DS/LS, 11.1+/-0.8 pg/microgram protein; P<0.01) compared with the DR groups (DR/HS, 13.9+/-0.6 pg/microgram protein; DR/LS, 14.6+/-0.6 pg/microgram protein), neuronal SP production was similar between all the groups. Thus, CGRP and substance P do not play a counterregulatory role in Dahl-salt hypertension. The decrease in neuronal CGRP expression in DS rats appears to be genetically determined as in SHR, however, and may contribute to the increase in blood pressure following salt-loading.
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PMID:Role of calcitonin gene-related peptide and substance P in Dahl-salt hypertension. 1156 55

Substance P, the principal neurokinin peptide in the mammalian brain and the natural ligand for the NK(1) tachykinin receptor, plays an integrative role in the regulation of cardiovascular, neuroendocrine and behavioural responses to stress. In rats, stimulation of periventricular NK(1) receptors in the forebrain induces a distinct pattern of cardiovascular responses which is accompanied by intense grooming behaviour. Ligands for NK(3) receptors induce a different pattern of cardiovascular and behavioural responses which comprises an increased release of vasopressin from the posterior pituitary and wet-dog shakes behaviour. To define the brain areas in the rat which respond to stimulation of forebrain NK(1) and NK(3) receptors and participate in the generation of these responses, the induction of c-Fos immunoreactivity was examined in brains following intracerebroventricular injections of substance P and neurokinin B in conscious rats. Stimulation of central NK(1) receptors by substance P (25, 100 and 500 pmol) injected into the lateral ventricle elicited grooming behaviour (face washing and hind limb grooming) and resulted in a marked c-Fos expression in the paraventricular, dorsomedial and parabrachial nuclei and in the medial thalamus. At 25 pmol, substance P did not significantly increase c-Fos expression, at 100 pmol, maximal c-Fos activation was induced in all four brain regions which responded to the peptide. Intracerebroventricular pretreatment of rats with the selective and high-affinity, non-peptide NK(1) receptor antagonist, RP 67580 (500 pmol), but not with its inactive enantiomer, RP 68651, completely abolished the behavioural response to substance P and reduced the substance P-induced c-Fos expression in all brain areas to nearly control levels. Intracerebroventricular injection of the natural ligand for NK(3) receptors, neurokinin B (500 pmol), elicited wet-dog shakes behaviour and activated c-Fos expression in localized regions of the forebrain including the organum vasculosum laminae terminalis, subfornical organ, median preoptic nucleus, paraventricular, supraoptic and anterior hypothalamic nuclei, medial thalamus and in the ventral tegmental area. These results demonstrate that the neurokinins, substance P and neurokinin B, induce specific and different patterns of c-Fos expression in distinct regions of the rat brain. Brain areas which selectively responded to substance P have been traditionally linked to the central regulation of cardiovascular and neuroendocrine reactions to stress or involved in the processing of nociceptive responses. On the other side, brain areas activated by neurokinin B are known to be involved in the central regulation of blood pressure, water and salt homeostasis or control of behaviour.
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PMID:C-FOS expression in the rat brain in response to substance P and neurokinin B. 1159 86

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