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)

In previous work we reported the elevation of circulating inflammatory cytokines in rodents maintained on a Mg(2+)-deficient diet. Within the first week of Mg2+ deficiency, significant elevation of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) occurs. The present study was designed to assess the effects of SP receptor blockade by CP-96,945 and its inactive enantiomer CP-96,344 on tissue cytokine levels and in vivo oxidative indexes. CP-96,345 had no significant effect on circulating levels of SP or CGRP; however, at the tissue level, a significant decrease (P < .01) in myocardial accumulation of SP occurred; the inactive enantiomer was only slightly effective. In addition, CP-96,345 significantly reduced (by 53%) the accumulation of tumor necrosis factor-alpha (TNF-alpha) (but not interleukin-1 and interleukin-6) within the lesions; the effect of the enantiomer was insignificant. We conclude that treatment with CP-96,345 inhibits SP and TNF-alpha tissue levels in cardiac lesions, indicating a linkage between this neuropeptide and TNF-alpha. Both SP and TNF-alpha can trigger free radical production; plasma thiobarbituric acid-reactive materials were elevated 2.5-fold and red blood cell reduced glutathione was reduced 55% during Mg2+ deficiency. In the presence of CP-96,345, both indexes of in vivo oxidation were significantly attenuated; the enantiomer was ineffective. These latter observations point to a neuropeptide/TNF-alpha/free radical-triggered mechanism that may be the major pathway of systemic oxidative injury inducing the cardiomyopathic lesions seen during Mg2+ deficiency.
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PMID:Blockade of cardiac inflammation in Mg2+ deficiency by substance P receptor inhibition. 751 52

The contractile effects of 5-hydroxytryptamine (5-HT) and influences of several kinds of divalent cations were investigated on longitudinal muscle strips of the guinea-pig isolated distal colon. 5-HT (10 nM-10 microM) produced phasic contractions which were partially inhibited by atropine (1 microM) and markedly inhibited by tetrodotoxin (1 microM), indicating that 5-HT acts mainly on the myenteric plexus and releases transmitters to cause contraction of the longitudinal muscle. The contractile response to 5-HT (3 microM) was almost completely inhibited by spantide (10 microM), a substance P antagonist, in the presence of atropine (1 microM), while spantide alone did not block 5-HT-induced contraction. Of several divalent cations including Cd2+, Co2+, Mg2+, Mn2+, Ni2+, Sr2+ and Zn2+, Cd2+ ions (10 mu-100 microM), which block L- and N-type Ca2+ channels, were most effective inhibitor of the 5-HT-induced contractions. While Sr2+ and Co2+ at a concentration of 100 microM did not have a significant effect. The order effectiveness of inhibition was Cd2+ >> Mn2+ > Mg2+ = Ni2+ = Zn2+. Bay K 8644 (1 microM), a L-type Ca2+ channel activator, did not influence the contractile response of the longitudinal muscle strip to 5-HT (3 microM). The present results suggest that 5-HT may mainly act on N-type Ca2+ channels in the myenteric neurones and cause the release of at least acetylcholine and substance P to induce contractions of the longitudinal muscle in the guinea-pig distal colon.
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PMID:Contractile responses of longitudinal muscle strip to 5-HT and influences of divalent cations in the guinea-pig isolated colon. 751 8

The frequency of spontaneous action potentials of locus coeruleus (LC) neurons was recorded extracellularly in pontine slices of the rat brain. Ethanol (1-100 mM) elevated the firing rate in most neurons; this effect was concentration-dependent. (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 0.03-1 microM), kainate (0.1-3 microM), N-methyl-D-aspartate (NMDA; 1-30 microM), substance P (0.01-1 microM), nicotine (0.1-10 microM) and alpha,beta-methylene ATP (alpha,beta-meATP; 0.3-30 microM), all increased the firing. Application of ethanol (10-100 mM) to the superfusion medium for 10 min, reproducibly and concentration-dependently inhibited the facilitatory effect of NMDA (10 microM). However, the inhibitory effect of ethanol (100 mM) decreased during a 30-min superfusion period and after the wash-out of ethanol the sensitivity of LC neurons to NMDA (10 microM) tended to overshoot above their initial level. Although NMDA was more potent in the absence than in the presence of external Mg2+, ethanol (100 mM) continued to depress the facilitatory effect of a low concentration of NMDA (3 microM) in a Mg(2+)-free medium. By contrast, in a medium containing normal Mg2+, ethanol (100 mM) failed to significantly interfere with the increase in firing rate induced by a high concentration of NMDA (30 microM). The effects of kainate (0.5 microM), AMPA (0.3 microM) and nicotine (1 microM) were also depressed by ethanol (100 mM), while the effects of substance P (0.03 microM) and alpha,beta-meATP (30 microM) were not changed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition by ethanol of excitatory amino acid receptors and nicotinic acetylcholine receptors at rat locus coeruleus neurons. 753 98

The use of non-hydrolyzable analogues of GTP in permeabilized secretory cells suggests that guanine nucleotide-binding regulatory proteins (G proteins) may be involved in regulated exocytosis. Because GTP analogues are known to modulate both monomeric low molecular mass G proteins and heterotrimeric G proteins, we have examined the effect of mastoparan, an activator of heterotrimeric G proteins, on secretion from intact and permeabilized chromaffin cells. In intact cells, mastoparan inhibited catecholamine secretion evoked by nicotine but had no effect on release induced by other secretagogues. In permeabilized cells, mastoparan inhibited calcium-dependent secretion providing that the pores created in the plasma membrane allow the penetration of the peptide into the cytoplasm. These results indicate that mastoparan blocks the exocytotic machinery through an intracellular target protein that may not be located just beneath the plasma membrane. Accordingly, mastoparan was able to stimulate G proteins associated with purified chromaffin granule membranes, in a range of concentration and Mg2+ requirement that was similar to its inhibitory effect on secretion. Mas 17, a mastoparan analogue inactive on purified G proteins, neither modified catecholamine secretion nor stimulated chromaffin granule G proteins. The substance P-related peptide, GPAnt-2, known to antagonize the effects of mastoparan on G(o), blocked both the inhibitory effect of mastoparan on secretion and the mastoparan-stimulated GTPase activity in chromaffin granule membranes. Moreover, specific antibodies raised against the carboxyl terminus of G(o) alpha reversed in a dose-dependent manner the inhibition by mastoparan on catecholamine release and the stimulation by mastoparan of chromaffin granule-associated G proteins. These results suggest that the secretory machinery in chromaffin cells can be blocked by activating a G(o) protein. Consistent with this finding, two other known activators of heterotrimeric G proteins, aluminum fluoride and benzalkonium chloride, inhibited calcium-evoked catecholamine secretion in streptolysin O-permeabilized chromaffin cells. We conclude that an inhibitory G(o) protein, possibly located on the membrane of secretory granules, is involved in the final stages of exocytosis in chromaffin cells.
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PMID:Exocytosis in chromaffin cells. Possible involvement of the heterotrimeric GTP-binding protein G(o). 768 3

Whole-cell patch recordings of neurons in the rostral (gustatory) nucleus tractus solitarius (rNTS) were performed in a brain slice preparation from rat medulla. Neural responses to brief applications (10-45 s) of substance P (SP), via a constant superfusion apparatus, were recorded. SP transiently depolarized 80 of 117 (68%) rNTS neurons in a dose-dependent manner. Sub-micromolar concentrations of SP had potent excitatory effects, and the half maximal response occurred at 0.6 microM. The depolarizing effect of SP was accompanied by an increase in input resistance in 81% of the responsive neurons. The excitatory effects of SP persisted in low Ca2+ (0.2 mM) and high Mg2+ (12 mM) saline as well as in the presence of 2 microM TTX (n = 5 for each), suggesting direct postsynaptic action on the recorded neurons. SP also hyperpolarized 4 neurons (4%) and had no effect on 33 neurons (28%). Each of the 4 neurons which were hyperpolarized by SP showed a decrease in input resistance. A more detailed assessment of the types of neurons in the rNTS which respond to SP was also conducted. Neurons were separated into 4 electrophysiological groups on the basis of their repetitive firing pattern induced by a hyperpolarizing and depolarizing current injection paradigm. Neurons belonging to each of the 4 electrophysiological groups responded to SP. Eighteen neurons, which were filled with 1% biocytin during recording, were categorized as ovoid, multipolar or fusiform based on their morphological characteristics. SP excited all 3 morphological types of neurons in similar proportion. These results suggest that SP is an excitatory neurotransmitter in the rNTS. The effects of SP are not restricted to a particular neuron type defined either biophysically or morphologically. The implications of these results on the possible role of SP in processing gustatory and somatosensory information within the rNTS are discussed.
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PMID:Substance P excites neurons in the gustatory zone of the rat nucleus tractus solitarius. 769 Jun 70

Applications of histamine to neurons in slices of trigeminal root ganglia (guinea-pig) produced slow changes in the steady-state membrane potentials and input resistances. Several types of response to histamine could be distinguished: (i) depolarizations accompanied by an increase, a decrease or no change in input resistance; (ii) small hyperpolarizations associated with a decreased or unchanged input resistance; and (iii) combined hyper- and depolarizations. The amplitudes of all response types waned during prolonged applications of histamine. The depolarizing responses to histamine appeared to depend on the presence of outward rectification in the region of the initial resting potential; neurons which possessed linear current-voltage relationships near the initial resting potential were depolarized by > 10 mV, whereas neurons with outward rectification near rest showed smaller depolarizing responses. Histamine also reduced the magnitude of the long-duration spike afterhyperpolarizations which had been attributed in the ganglionic neuron to a Ca(2+)-activated K+ conductance mechanism. Application of substance P, another possible neuromodulator in the trigeminal system, had depolarizing, desensitizing actions similar to those of histamine. Substance P and histamine did not cross-desensitize during prolonged applications. Histamine-induced depolarizations were unchanged under zero Mg2+ extracellular conditions, in contrast to a dependency of the substance P-induced effects on external Mg2+.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Histamine actions and comparison with substance P effects in trigeminal neurons. 769 Sep 11

Using the novel ligand [4,5-3H-Leu9]neurokinin A ([4,5-3H-Leu9] NKA) in a receptor binding assay, we characterized the pharmacology of a cloned neurokinin NK-2 receptor from human lung (hNK-2R), expressed in baculovirus-infected Sf-21 insect cells. Functional hNK-2R cDNA clones were isolated from human lung using a polymerase chain reaction-based methodology. hNK-2R was cloned into pAcYM1, a vector designed to couple expression to the polyhedrin promoter, and the recombinant baculovirus was isolated and used to infect Sf-21 insect cells. hNK-2R expression levels were monitored by Northern blots and 125-I-NKA binding assays. Isolates demonstrating the highest specific binding of 125-I-NKA were grown and membrane preparations from high-speed centrifugations were prepared from both hNK-2R-expressing and wild-type virus-infected cells. [3H]NKA bound in a protein-dependent, saturable (Bmax = 820 +/- 167 fmol/mg of protein), and highly specific (88 +/- 5%) manner to hNK-2R, but not to membranes from cells infected with wild-type virus (14 +/- 8%, 7 +/- 10 fmol/mg of protein). [3H]NKA binding was rapid (k1 = 0.085 nM-1 x min-1) and reversible (t1/2 = 4-5 min). Equilibrium binding experiments demonstrated binding to a mixture of receptors in high and low affinity states (Kd1 = 2.28 +/- 0.26 nM and Kd2 = 266 +/- 91 nM). Binding to hNK-2R was greatly enhanced (400%-600%) by Ca2+ and Mg2+ (EC50 values of 30 microM and 140 microM, respectively), whereas guanosine-5'-O-(3'-thio)triphosphate and guanosine-5'-(beta, gamma-imido)diphosphate were inhibitory. Competition experiments with agonists also demonstrated binding to high and low affinity states, with the following order of potency: NKA > [Nle10]NKA(4-10) > [beta-Ala8]NKA(4-10) >> substance P; Senktide and the NK-1 antagonist CP96,345 (10 microM) did not inhibit binding. Inhibition of binding by selective NK-2 antagonists was consistent with a single affinity state and demonstrated the following order of affinity: SR48,968 >> MEN10,376 > L659,877 > R396. These data suggest that infection of Sf-21 cells with baculovirus expression vector harboring the cDNA of hNK-2R resulted in expression of high affinity, G protein-coupled hNK-2R, with pharmacological selectivity compatible with the NK-2A receptor subtype.
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PMID:Pharmacological characterization of cloned human NK-2 (neurokinin A) receptor expressed in a baculovirus/Sf-21 insect cell system. 839 92

Magnesium(Mg)-deficiency, whether dietary or an effect of a clinical condition such as diabetes, results in a variety of cardiovascular pathologies. Substance P (SP) has been implicated in the induction of cardiac focal inflammatory lesions that occur during Mg-deficiency. Blockade of SP receptors results in a significant reduction in the incidence of lesion formation. In an effort to identify potential endogenous cell populations of the heart, which may play a role in SP-dependent lesion formation, film- and light-microscopic autoradiography were used to map the distribution of specific SP binding sites in frozen sections of the normal rat heart and adjacent great vessels. Binding was assessed with 0.1 nM I-125 Bolton-Hunter labelled SP in the absence (total binding) or presence (non-specific binding) of excess unlabelled SP, prolactin, or L-703,606, a non-peptide antagonist of SP receptors. Film autoradiograms revealed prominent small foci of intense autoradiographic reactions dispersed intermittently around the periphery of the great vessels and coronary arteries, among the interstitial connective tissue of the heart, and along the cusps of the cardiac valves. Excess unlabelled SP caused a significant reduction (97.7% displacement; P < 0.001) in the focal autoradiographic reactions. L-703,606 caused a similar reduction in SP binding (97.3% displacement; P < 0.001), while prolactin had no statistically significant effect on the binding of radiolabelled SP. Light-microscopic autoradiograms revealed that the SP binding sites occurred within clusters of connective tissue cells or in rarely observed parasympathetic ganglia. No evidence was found to suggest the presence of SP receptors on endothelial cells, cardiac muscle fibers, or smooth muscle fibers. The connective tissue cells which bound SP within the heart will likely include types that are susceptible to SP activation and thus may play a role in initiation of the focal inflammation characteristic of Mg-deficiency.
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PMID:Distribution of specific substance P binding sites in the heart and adjacent great vessels of the Wistar white rat. 864 67

The effect of extracellular ATP on the intracellular calcium concentration ([Ca2+]i) in rat submandibular glands was tested. The dose-response curve for ATP was biphasic with a first increase in the 1-30 microM concentration range and a further increase at concentrations higher than 100 microM. Among ATP analogs, only benzoyl-ATP stimulated the low affinity component. ATP tau S blocked this response. All the other analogs tested reproduced the high-affinity low capacity response. Magnesium and Coomassie blue selectively blocked the low affinity component. High concentrations of ATP blocked the increase of the intracellular calcium concentration [Ca2+]i in response to 100 microM carbachol. By itself, substance P (100 pM-1 microM) increased the [Ca2+]i. One mM ATP potentiated the response to concentrations of substance P higher than 10 nM. This potentiation was reversed by extracellular magnesium. Carbachol 100 microM and substance P (100 pM-1 microM) increased the release of inositol trisphosphate (IP3) from polyphosphoinositides (polyPI). Activation of the low affinity ATP receptors did not activate the polyPI-specific phospholipase C but inhibited its activation by 100 microM carbachol (-50%) and by 100 nM substance P (-60% at 1 nM substance P and -40% at 100 nM substance P). Substance P induced a strong homologous desensitization: a preincubation with 1 nM substance P nearly completely abolished the response to 1 microM substance P. When the cells were exposed to ATP before the second addition of substance P, the purinergic agonist partially restored the response to the tachykinin without totally reversing the desensitization. It is concluded that two types of purinergic receptors coexist in rat submandibular glands; a high-affinity, low capacity receptor which remains pharmacologically and functionally undefined and a low affinity site, high capacity receptor of the P2z type coupled to a non-selective cation channel. The occupancy of these low affinity sites blocks the increase of the [Ca2+]i in response to a muscarinic agonist and the activation of polyPI-specific phospholipase C by carbachol and substance P. It potentiates the effect of high concentrations of substance P on the [Ca2+]i.
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PMID:Low affinity purinergic receptor modulates the response of rat submandibular glands to carbachol and substance P. 870 82

1. Microinjection of angiotensin (Ang) II or substance P (SP) into the medial nucleus tractus solitarii (nTS) produces similar decreases in arterial pressure and heart rate. We previously reported that some medial nTS neurons responsive to SP were also excited by Ang II, and that Ang II increased the release of SP from medulla slices. Both electrophysiological and anatomic data suggest that the cardiovascular effects of these peptides may be mediated by a common neuronal pathway consisting of SP-containing vagal afferent fibers with presynaptic Ang II receptors that innervate medial nTS neurons with SP receptors. To evaluate the validity of this model, we established the presynaptic or postsynaptic location of the receptors for Ang II and SP that mediate excitation of medial nTS neurons by determining the capacity of each peptide to activate the cell before and after blocking synaptic transmission in rat dorsal medulla slices. 2. Extracellular recordings were obtained from 55 medial nTS neurons responsive to Ang II or SP in 400-microns horizontal slices of the dorsal medulla. Neuronal excitation by Ang II and SP was tested before, during, and after reversal of synaptic blockade with low-Ca2+ (0.2 mM), high Mg2+ (5 mM) artificial cerebrospinal fluid (aCSF). Elimination of synaptically evoked short latency responses of the neuron to current pulses applied to afferent fibers in the solitary tract (TS) documented blockade of synaptic transmission by low-Ca2+ aCSF. In most cases, the basal firing rate of the cell increased slowly during perfusion with low-Ca2+ aCSF and stabilized after approximately 30 min at a higher level of spontaneous activity. Responses to the peptides and TS stimulation were also documented after synaptic blockade had been reversed by adding aCSF containing 2-mM Ca2+. 3. Of the 55 medial nTS neurons, 41 were responsive to Ang II; whereas, 50 of the 55 cells were responsive to SP. The neurons were divided into three subgroups on the basis of their responsiveness to Ang II and SP. Although most neurons were responsive to both Ang II and SP (n = 36), five other cells were excited only by Ang II, and 14 neurons were activated only by SP. Of the 55 neurons, 26 were also responsive to L-glutamate: 14 of 17 cells responsive to both Ang II and SP, all 5 neurons excited by Ang II but not by SP, and 7 of 10 neurons responsive only to SP were also excited by L-glutamate. The latency of the action potentials evoked by TS stimulation was much shorter in those neurons responsive only to Ang II (3.6 ms) than in cells excited by both Ang II and SP (6.8 ms) or responsive only to SP (7.4 ms). 4. In 21 of the 36 medial nTS neurons responsive to both Ang II and SP, Ang II continued to excite the cell when synaptic responses to TS stimulation were prevented by low-Ca2+ aCSF, but had no effect on the firing rate of the other 15 neurons during synaptic blockade. Excitation induced by Ang II was also prevented in two of the five medial nTS neurons responsive only to Ang II when synaptic transmission in the slice was blocked. Low-Ca2+ aCSF failed to prevent excitation by SP or L-glutamate in all medial nTS cells responsive to these agonists (n = 50 and n = 26, respectively). In contrast to these observations in medial nTS neurons, Ang II-induced excitation was not altered during synaptic blockade in any of the six dmnX cells studied. No responses to SP or L-glutamate were blocked in dmnX neurons, as also seen in the medial nTS. 5. When all medial nTS neurons responsive to Ang II were examined, the latencies of the response to TS stimulation were significantly shorter in those neurons with presynaptic Ang II receptors than in the group of cells with postsynaptic receptors. In addition, neurons with presynaptic Ang II receptors were distributed differently within the medial nTS than cells with postsynaptic Ang II receptors.(ABSTRACT TRUNCATED)
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PMID:Presynaptic or postsynaptic location of receptors for angiotensin II and substance P in the medial solitary tract nucleus. 879 36


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