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)

We have determined the ability of the novel nonpeptide tachykinin (TK) NK3 receptor antagonist, SR 142801, [(S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methylaceta mide] in inhibiting the nitric oxide (NO)-independent prejunctional inhibition of cholinergic twitches and the NO-dependent relaxation produced by the NK3 receptor selective agonist, senktide, in the circular muscle of the guinea-pig proximal colon. Under moderate load (10 mN) and isometric recording of mechanical activity, single pulse electrical field stimulation (EFS) produced atropine- and tetrodotoxin-sensitive twitch contractions of mucosa-free circular muscle strips from the guinea-pig proximal colon. In the presence of NK1 and NK2 receptor antagonists (SR 140333 0.01 microM and GR 94800 0.1 microM, respectively) the NK3 receptor selective agonist, senktide (EC50 33 pM) and the NK3 receptor preferring natural TK, neurokinin B (NKB, EC50 13 pM) produced a concentration-dependent slowly developing inhibition of cholinergic twitches. Senktide (1 nM) did not affect the contractile response to acetylcholine (1 microM) indicating that depression of evoked twitches occurs prejunctionally. The inhibitory effect of senktide was unaffected when evoked in the presence of the cyclooxygenase inhibitor (S)-ketoprofen (10 microM), guanethidine (10 microM), naloxone (0.3 microM), the GABAB receptor antagonist 2-hydroxysaclofen (10 microM) or the combined application of the adenosine A1 and A2 receptor antagonists, 8-cyclopentyl-1,3-dipropylxanthine (10 microM) and 3,7-dimethyl-1-propargylxanthine (30 microM) respectively. In the presence of NK1 and NK2 receptor antagonists, the NO-synthase inhibitor L-nitroarginine (L-NOARG 30-100 microM) did not affect twitch inhibition induced by senktide (EC50 33 pM). The response to NKB (EC50 95 pM) was slightly reduced by L-NOARG, yet the bulk of the inhibitory effect of both agonists on cholinergic twitches was substantially independent of NO generation. SR 142801 (0.1-0.3 microM) produced a moderate rightward shift of the concentration-response curve to senktide without depression of the Emax to the agonist, yielding an apparent pKB value of 7.65. Under low resting tone (3 mN) and isotonic recording of mechanical activity, mucosa-free circular muscle strips from the guinea-pig proximal colon gained a high intrinsic tone suitable for testing the response to relaxant agents. In the presence of atropine (1 microM), guanethidine (3 microM), SR 140333 (0.01 microM) and GR 94800 (0.1 microM), senktide (EC50 50 pM) produced a concentration-dependent relaxation of the strips, which was blocked by L-NOARG. SR 142801 (0.01-0.1 microM) produced a large rightward shift of the L-NOARG-sensitive concentration-response curve to senktide yielding an apparent pKB value of 8.62. Under isometric recording condition, SR 142801 (0.1 microM) did not affect twitch inhibition produced by 3 nM clonidine. Under isotonic recording condition, SR 142801 did not affect the L-NOARG-sensitive relaxation produced by EFS. The present results indicate that NK3 receptor stimulation produces a NO-dependent relaxation of the guinea-pig colon and a substantially NO-independent prejunctional inhibition of cholinergic twitches. The variable affinities of SR 142801 in antagonizing various senktide-induced neuromodulatory effects in the guinea-pig intestine suggest a possible intraspecies heterogeneity of NK3 receptors in the enteric nervous system.
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PMID:Effect of SR 142801 on nitric oxide-dependent and independent responses to tachykinin NK3 receptor agonists in isolated guinea-pig colon. 875 Oct 80

Endogenously released cyclooxygenase products modulate the bronchoconstrictor response to various stimuli in asthma. Little is known of the change in airway responsiveness to neurokinin A (NKA) after cyclooxygenase blockade. In this randomized, double-blind, placebo-controlled study, we have investigated the effect of the potent cyclooxygenase inhibitor, lysine acetylsalicylate (L-ASA) administered by inhalation, on the bronchoconstrictor response both to neurokinin A (NKA) and methacholine in nine asthmatic subjects. Subjects attended the laboratory on four separate occasions to receive nebulized L-ASA (solution of 90 mg.mL-1) or matched placebo (glycine, solution of 30 mg.mL-1) 15 min prior to bronchial challenge with NKA or methacholine, in a randomized, double-blind order. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1) and agonist responsiveness, expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). L-ASA elicited a significant fall in FEV1 from baseline. When compared with placebo, inhaled L-ASA reduced the airway responsiveness to NKA in 8 of the 9 subjects studied, the geometric mean (range) values for PC20 NKA increasing significantly from 153.2 (52.0-258.9) to 303.1 (83.4-668.5) micrograms.mL-1 after placebo and L-ASA, respectively. However, no significant change in airway responsiveness to methacholine was recorded after L-ASA, their geometric mean (range) PC20 values being 1.60 (0.17-9.59) and 1.53 (0.09-14.01) mg.mL-1 after placebo and L-ASA, respectively. The small decrease in airway responsiveness to neurokinin A after administration of lysine acetylsalicylate by inhalation suggests that endogenous prostaglandins may play a contributory protective role in the airway response to neurokinin A in human asthma.
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PMID:Changes in neurokinin A airway responsiveness with inhaled lysine-acetylsalicylate in asthma. 880 29

The purpose of this study was to examine the potential functional significance of the sensory nerve inhibitory system in modulating contraction. Tension development in response to electrical field stimulation (EFS) and exogenous acetylcholine was monitored in segments of intrapulmonary bronchi isolated from male Sprague-Dawley rats. Contractile responses to EFS were enhanced by desensitization of sensory nerves with capsaicin, by antagonizing neurokinin NK1 receptors with RP-67580, and by inhibition of cyclooxygenase with meclofenamate. Except for RP-67580, which had a slight inhibitory effect on acetylcholine-induced contractions, these interventions were without effect on contraction to acetylcholine. Incubation of capsaicin-desensitized airway segments with substance P attenuated contractions evoked by a half-maximal frequency of EFS by approximately 92%, whereas contractions elicited by a half-maximal concentration of acetylcholine were not affected. Contractile responses elicited by a lower concentration of acetylcholine were inhibited by approximately 50% by substance P. The inhibitory effect of substance P was blocked by RP-67580, meclofenamate, and epithelial denudation. We conclude that the sensory nerve inhibitory system modulates cholinergic contractions and thus plays a role in the regulation of airway smooth muscle tone.
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PMID:Antagonism of cholinergic nerve-mediated contractions by the sensory nerve inhibitory system in rat bronchi. 882 73

The purpose of the present study was to examine the mechanism of the stimulatory effect of substance P (SP) on cyclic AMP (cAMP) accumulation in dog iris sphincter. We found that: (1) SP increased cAMP accumulation in a time- and concentration-dependent manner, the T1/2 and EC50 values being 1.2 min and 44 nM, respectively. SP has no effect on inositol trisphosphate and muscle contraction in this tissue. (2) SP-stimulated cAMP formation was inhibited by quinacrine, a non-specific phospholipase A2 inhibitor (IC50 = 9.5 microM), and by indomethacin (Indo), a cyclooxygenase inhibitor (IC50 = 3.5 nM), in a concentration-dependent manner, suggesting that SP induces cAMP accumulation via an Indo-sensitive pathway. (3) SP-induced arachidonic acid release and SP-induced prostaglandin E2 (PGE2) release were inhibited concentration dependently by quinacrine and Indo, with IC50 values of 11 microM and 0.8 nM, respectively. (4) PGE2 (1 microM) increased cAMP formation in the sphincter muscle by 94%, and, furthermore, the PG, but not SP, stimulated the activity of adenylyl cyclase in membrane fractions isolated from this tissue. (5) Indo (1 microM) blocked the relaxing effect of SP (1 microM) in iris sphincter precontracted with carbachol (1 microM). (6) The inhibitory effect of Indo on SP-induced cAMP accumulation was species specific. Increases in cAMP represent a mechanism by which extracellular SP can regulate smooth muscle function. Thus, we conclude from these studies that in dog iris sphincter SP-induced cAMP accumulation is mediated through PGs, and that in this cholinergically innervated muscle SP via cAMP could function, in part, to modulate the physiological responses to muscarinic receptor stimulation.
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PMID:Mediation by prostaglandins of the stimulatory effect of substance P on cyclic AMP production in dog iris sphincter smooth muscle. 893 34

Experiments were performed in the longitudinal muscle strip of the guinea pig ileum to characterize the receptors involved in the contractile response of this preparation to neurokinins. Antagonists for the NK-1 (CP 96345, CP 99994) and NK-2 (SR 48968) receptors, atropine for NK-3 receptors, as well as diphenhydramine (histamine H1 receptor antagonist) and indometacin (cyclooxygenase inhibitor) were used to determine the relative contribution of neurokinin receptors and some endogenous agents to the myotropic effects of substance P (SP) and neurokinin receptor selective agonists. The present findings indicate that the three neurokinin receptor types take part in the contractile activities of SP-related peptides. NK-1 receptors, probably localized in the smooth muscle, are inhibited only by the two CP compounds and not by atropine or the other agents. NK-2 receptors contribute to the contraction by 5-10% and are blocked by SR 48968. NK-3 receptors act indirectly through the release of acetylcholine from the myenteric plexus, since activities of [MePhe7]NKB and senktide are blocked by atropine. Septide behaves as a selective NK-1 receptor agonist and does not show any difference with SP, except for higher sensitivity to CP antagonists. The same is observed with Ac[Arg6,Sar9,Met(O2)11]SP(6-11), another NK-1-selective fragment. Discrepancies between antagonist pA2 values obtained against undeca- and hexapeptide agonists are interpreted as due to a stronger binding affinity of undecapeptide agonists as compared with the hexapeptides. Results of binding assays confirm data from the literature by showing that undecapeptide agonists have higher affinities than hexapeptides, particularly septide,, and such discrepancies (with the biological assays) can also be explained by the reduction or absence of the cationic charge at the N terminal of septide.
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PMID:Neurokinin receptors in the guinea pig ileum. 896 1

Antinociception by nonsteroidal antiinflammatory drugs, notably diclofenac and S(+)-ibuprofen, has traditionally been attributed to peripheral tissue cyclooxygenase inhibition. This study investigates the potential role of the nitric oxide system for the central antinociceptive effects of diclofenac, S(+)-, and R(-)-ibuprofen. Diclofenac and S(+)- but not R(-)-ibuprofen inhibited the behavioral response dose dependently, "biting, scratching, and licking (BSL)," induced by the spinal application of N-methyl-D-aspartate, but not that of amino-methylisoxazole-propionic acid or substance P. Diclofenac and S(+)-ibuprofen induced a parallel shift in the number of BSL responses and in the duration of the response in the behavioral model at their approximate median effective doses (diclofenac 1 mumol and S(+)-ibuprofen 5 mumol). Pretreatment with L-arginine, the natural substrate for the nitric oxide synthetase, antagonized diclofenac, and S(+)-ibuprofen-induced suppression of the biting, scratching, and licking response evoked by intrathecal N-methyl-D-aspartate. D-arginine did not antagonize the diclofenac- and S(+)-ibuprofen-induced antinociception. The study results indicate that analgesia after diclofenac and S(+)-ibuprofen involves a central mechanism which may add to the peripheral antinociceptive effect of these agents. The central action of diclofenac and S(+)-ibuprofen is partly mediated by an interaction with the N-methyl-D-aspartate receptor and nitric oxide-generating mechanisms.
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PMID:Nonsteroidal antiinflammatory drug modulation of behavioral responses to intrathecal N-methyl-D-aspartate, but not to substance P and amino-methyl-isoxazole-propionic acid in the rat. 901 80

The pathogenesis of filariasis has generally been attributed to either physical presence of the adult parasites or the host's immune response to the parasites. However, the spectrum of filariasis cannot be entirely explained by these causes, and other mechanisms must be operative. It is now evident that factors released by filarial parasites likely contribute to the pathogenesis of filarial diseases. Adult heartworms (Dirofilaria immitis) reside in the right heart and pulmonary artery, so the pulmonary artery should be exposed to the highest concentration of filarial factors. We tested the hypothesis that endothelium-dependent relaxation is altered in the in vitro pulmonary artery from heartworm-infected dogs. Relaxation responses to endothelium-dependent vasodilators (methacholine, bradykinin, substance P, and A-23187) and the nonendothelium-dependent vasodilator nitroglycerin and contractile responses were measured in rings of pulmonary artery from control and heartworm-infected dogs. Endothelium-dependent relaxation was assessed in the presence and absence of inhibitors of nitric oxide synthase, cyclooxygenase, and guanylate cyclase. Responses to methacholine, substance P, and A-23187, but not to bradykinin, nitroglycerin, norepinephrine, or KCl, were depressed in pulmonary artery from heartworm-infected dogs when compared with control, suggesting that changes in endothelial cell and not vascular smooth muscle behavior are involved in altered relaxation. The mechanism of endothelium-dependent relaxation in control pulmonary artery appears to involve nitric oxide in the case of methacholine and both nitric oxide and a cyclooxygenase product in the case of bradykinin and A-23187. The mechanism of endothelium-dependent relaxation in pulmonary artery from heartworm-infected dogs was not clearly elucidated. These data provide no evidence that heartworm infection globally influences either endothelial cell receptor function or the vascular smooth muscle guanylate cyclase guanosine 3',5'-cyclic monophosphate system, making it likely that changes in intracellular signaling are primarily responsible for the observed alteration of endothelium-mediated relaxation. Alteration of endothelial cell function by filarial parasites may be an important component in the pathology associated with filariasis.
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PMID:Dirofilaria immitis: heartworm infection alters pulmonary artery endothelial cell behavior. 904 15

Sensory C-fibers have been implicated in the control of vascular tone and are believed to be predominantly arteriolar in the microvasculature. There have been no direct investigations into the effects of C-fiber activation in venous microvessels. Therefore, we have investigated the effects of neuropeptides and activation of sensory C-fibers in rat small mesenteric veins. Small second- or third-order veins were dissected from the rat mesentery and mounted in a tension myograph for measurement of reactivity. Neither substance P or calcitonin gene-related peptide (CGRP) relaxed precontracted veins. However, substance P caused a concentration-dependent contraction. The curve was shifted to the right in a concentration-dependent manner by the tachykinin neurokinin1 receptor antagonist RP 67,580 (0.1-1 microM). To activate sensory C-fibers, capsaicin was applied. Capsaicin had no contractile activity in these vessels but caused concentration-dependent relaxation. This response was significantly attenuated in veins taken from animals in which C-fibers had been largely destroyed (P < .001, n = 5) and in vessels that had been pretreated with the vanilloid receptor blocker ruthenium red (P < .01, n = 5). Endothelial denudation (n = 6) also abolished the response, but the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (100 microM, n = 5) did not inhibit the response; N(omega)-nitro-L-arginine methyl ester (100-300 microM, n = 4) did inhibit the response. The guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one also significantly attenuated the response (n = 5). The cyclooxygenase inhibitor indomethacin (5 microM, n = 5) and the CGRP receptor antagonist CGRP(8-37) (1 microM) were without effect. These results demonstrate that capsaicin, a selective C-fiber activator, relaxes small veins in an endothelium-dependent but CGRP- and substance P-independent manner, and they demonstrate that the venous side of the microcirculation responds directly to sensory stimulation.
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PMID:Evidence for functional responses to sensory nerve stimulation of rat small mesenteric veins. 910 74

The present investigation examined the correlation between the regulation of mucosal prostaglandin (PG) biosynthesis and the release of the neuropeptide substance P (SP) in rat stomachs by indomethacin, a cyclooxygenase inhibitor. When given subcutaneously at the dose of 5 mg/kg, indomethacin reduced mucosal biosynthesis of PGE2 and concurrently lowered mucosal SP level. The inter-relationship between mucosal generation of PG and SP was further demonstrated by using [D-Pro2, D-Trp7,9]-SP, which also inhibited PGE2 production besides its suppression on SP release. Co-administration of either arachidonic acid, the PGE2 precursor, or SP reversed the inhibitory actions of indomethacin and [D-Pro2, D-Trp7,9]-SP, respectively, on mucosal levels of PGE2 and SP. Our findings suggest that indomethacin, aside from its depletion of endogenous PG, also exerts a secondary action in regulating the release of SP, which is mediated indirectly through PG in the gastric mucosa. These actions may play a role in the modulation of gastric mucosal integrity.
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PMID:Co-regulation of mucosal prostanoids and substance P by indomethacin in rat stomachs. 912 30

In this work, we have studied the effects and the possible cellular mechanism of Substance P (SP) on corticosteroid secretion by the adrenal gland of the urodele crested newt, Triturus carnifex. Adrenals were in vitro superfused with SP, prostaglandin E2 (PGE2), nitric oxide (NO) donor, cyclic GMP (cGMP) analogue, and inhibitors of phospholipase A1, phospholipase A2 (PLA2), phospholipase C, adenylate cyclase (AC), cyclooxygenase (COX), NO synthase (NOS), and soluble guanylate cyclase (sGC). PGE2, corticosterone, and aldosterone release and NOS activity were determined. SP, PGE2, NO donor, and cGMP analogue increased corticosterone and aldosterone; SP and PGE2 increased NOS, and SP increased PGE2. PLA2, AC, COX, NOS, and sGC inhibitors counteracted SP and PGE2 effects, except for PLA2, which did not affect PGE2. These results suggest that SP exhibits a stimulatory role on the corticosteroidogenesis of T. carnifex adrenal gland. In particular SP enhances PLA2 activity, increasing PGE2; this prostaglandin affects AC, which, in turn, enhances NO, and the latter therefore affects sGC, with the consequent corticosteroidogenesis increase.
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PMID:Cellular mechanism of substance P in the regulation of corticosteroid secretion by newt adrenal gland. 914 46


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