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 studied the effect of bradykinin on ciliary activity and its modulation by peptidases in cultured rabbit tracheal epithelium in vitro. Bradykinin (10(-7) M) elicited a rapid, transient increase in ciliary beat frequency (CBF) from the baseline values of 1,031 +/- 25 to 1,388 +/- 38 beats/min (mean +/- SE, p less than 0.001), followed by a decline to a steady-state value of 1,180 +/- 30 beats/min, which was still greater than the baseline CBF. This ciliostimulation was dose-dependently inhibited by the B2-receptor antagonist (D-Arg,Hyp3,Thi5.8,D-Phe7)-bradykinin but not by the B1-receptor antagonist (Des-Arg9,Leu8)-bradykinin. Nifedipine, Ca2+-free medium, indomethacin, the phospholipase A2 inhibitor mepacrine, and the methyltransferase inhibitor 3-deazaadenosine reduced the change in CBF. Involvement of tachykinins, leukotrienes, prostaglandin D2, or thromboxane A2 was ruled out because bradykinin's action was not affected by (D-Pro2,D-Trp7.9)-substance P, nordihydroguaiaretic acid, or SQ29548, an antagonist for prostaglandin D2 and thromboxane A2. Bradykinin also increased prostaglandin E2 release (p less than 0.01), an effect that was abolished by indomethacin and Ca2+ deficiency. The CBF dose-response curve for bradykinin was shifted to lower concentrations by 1 log U by the neutral endopeptidase inhibitor phosphoramidon (p less than 0.01), whereas the angiotensin-converting enzyme inhibitor captopril was without effect. These results suggest that bradykinin interacts with B2-type receptors and stimulates ciliary activity through Ca2+-dependent prostaglandin E2 release, and that neutral endopeptidase may play a role in modulating the effect of bradykinin on airway mucociliary transport.
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PMID:Effect of bradykinin on airway ciliary motility and its modulation by neutral endopeptidase. 276 79

The objective of this study was to elucidate the mechanisms by which bradykinin and vasoactive intestinal polypeptide (VIP) relax bovine intrapulmonary artery and bradykinin, but not VIP, relaxes intrapulmonary vein. Bradykinin and VIP elicited entirely endothelium-dependent relaxation of phenylephrine-precontracted arterial rings, and this was associated with arterial accumulation of both guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP). Bradykinin, but not VIP, relaxed precontracted venous rings and increased cGMP, but not cAMP levels, by endothelium-dependent mechanisms. Neither arteries nor veins relaxed in response to substance P, thrombin, bombesin, arginine vasopressin, or angiotensin II. Methylene blue or indomethacin each partially antagonized, whereas both, when together, abolished arterial relaxant responses to bradykinin and VIP. Methylene blue or indomethacin, respectively, abolished arterial cGMP or cAMP accumulation elicited by bradykinin and VIP. Venous relaxation and cGMP accumulation elicited by bradykinin was abolished by methylene blue but was unaltered by indomethacin. Thus bradykinin and VIP relaxed bovine intrapulmonary artery by endothelium-dependent mechanisms involving the actions of cGMP and cAMP whose formation may be stimulated by endothelium-derived relaxing factor and prostacyclin, respectively. In contrast, bradykinin relaxed intrapulmonary vein by endothelium-dependent mechanisms involving only cGMP.
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PMID:Mechanisms of endothelium-dependent vascular smooth muscle relaxation elicited by bradykinin and VIP. 282 43

The newly discovered bradykinin antagonist [Thi5,8,D-Phe7]Bradykinin, supplied by J.-M. Stewart and three other compounds, [D-Phe7]BK, [Thi5,8,D-Phe7]Bradykinin and [Thi6,9,D-Phe8]Kallidin synthesized in our laboratory, were tested for their ability to antagonize bradykinin in four B2 receptor systems, the guinea-pig ileum, the rabbit jugular vein, the dog carotid artery and the dog urinary bladder as well as against desArg9-bradykinin in the rabbit aorta (a B1 receptor system). [D-Phe7]Bradykinin is a partial agonist, while [Thi5,8,D-Phe7]Bradykinin and [Thi6,9,D-Phe8]Kallidin are pure antagonists, the second one showing little BK-like activity on three of the four preparations. The kallidin analogue is more potent in all preparations than the bradykinin one. The two [Thi5,8,D-Phe7]BK (that supplied by J.-M. Stewart and that prepared in our laboratory) show very similar affinities in all preparations. The bradykinin analogue as well as the kallidin one are also active against desArg9-bradykinin in the rabbit aorta, at concentrations similar to those active on B2 receptor systems. The kinin antagonists are however specific for the kinins, since they do not interfere with the myotropic effects of angiotensin or substance P (SP) in the various preparations.
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PMID:The actions of kinin antagonists on B1 and B2 receptor systems. 287 74

The effect of bradykinin on the neuroeffector junction of the isolated rat vas deferens was studied in tissues stimulated transmurally at a frequency of 0.15 Hz. Bradykinin caused two distinct and independent actions: it potentiated the magnitude of the muscular response to the electrically driven twitches and, in addition, contracted the smooth muscle generating an increased muscular tone. The former action is referred to as the neurogenic or presynaptic effect, whereas the latter effect is called the musculotropic or postjunctional action. The neurogenic effect was abolished by tetrodotoxin or tissue denervation either by cold storage or chemical sympathectomy after 6-hydroxydopamine administration. However, these procedures did not significantly modify the musculotropic potency of bradykinin. Both actions of the peptide are receptor-mediated, as minor structural modifications in the amino acid sequence caused significant changes in biological potency. In addition, the peptide analog, [Thi5,8-D-Phe7]-bradykinin, behaved as an agonist at the presynaptic site but as an antagonist at the muscular site. The most potent peptide analog to produce the neurogenic effect was Met-Lys-bradykinin followed by Lys-bradykinin and [Tyr8]-bradykinin. In contrast, the potency of these peptide analogs acting at the postsynaptic site was about the same. des Arg9 bradykinin and des Arg9-[Leu8]-bradykinin were inactive at the pre- and postjunctional site. The neurogenic action of bradykinin was not mimicked by angiotensin II, neurotensin, substance P or vasopressin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of pre- and postsynaptic bradykinin receptor sites in the vas deferens: evidence for different structural prerequisites. 288 2

1. The afferent innervation of the distal ileum has been examined in normal rats and in rats treated at birth with capsaicin. Electrophysiological recordings were made using an in vitro preparation of distal ileum and its associated mesenteric nerves. The fibre composition of the mesenteric nerves was examined by electron microscopy and the numbers of primary afferent fibres innervating a segment of distal ileum was estimated using retrograde tracing. 2. Recordings were made from 120 single afferent units all of which showed some degree of background activity. The conduction velocities of sixty-seven afferent units were estimated, and all were found to be in the C-fibre range (less than 2 m/s). Eighty-two units were sufficiently studied to allow their classification according to whether they responded to mechanical stimuli (M units), chemical stimuli (Ch units) or both mechanical and chemical stimuli (MCh units). In control rats 85.5% were classified as MCh units, 11.9% as M units and 2.6% as Ch units. In capsaicin-treated rats six single and three multi-units were MCh and one multi-unit was classified as an M recording. 3. The effects of intraluminal distension were investigated in sixty-seven units which were classified according to whether or not they adapted during the distension. About half the total units were classified as rapidly adapting, the other half were slowly adapting. This distribution was similar for the MCh-units, but of the eight M units tested, seven adapted during distension. The distension thresholds were tested in thirty units, of which twenty-eight responded at thresholds below 18 mmHg. There were no differences in the thresholds of units from control and capsaicin-treated rats. 4. The chemosensitivity of units was tested in response to acetylcholine (ACh), bradykinin and substance P. Most units tested responded to ACh (78% of MCh units tested) and bradykinin (80% of MCh units), but fewer units responded to substance P (about 50% of MCh units). ACh produced an increased tension which outlasted the increase in afferent activity. Bradykinin gave long-lasting afferent responses which were not always accompanied by increases in tension. The increases in afferent activity produced by substance P were often seen after an increase in tension. 5. The fluorescent dye True Blue injected into the wall of the ileum labelled cell bodies in the spinal and nodose ganglia, predominantly on the left side of an animal. The mean number of labelled cells per animal was eighty-seven, of which the majority was in the T10-T13 spinal ganglia.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:An electrophysiological and anatomical study of intestinal afferent fibres in the rat. 317 91

Neutral endopeptidase (NEP) (enkephalinase, EC 3.4.24.11) and angiotensin converting enzyme (ACE) are two peptidases that can cleave the C-terminal dipeptide bradykinin(8-9) from bradykinin. To determine whether these peptidases play roles in modulating kinin-induced contractions in the airways, we studied the effects of captopril, an ACE inhibitor, and of leucine-thiorphan and phosphoramidon, two NEP inhibitors, on the contractile responses to bradykinin and lysyl-bradykinin in isolated segments of ferret trachea. Bradykinin and lysyl-bradykinin-induced contractions in a concentration-dependent fashion (P less than .001), with a threshold of 10(-7) M and 5 x 10(-7) M, respectively. In contrast, the bradykinin(8-9) and the N-terminal heptapeptide bradykinin(1-7), the major fragments of hydrolysis of bradykinin by NEP and ACE, had a very weak or no effect on tracheal contraction in concentrations as great as 10(-5) M. Captopril, leucine-thiorphan and phosphoramidon (each inhibitor at 10(-5) M, 15 min) shifted the concentration-response curves to lower concentrations by approximately 1 to 1.5 log U (P less than .05). Both NEP inhibitors and the ACE inhibitor potentiated the response to bradykinin in a concentration-dependent fashion (P = .0001), and the combination of phosphoramidon and captopril resulted in an additive potentiation of bradykinin-induced contraction (P less than .02). [D-Pro2-D-Trp7,9]-substance P, a substance P antagonist, did not modify the potentiation of bradykinin-induced contraction by NEP inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neutral endopeptidase and angiotensin converting enzyme inhibitors potentiate kinin-induced contraction of ferret trachea. 327 79

1 The inhibition of the bradykinin-induced plasma extravasation by six bradykinin (Bk) antagonists was tested on rabbit skin. All of them showed inhibitory effects without an agonistic action in the does used. B4310 (Lys-Lys-3-Hyp-5,8-Thi-7-DPhe-Bk) was the most active antagonist and was therefore used in the subsequent experiments. 2 B4310 (5-500 nM) antagonized the bradykinin-induced reduction of the venous outflow from the rabbit isolated ear in dose-dependent manner without affecting the arterial vasoconstriction induced by angiotensin II. 3 The bradykinin-induced release of prostaglandin E2 (PGE2) from the perfused rabbit ear was reduced by 63% when B4310 (800 nM) was infused before, during and after the bradykinin injection. 4 Bradykinin was injected into the ear artery of anaesthetized rabbits and the reflex hypotensive response was used as indicator of the nociception. The response was antagonized by a local infusion of B4310 (50 and 500 nM). The antagonism was dose-dependent and reversible. The parallel shift of the dose-response curve to bradykinin suggests a competitive inhibition. However, B4310 did not antagonize acetylcholine-induced nociceptor stimulation. 5 B4310 inhibited bradykinin-induced stimulation of the trigeminal nerve which results in a substance P-mediated contraction of the iris sphincter muscle. A pA2 of 7.59 was calculated. B4310 did not inhibit capsaicin-induced contractions. 6 It is concluded that B4310 inhibits specifically five different actions of bradykinin which are related to its possible pathophysiological role.
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PMID:Effect of bradykinin antagonists on bradykinin-induced plasma extravasation, venoconstriction, prostaglandin E2 release, nociceptor stimulation and contraction of the iris sphincter muscle in the rabbit. 347 23

The bronchial arteries extend to all lung structures in man with the exception only of the alveolar wall. In addition to providing nutrition to the lungs, the bronchial vessels can also function as a hemodynamic and gas-exchange system due to anastomoses with the pulmonary arteries; they also play a significant role in controlling the clearance of chemical mediators, regulating the development of airway wall edema, and controlling heat exchange in the tracheobronchial tree. We have measured the effects of inflammatory and other mediators on tracheal mucosal thickness and the changes in tracheal vascular resistance in dogs. Bradykinin, histamine, and methacholine had large "vasodilator" effects, decreasing vascular resistance, and they also clearly increased the thickness of the mucosa. Substance P, VIP, PGF2 alpha, and PGE1 had as large a response on vascular resistance as the drugs mentioned above, but only had small effects in increasing tracheal mucosal thickness. Salbutamol fell between these 2 groups with regard to the pattern of response. Phenylephrine had an opposite action, causing an increase in vascular resistance and a decrease in mucosal thickness. Despite the vasodilatation and the increase in vascular permeability due to vasoactive drugs, the changes in mucosal thickness were rather small and could not be correlated with the decreases in vascular resistance due to the different drugs. Such changes are unlikely to have an appreciable effect on tracheal airway resistance. The change in mucosal thickness may be more significant in those parts of the airways where the ratio of change in mucosal thickness to the radius of adjacent lumen is large, such as the nose and small conducting airways.
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PMID:Effects of inflammatory and other mediators on airway vascular beds. 359 20

A method for assessing inflammatory pain response was developed by modification of the formalin test. Formalin (0.5%, 25 microliters) was injected into the hindpaw of the mouse, and the durations spent in licking or biting response were measured as an indicator of pain response. The response curve was biphasic, having two peaks, from 0 to 5 min (first phase) and from 15 to 20 min (second phase). Morphine, ethylketocyclazocine, ketocyclazocine and pentazocine inhibited the response dose-dependently at the first and the second phases. Aspirin, oxyphenbutazone and dexamethasone inhibited only the second phase. Aminopyrine and mefenamic acid which acted at both central and peripheral sites inhibited both phases; however, the inhibition of the second phase was stronger than that of the first phase. Substance P (SP) antagonist inhibited only the first phase. Bradykinin (BK) inhibitor caused a inhibition of both first and second phases, and pretreatment of compound 48/80 and indomethacin inhibited only the second phase. From these facts, it was suggested that SP and BK played a role in the pain response at the first phase, and histamine, BK and PG were involved at the second phase. Naloxone produced hyperalgesia and bestatin produced analgesia at the second phase; then, it seems that the endogenous opioid system is activated by formalin stimulation and modulates the pain perception. Based on these findings, it is presumed that the pain of the first phase is evoked by the direct stimulation of the nerve fibers, and that of the second phase is due to the inflammatory reaction.
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PMID:[Studies of inflammatory pain response: related pain producing substance and endogenous opioid system]. 372 60

Saliva of the tick, Ixodes dammini, antagonizes anaphylatoxin, abolishing both the effects of anaphylatoxin on guinea pig ileum preparations regularly stimulated with histamine and the local edema caused by intradermal injection of anaphylatoxin into guinea pigs. Saliva of these ticks, however, did not modify polymorphonuclear leukocyte aggregation induced by anaphylatoxin. Bradykinin and lysil-bradykinin were inactivated, but angiotensin I, angiotensin II, and substance P were not affected. Amino acids were released rapidly following incubation of saliva with bradykinin, but slowly from des-arg-9-bradykinin. These results suggest the presence of a salivary carboxypeptidase with specificity for terminal basic amino acids. Such activity may inactivate anaphylatoxin and bradykinin at the site of tick attachment.
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PMID:Ixodes dammini: salivary anaphylatoxin inactivating activity. 374 19


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