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)

Substance P is a vasoactive peptide. Nerve fibers containing substance P are present in the media of pulmonary arteries but the physiologic function of substance P in the pulmonary vasculature is unknown. Several doses of substance P were infused intravenously in the anesthetized dog to ascertain its effects on the pulmonary vasculature, both during normoxia and following preconstriction with hypoxia (F1O2 0.1) or prostaglandin F2 alpha (PGF2 alpha 5 mug/kg/min). Substance P resulted in systemic vasodilation during normoxia but had minimal effect on the pulmonary vasculature. During hypoxia and PGF2 alpha-induced pulmonary vasoconstriction, substance P significantly lowered pulmonary artery pressure, pulmonary vascular resistance, mean aortic pressure, and total systemic resistance. It had no effect on cardiac output, wedge pressure, and arterial blood gases. To investigate possible mechanisms for substance P-induced vasodilation, substance P was studied following pretreatment with N-acetylcysteine (a radical scavenging agent), methylene blue (an inhibitor of guanylate cyclase), meclofenamate (a cyclooxygenase inhibitor), and atropine (a muscarinic receptor antagonist). None of these agents impaired substance P-induced vasodilation. Substance P given intravenously is a nonselective vasodilator in the dog but the mechanism of its action remains uncertain.
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PMID:The effects of substance P on the preconstricted pulmonary vasculature of the anesthetized dog. 242 48

Guinea pigs were inoculated by nasal insufflation with parainfluenza 3 (P-3) or virus growth medium 4 days before performing in vitro pharmacologic studies on left bronchial ring segments. Cumulative dose-response studies with capsaicin revealed an enhanced contractile response after P-3 infection. The sensitivity and magnitude of contractile effects of substance P in the left bronchi were also enhanced by P-3 infection. After pretreatment of the isolated tissues with phenoxybenzamine to block histamine H1 (with metiamide to block histamine H2), muscarinic, serotonergic, and alpha adrenergic receptors, or indomethacin to block the cyclooxygenase pathway of arachidonic acid metabolism, P-3 remained effective in enhancing contractile responses, even though these pretreatments altered the sensitivity and/or magnitude of contractions produced by substance P. When ETYA or NDGA were combined with indomethacin to also block the lipoxygenase pathway of arachidonic acid metabolism, the sensitizing effect of P-3 infection was diminished or abolished, especially at larger concentrations of substance P. With combination of FPL55712 and indomethacin, the sensitizing effect of P-3 was not abolished. Contractile responses to LTC4 and LTD4 were not enhanced by P-3 infection. The data suggest a selective influence of P-3 infection on the substance P system and provide evidence for a role of the lipoxygenase pathway of arachidonic acid metabolism in the sensitizing action. Peptide leukotrienes do not appear to be the lipoxygenase products involved in this effect of virus.
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PMID:Enhancement by parainfluenza 3 infection of contractile responses to substance P and capsaicin in airway smooth muscle from the guinea pig. 244 48

In the presence of the neutral metalloendopeptidase inhibitor, phosphoramidon, substance P (SP) is a highly potent spasmogen for isolated lung parenchymal strips as well as tracheal rings from the guinea pig. We studied the mechanism of action of this peptide, and of the related tachykinin, substance K (SK), on both tissue preparations. The cyclooxygenase inhibitors, indomethacin (1 microM) or aspirin (100 microM), in combination with phosphoramidon (1 microM) effectively block SP-induced contractions in lung parenchymal strips. The lipoxygenase inhibitor, nordihydroguaiaretic acid (10 microM), the H1 antihistamine, pyrilamine (1 microM) and the anticholinergic agent, atropine (1 microM), all had no significant effect on SP-induced contractions. No detectable levels of thromboxane B2, or prostaglandins D2, E2, F2 alpha, or 6-keto-F1 alpha were released into the tissue bathing fluid. These data suggest that the contractile response of guinea pig lung parenchymal strips is mediated by cyclooxygenase metabolites, which are not released in significant concentration from the cells. In the presence of phosphoramidon, SK has a concentration-response curve similar to SP on guinea pig lung parenchymal strips. Its contractile activity is also inhibited by indomethacin but less effectively than SP. In marked contrast, the contractile responses of guinea pig tracheal tissues to the tachykinins were not affected significantly by indomethacin, alone or in combination with phosphoramidon. Additionally, tracheal tissue is 20- to 100-fold more sensitive to SK than SP in the presence or absence, respectively, of the endopeptidase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of substance P contractile activity on isolated guinea pig lung tissues. 244 71

We examined the effects of the neuropeptide substance P on pulmonary hemodynamic and transvascular fluid filtration in isolated Ringer's-perfused and blood-enriched Ringer's-perfused guinea pig lung and on albumin flux across bovine pulmonary artery endothelial monolayer. Mean pulmonary artery, left atrial, and capillary pressures were determined and used to calculate arterial and venous resistances, and lung weight was continuously monitored. Substance P (0.01-1.0 microM) caused marked increases in pulmonary arterial pressure, capillary pressure, venous resistance, and lung weight within 3-5 minutes after administration. These responses remained elevated above baseline at the end of the 30-minute experimental period in the Ringer's-perfused lungs but not in the blood-enriched Ringer's-perfused lungs. Substance P did not alter the capillary filtration coefficient in isolated lungs and transendothelial albumin permeability in the endothelial monolayer. Substance P resulted in an increase in venous effluent thromboxane B2 concentrations in perfused lungs but had no effect on 6-keto-prostaglandin F1 alpha concentrations. Papaverine (0.27 mM) (a smooth-muscle relaxant) abolished the pulmonary microvascular response to substance P in Ringer's-perfused lungs, and meclofenamate (0.15 mM) (a cyclooxygenase inhibitor) attenuated the pulmonary vasoconstriction and lung weight increase. Pyrilamine (1.0 microM) (a histamine1-receptor antagonist) did not alter the responses to substance P. In conclusion, substance P does not affect pulmonary vascular permeability to water and protein. Substance P induces an intense pulmonary vasoconstriction (due to greater constriction of postcapillary vessels) and an elevation in pulmonary capillary pressure that increases net transvascular fluid filtration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Substance P-induced pulmonary vasoreactivity in isolated perfused guinea pig lung. 244 56

We have studied the effect of epithelium removal on the contractile responses to exogenous tachykinins and to endogenous tachykinins released by capsaicin in guinea pig trachea. We also studied the effects of inhibition of endopeptidase (by phosphoramidon, 10 microM, and thiorphan, 100 microM), and of inhibition of cyclooxygenase (by indomethacin, 5 microM) on these responses. The order of potency of exogenous tachykinins was neurokinin A (NKA) greater than neurokinin B (NKB) greater than substance P (SP). Epithelium removal enhanced the sensitivity and magnitude of the contractile response to SP, and to a lesser extent NKA and NKB. Capsaicin induced only a weak contractile response in guinea pig trachea. Phosphoramidon and thiorphan increased the sensitivity to SP, but had no effect on acetylcholine responses. The leftwardshift due to epithelium removal was reduced, but not abolished, by phosphoramidon and thiorphan. NKA- and NKB-induced contractions were also enhanced significantly by phosphoramidon. The effect of epithelium removal was abolished for NKA, but not for NKB. Phosphoramidon also increased significantly the contraction to capsaicin in the presence of epithelium, without altering the response obtained in the absence of epithelium. Indomethacin potentiated the sensitivity and maximal contractile response to all the tachykinins with the greatest effect on SP responses, and to capsaicin. The combination of indomethacin with phosphoramidon or thiorphan abolished the effect of epithelium removal for all the tachykinins. We conclude that the effects of exogenous and endogenous tachykinins are enhanced by removal of epithelium and by inhibition of metalloendopeptidase and cyclooxygenase, suggesting that tachykinins may be degraded by epithelial enzymes, and may release relaxant prostanoids in airways.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Influence of epithelium on guinea pig airway responses to tachykinins: role of endopeptidase and cyclooxygenase. 246 59

Neuropeptide Y (NPY) inhibits electrogenic Cl secretion in rat jejunal epithelium under voltage clamp conditions. This effect is dependent upon endogenous eicosanoid formation since it is blocked by the cyclooxygenase inhibitor, piroxicam, which itself has an inhibitory action upon chloride secretion. A number of chloride secretagogues have been examined for their ability to restore the antisecretory effects of NPY. Data presented here shows that NPY responsiveness is restored, in piroxicam pretreated tissues, by vasoactive intestinal polypeptide (VIP), forskolin, prostaglandin E2 (PGE2) isobutyl-1-methyl-xanthine (IBMX) and dibutyryl cAMP added prior to the neuropeptide. While all these agents cause chloride secretion by elevating intracellular cAMP, NPY is also effective in inhibiting the secretory effects of carbachol (CCh) and substance P (SP), agents believed to act by raising intracellular calcium (Cai). Although there is evidence that NPY can inhibit adenylate cyclase, its ability to attenuate chloride secretion brought about by secretagogues acting through both adenylate cyclase and calcium mechanisms, implies that NPY has either a more general fundamental mechanism or has multiple interactions with different second messenger systems.
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PMID:Neuropeptide Y antagonises secretagogue evoked chloride transport in rat jejunal epithelium. 246 61

We performed three consecutive dose-response curves to rapid intravenous infusions of substance P (SP) in anesthetized, mechanically ventilated guinea pigs. The dose of SP required to decrease pulmonary conductance to 50% of its base-line value (ED50GL) decreased 2.8-fold (P less than 0.002) and 3.3-fold (P less than 0.001) on the second and third dose-response curves, respectively, compared with the first. SP did not alter airway responses to intravenous histamine but did cause a significant (3.7-fold) decrease in ED50GL for dose-response curves to intravenous capsaicin, an agent that causes bronchoconstriction by release of endogenous tachykinins. The neutral metalloendopeptidase inhibitor thiorphan (0.5 mg) and the angiotensin-converting enzyme inhibitor captopril (1.7 mg) both caused a marked enhancement of airway responses to SP observed on the first dose-response curve but did not alter the enhancement of SP-induced airway responses produced by repeated SP challenge. The anticholinergic atropine (5 mg/kg iv), the antihistamine mepyramine (8 mg/kg iv), and the cyclooxygenase inhibitor indomethacin (30 mg/kg ip) had no effect on the first SP dose-response curve. Atropine and mepyramine did not prevent the enhancement of SP responses observed with repeated challenge, but after pretreatment with either indomethacin or acetylsalicylic acid, dose-response curves to SP were reproducible. Our results indicate that airway responses to intravenous SP are enhanced with repeated SP challenge and suggest that cyclooxygenase products of arachidonic acid metabolism are involved in the mediation of this phenomenon.
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PMID:Enhanced airway responses to substance P after repeated challenge in guinea pigs. 246 38

Xylazine, an alpha 2 adrenoceptor agonist, reduces short circuit current (SCC) in epithelial preparations of rat jejunum. The alpha 2 antagonist yohimbine, abolished this response while prazosin was without effect. The cyclooxygenase inhibitor, piroxicam, also attenuated xylazine responses indicating that the antisecretory effects were dependent upon endogenous eicosanoid formation. If the secretory state of piroxicam treated tissues was restored by addition of either forskolin, vasoactive intestinal polypeptide (VIP), prostaglandin E2 (PGE2) or isobutyl-1-methyl-xanthine (IBMX) then subsequent additions of xylazine were effective in reducing SCC. All these agents are known to increase SCC and cause Cl secretion by elevating intracellular cAMP. In addition, xylazine was also able to inhibit the Ca2+-mediated secretory responses of carbachol (CCh) and substance P (SP) in rat jejunum. This ability of xylazine to inhibit cAMP- and Ca2+-mediated secretion may indicate that alpha 2 adrenoceptors interact with more than one type of G protein or alternatively suggests a more general interaction between second messenger systems within epithelia of the small intestine.
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PMID:Antisecretory activity of the alpha 2-adrenoceptor agonist, xylazine in rat jejunal epithelium. 247 90

The effects on plasma extravasation of three increasing doses from 6.5 pmol to 650 nmol/kg of substance P (SP), SP fragments, neurokinin A (NKA), neurokinin B (NKB) and selective agonists for neurokinin receptors were assessed in three cutaneous tissues (skin of hind paws, dorsal skin and ears) by intravenous (i.v.) administration in the pentobarbitone anaesthetized rat. Dose-dependent increases in plasma extravasation were observed with the following rank orders of potency (SP greater than NKA greater than NKB) for neurokinins and (SP greater than [p-Glu6]SP(6-11) greater than SP(4-11) greater than [p-Glu5]SP(5-11) greater than SP(7-11] for C-terminal SP fragments. The metabolically stable SP analogue [p-Glu5, MePhe8, Sar9]SP(5-11) was slightly more potent than [p-Glu5]SP(5-11). The N-terminal fragments SP(1-4), SP(1-7) and SP(1-9) were inactive up to 650 nmol/kg. The NK-1 receptor selective agonists [Sar9, Met(O2)11]SP and [beta-Ala4, Sar9, Met (O2)11]SP(4-11) were more potent than the NK-2 [( Nle10]NKA(4-10] and NK-3 [( MePhe7]NKB and [beta-Asp4, MePhe7]NKB(4-10] receptor selective agonists. Plasma extravasation induced by SP (6.5 nmol/kg) was unchanged in the presence of atropine, methysergide, diphenhydramine or during the i.v. and intra-arterial (i.a.) infusion of D-Arg0[Hyp3.D-Phe7]BK, an antagonist of bradykinin. Plasma extravasation induced by SP and [Sar9, Met(O2)11]SP was significantly reduced by indomethacin while that induced by NKA, NKB, [beta-Ala4, Sar9, Met(O2)11]SP(4-11), SP(4-11) and [p-Glu6]SP(6-11) was unaffected by the cyclooxygenase inhibitor. Compound 48/80 (0.75 mg/kg), histamine (10 mg/kg) and 5-HT (10 mg/kg) caused an increase in plasma extravasation, only the effect of compound 48/80 was abolished by indomethacin. Pretreatment with compound 48/80 prevented its own action on plasma extravasation and significantly reduced that induced by 6.5 nmol/kg of SP. These results rule out the involvement of acetylcholine (muscarinic receptors), 5-HT (5-HT1 and 5-HT2 receptors), histamine (H1 receptors) and kinins (B2 receptors) in the response to SP and indicate that the two positively charged amino acids (Arg, Lys) at the N-terminal end of the SP molecule are essential to trigger the release of prostaglandins from mast cells. This mechanism is responsible for the indirect effect of SP and related peptides on capillary permeability and does not appear to be mediated by a selective SP receptor. In addition, neurokinins may increase capillary permeability by direct activation of a NK-1 receptor type on the vascular endothelium.
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PMID:Capillary permeability induced by intravenous neurokinins. Receptor characterization and mechanism of action. 247 92

The mechanism of the blood pressure (BP)-lowering effect of neurotensin (NT) in the anesthetized, ganglion-blocked guinea pigs was further examined using animals in which the basal BP was artificially raised by an IV infusion of noradrenaline (NA) to overcome the BP-lowering effect of the anesthesia as well as of the ganglion blocker. The animals were also vagotomized and given atropine at the beginning of the experiments to prevent potential baroreceptor-mediated vagal reflexes and/or activation of muscarinic receptors by endogenous acetylcholine. Under these experimental conditions, the IV bolus injections of NT as well as of capsaicin (a reference drug) produced dose-dependent hypotensive effects and variable levels of tachycardia. Omitting the ganglion blocker from the animal drug regimen attenuated but did not abolish the BP-lowering effect of NT and of capsaicin. Neither the hypotensive nor the tachycardic effects of NT and of capsaicin in ganglion-blocked guinea pigs were affected by prior animal treatment with propranolol (a beta adrenoceptor blocker), antihistaminics (mepyramine, cimetidine) or indomethacin (a cyclooxygenase inhibitor). Morphine was found to slightly reduced the hypotensive effect of NT without altering its slight tachycardic effect. Both the hypotensive and tachycardic effects of NT and of capsaicin, in contrast to those elicited by substance P (SP) and calcitonin gene-related peptide (CGRP), were inhibited in ganglion-blocked guinea pigs pretreated four days previously with capsaicin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Capsaicin-sensitive primary afferents are involved in the hypotensive effect of neurotensin in ganglion-blocked guinea pigs. 248 46


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