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Query: UNIPROT:P20366 (substance P)
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1. Exogenous tachykinins modulate cholinergic neurotransmission in rabbit and guinea-pig airways. We have investigated the effect of selective tachykinin receptor agonists and antagonists on cholinergic neurotransmission evoked by electrical field stimulation (EFS) of bronchial rings in rabbit, guinea-pig and human airways in vitro to assess which type of tachykinin receptor is mediating this facilitatory effect. 2. Bronchial rings were set up for isometric tension recording. Contractile responses to EFS (60 V, 0.4 ms, 2 Hz for 10 s every min) and exogenous acetylcholine (ACh) were obtained and the effects of selective tachykinin agonists and antagonists were investigated. 3. In rabbit bronchi the endogenous tachykinins, substance P (SP) and neurokinin A (NKA) (10 nM) potentiated cholinergic responses to EFS (by 287.6 +/- 121%, P < 0.01 and 181.4 +/- 56.5%, P < 0.001 respectively). 4. The NK1 receptor selective agonist, [Sar9]SP sulphone (10 nM) evoked a maximal facilitatory action on cholinergic responses of 334.9 +/- 63% (P < 0.01) (pD2 = 8.5 +/- 0.06) an effect which was blocked by the selective NK1-receptor antagonist, CP 96,345 (100 nM) (P < 0.05) but not by the NK2 receptor antagonist, MEN 10,376 (100 nM). The NK2 receptor selective agonist, [beta Ala8]NKA(4-10) (10 nM), produced a maximum enhancement of 278 +/- 83.5% (P < 0.01) (pD2 = 8.7 +/- 0.1) an effect which was blocked by MEN 10,376 (100 nM) (P < 0.05) and not by CP 96,345. [MePhe7]NKB, an NK3 receptor selective agonist was without effect. 5. The rank order of potency of NK2 receptor antagonists against enhancement of cholinergic responses by [Beta Ala8]NKA(4-10) was MEN 10,376> L 659,877> R 396. This pattern together with the observation of the full agonist activity of MDL 28,564 indicates that the NK2 receptors in the rabbit bronchus are similar to those which are present in the rabbit pulmonary artery.6. Neither [Sar9]SP sulphone (5 nM) nor [Beta Ala8]NKA(4- 10) (1 nM) had any effect on contractile responses to ACh (10 MicroM) suggesting a pre-junctional mechanism of action.7. By contrast, in guinea-pig bronchi only the NK1-receptor agonist [Sar9]SP sulphone (3 nM) was effective in enhancing cholinergic neurotransmission but the effect was relatively small (maximal enhancement 25.7 +/- 5.5%, P<0.01). In human bronchial rings all the selective neurokinin agonists were without effect on cholinergic neurotransmission.8. These results suggest that tachykinins may play an important role in modulating cholinergic neurotransmission in rabbit (via NK1 and NK2 receptors) and guinea-pig airways (via NK1 receptor) but have no demonstrable effect on human airways
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PMID:Facilitatory effects of selective agonists for tachykinin receptors on cholinergic neurotransmission: evidence for species differences. 751 99

1. The aim of this study was the pharmacological characterization of tachykinin NK1 and NK2 receptors mediating contraction in the circular muscle of the guinea-pig ileum and proximal colon. The action of substance P (SP), neurokinin A (NKA) and of the synthetic agonists [Sar9]SP sulphone, [Glp6,Pro9]SP(6-11) (septide) and [beta Ala8]NKA(4-10) was investigated. The affinities of various peptide and nonpeptide antagonists for the NK1 and NK2 receptor was estimated by use of receptor selective agonists. 2. The natural agonists, SP and NKA, produced concentration-dependent contraction in both preparations. EC50 values were 100 pM and 5 nM for SP, 1.2 nM and 19 nM for NKA in the ileum and colon, respectively. The action of SP and NKA was not significantly modified by peptidase inhibitors (bestatin, captopril and thiorphan, 1 microM each). 3. Synthetic NK1 and NK2 receptor agonists produced concentration-dependent contraction of the circular muscle of the ileum and proximal colon. EC50 values were 83 pM, 36 pM and 10 nM in the ileum, 8 nM, 0.7 nM and 12 nM in the colon for [Sar9]SP sulphone, septide and [beta Ala8]NKA-(4-10), respectively. The pseudopeptide derivative of NKA(4-10), MDL 28,564 behaved as a full or near-to-full agonist in both preparations, its EC50s being 474 nM and 55 nM in the ileum and colon, respectively. 4. Nifedipine (1 microM) abolished the response to septide and [Sar9]SP sulphone in the ileum and produced a rightward shift and large depression of the response in the colon. The response to [beta Ala8]NKA(4-10) was abolished in the ileum and largely unaffected in the colon. 5. The NK1 receptor antagonists, (+/-)-CP 96,34, FK 888 and GR 82,334 competitively antagonized the response to septide and [Sar9]SP sulphone in both preparations without affecting that to [beta Ala8]NKA(4-10). In general, the NK1 receptor antagonists were significantly more potent toward septide than [Sar9]SP sulphone in both preparations. 6. The NK2 receptor antagonists, GR 94,800 and SR 48,968 selectively antagonized the response to [beta Ala8]NKA(4-10) without affecting that to [Sar9]SP sulphone or septide in the ileum and colon. SR 48,968 produced noncompetitive antagonism of the response to the NK2 receptor agonist in the ileum and competitive antagonism in the colon. 7. MEN 10,376 and the cyclic pseudopeptide MEN 10,573 antagonized in a competitive manner the response to [beta Ala8]NKA(4-10) in the ileum and colon. While MEN 10,573 was equipotent in both preparations, MEN 10,376 was significantly more potent in the colon than in the ileum. MEN 10,376was also effective against septide in both preparations, without affecting the response to [Sar9] SP sulphone. MEN 10,573 antagonized the response to [Sar9]SP sulphone and septide in both preparations,pKB values against septide being intermediate, and significantly different from, those measured against[Beta Ala 8]NKA(4-10) and [Sa9]lSP sulphone.8. These findings show that tachykinin NK1 and NK2 receptors mediate contraction of the circular muscle of the guinea-pig ileum and colon. In both preparations NK1 receptor antagonists display higher apparent affinity when tested against septide than [Sar9]SP sulphone. These findings are compatible with the proposed existence of NK1 receptor subtypes in guinea-pig, although alternative explanations (e.g.agonist binding to different epitopes of the same receptor protein) cannot be excluded at present.Furthermore, an intraspecies heterogeneity of the NK2 receptor in the circular muscle of the guinea-pig ileum and colon is suggested.
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PMID:Comparison of tachykinin NK1 and NK2 receptors in the circular muscle of the guinea-pig ileum and proximal colon. 751 2

NK-1 and NK-2 tachykinin receptors in guinea pig airways appear to have some unusual characteristics. The analog [pGlu6,Pro9] SP(6-11) (septide) may also act on atypical NK-1 receptors in guinea pig ileum. In this study, we used new tachykinin antagonists to investigate further the receptors in the guinea pig bronchus. In the presence of 1 microM indomethacin and phosphoramidon, the selective agonists [Sar9,Met(O2)11]-SP and [Pro9]-SP (both NK-1), [Lys5,MeLeu9,Nle10]-NKA(4-10) (NK-2) and septide were full agonists, with pD2 values of 8.00, 7.78, 9.11 and 8.52, respectively on epithelium-intact preparations. Contractions to septide were unaffected by atropine (5 microM) and tetrodotoxin (1 microM). Denudation of epithelium significantly enhanced the potency of [Sar9,Met(O2)11]-SP and [Pro9]-SP but not of septide and [Lys5,MeLeu9,Nle10]-NKA(4-10). The potency order for NK-2-selective antagonists against [Lys5,MeLeu9,Nle10]-NKA(4-10) was GR 94800 > SR 48968 MDL 29913 > MEN 10207 (pA2 values 8.97, 8.73, 7.11 and 6.49, respectively). The NK-1 selective antagonists, OP 96345, GR 82334 and RP 67580 were weak or ineffective against [Sar9,Met(O2)11]-SP and [Pro9]-SP (pA2 6.69 or less), whereas they were more than one order of magnitude more potent against septide (pA2, 7.78, 7.48 and 6.58, respectively). In epithelium-denuded bronchi, the antagonist potency of GR 82334 was unchanged. These data indicate that septide interacts with tachykinin receptors in guinea pig bronchial smooth muscle in a manner different from that of [Sar9,Met(O2)11]-SP and [Pro9]-SP, and provide some evidence for heterogeneity of NK-1 receptors in the guinea pig airways.
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PMID:Use of selective antagonists for further characterization of tachykinin NK-2, NK-1 and possible "septide-selective" receptors in guinea pig bronchus. 752 58

The purpose of this study was to determine the effects of tachykinins on prostanoid production by the dog ileum and to characterize the tachykinin receptor(s) responsible for the principal eicosanoid shown to be released, 6-keto-PGF1 alpha. Substance P, the selective NK1 receptor agonist [Sar9,Met(O2)11]substance P and neurokinin A caused concentration-dependent production of 6-keto-PGF1 alpha; neurokinin A was least potent. The selective NK2 agonist [Nle10]neurokinin A(4-10) had no effect. The selective NK1 antagonist CP-96,345 (10(-7) M), blocked 6-keto-PGF1 alpha release from substance P (10(-7) M), [Sar9,Met(O2)11]substance P (10(-7) M) and neurokinin A (10(-7) M). Although the putative NK2 antagonist MEN 10207 (10(-7) M) partially blocked the 6-keto-PGF1 alpha release induced by neurokinin A (10(-7) M), we conclude that all these peptides acted primarily on NK1 receptors to induce 6-keto-PGF1 alpha. Additional experiments suggest that a major site of production of 6-keto-PGF1 alpha in the canine ileum may be the vasculature, but these experiments do not exclude other sources such as intestinal muscle for this prostanoid. Calcium-free Krebs' solution partially reduced the release of 6-keto-PGF1 alpha to substance P (10(-7) M), implying that extracellular calcium helps support tachykinin-induced production of 6-keto-PGF1 alpha. Blockade of synthesis of another vasoactive mediator, endothelium-derived relaxing factor (nitric oxide), by N omega-L-arginine methyl ester) did not alter substance P-induced release of 6-keto-PGF1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:NK1 receptors mediated release of 6-keto-PGF1 alpha from the ex vivo perfused canine ileum. 752 25

The present study examined the role of substance P (SP) as a sensory neurotransmitter in cardiovascular responses to bradykinin applied on the gallbladder. Experiments were performed in anesthetized cats in which sympathetic chains were transected at the T5-T6 level, and the tip of the intrathecal catheter was positioned at T6-T7 to limit the injectate between T6 and L2. Bradykinin (10 micrograms/ml) was applied onto the gallbladder before and after intrathecal injection of [D-Pro2,D-Phe7,D-Trp9]SP (100-200 micrograms, NK1/NK2-receptor antagonist), CP-99,994 (50-100 micrograms, selective NK1 antagonist), MEN-10,376 (100-500 micrograms, selective NK2 antagonist), or vehicle. Intrathecal injection of NK1 but not NK2 antagonist significantly reduced increases in mean arterial pressure, heart rate, and maximal rate of left ventricular pressure change by 28 +/- 2 mmHg (33 +/- 4%), 4 +/- 1 beats/min (42 +/- 5%), and 497 +/- 46 mmHg/s (36 +/- 4%), respectively. Intrathecal injection of NK1 or NK1/NK2 antagonist had no effect on cardiovascular responses evoked by electrical stimulation in the rostral ventral lateral medulla. These data suggest that endogenous SP, acting as a sensory neurotransmitter, is involved in the excitatory cardiovascular reflex caused by chemical stimulation of the gallbladder through its action on NK1 receptors in the spinal cord.
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PMID:Role of spinal NK1 receptors in cardiovascular responses to chemical stimulation of the gallbladder. 753 72

1. The receptors involved in mammalian tachykinin-induced contractions of longitudinal smooth muscle strips of the rat gastric fundus were characterized pharmacologically. 2. Substance P (SP), neurokinin A, neurokinin B and senktide contracted the strips in a concentration-dependent manner with a potency order of neurokinin A > or = senktide > neurokinin B > substance P. The contractions were not influenced by tetrodotoxin and atropine. 3. L 659877, a NK2B-receptor-preferring antagonist reduced neurokinin A- and neurokinin B-induced contractions (estimated pKB 6.9 and 6.3, respectively) but had less pronounced effects on SP-induced contractions and none on contractions induced by senktide. MEN 10376, an NK2A-receptor-preferring antagonist, reduced the neurokinin A-induced contractions (estimated pKB 5.2), while dactinomycin, reduced the neurokinin A-induced contractions only to a minor extent at 10(-4) M. 4. CP 96345, an NK 1-receptor antagonist, reduced substance P- and neurokinin A-induced responses, but also reduced the contractions induced by KCl and methacholine. RP 67580, another non-peptide NK1-receptor antagonist had no effect on the substance P-, neurokinin A- and neurokinin B-induced contractions up to a concentration of 3 x 10(-6) M. 5. These results suggest that the mammalian tachykinins induce contractions of the longitudinal smooth muscle strip of the rat gastric fundus by direct action at muscular NK2B- and NK3-receptors.
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PMID:Tachykinin receptors involved in the contractile effect of the natural tachykinins in the rat gastric fundus. 753 68

When instilled intravesically in normal, unanesthetized rats, neurokinin A (NKA), but not substance P (SP) and neurokinin B (NKB), stimulated micturition. The effect of NKA was inhibited by the NK2 receptor selective antagonists SR 48,968 and MEN 10,627, but not by the NK1 receptor selective antagonist RP 67,580, suggesting that the effect was mediated by stimulation of NK2 receptors. Given intra-arterially near the bladder, NKA produced an increase in basal intravesical pressure before initiating micturition, indicating that the tachykinin had a direct contractant effect on the detrusor smooth muscle. Such a contractile effect was not observed when NKA was given intravesically. The effect of intra-arterial NKA could not be blocked by the NK1 receptor selective antagonist SR 140,333 or the NK2 receptor selective antagonist SR 48,968, but by their combination. Also intra-arterial NKB stimulated micturition, but was less potent than NKA. Intra-arterial SP had only weak stimulating effects. The results suggest that intravesically administered NKA can initiate micturition in the normal rat by stimulation of superficially located NK2 receptors in the urothelium. Intra-arterially administered NKA caused bladder hyperactivity via stimulation of both NK1 and NK2 receptors.
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PMID:Tachykinin effects on bladder activity in conscious normal rats. 753 64

1. In the presence of atropine (1 microM), guanethidine (3 microM), indomethacin (3 microM), apamin (0.1 microM) and L-nitroarginine (L-NOARG, 30 microM), electrical field simulation (EFS) produced a nonadrenergic, noncholinergic (NANC) excitatory junctional potential (e.j.p.), action potentials and contraction of the circular muscle of the guinea-pig proximal duodenum, recorded by the single sucrose gap technique. 2. The selective tachykinin (TK) NK1 receptor antagonist, GR 82,334 (30 nM-3 microM) produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. and contraction. Similarly, the selective NK2 receptor antagonists, MEN 10,627 (30 nM-3 microM) and GR 94,800 (100 nM-10 microM), both produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. and contraction. GR 82,334 inhibited the electrical and mechanical NANC responses to EFS in an almost parallel manner, while MEN 10,627 and GR 94,800 were more effective in inhibiting the mechanical than the electrical response to EFS. 3. Activation of the NK1 or NK2 receptor by the selective agonists, [Sar9]substance P (SP) sulphone and [beta Ala8]neurokinin A (NKA) (4-10), respectively (0.3 microM each), produced depolarization, action potentials and contractions. GR 82,334 selectively inhibited the responses to [Sar9]SP sulphone, without affecting the responses to [beta Ala8]NKA (4-10). MEN 10,627 and GR 94,800 inhibited or abolished the responses to [beta Ala8]NKA (4-10), without affecting the responses to [Sar9]SP sulphone. 4. Nifedipine (1 microM) abolished the action potentials and contraction produced either by EFS or by the TK receptor agonists [Sar9]SP sulphone or [beta Ala8]NKA (4-10). 5. In the presence of nifedipine, the NANC e.j.p. produced by EFS was biphasic: in the majority of strips tested (21 out of 29) an early fast phase of depolarization was followed by a second slow component. The combined administration of GR 82,334 and GR 94,800 (3 microM each) reduced both components, the slow phase being inhibited to a greater extent than the fast phase. 6. The P2 purinoreceptor antagonist, suramin (100 microM) reduced the fast phase of the e.j.p. produced by EFS in the presence of nifedipine, without affecting the slow phase. The combined administration of suramin, GR 82,334 and GR 94,800 produced a nearly complete blockade of the e.j.p. produced by EFS in the presence of nifedipine. 7. When tested in the absence of apamin and L-NOARG, EFS induced a NANC inhibitory junction potential (i.j.p.) followed by an e.j.p., and the selective P2Y receptor agonist, adenosine-5'-O-(2-thiodiphosphate) (ADP beta S, 10 microM), produced membrane hyperpolarization. After addition of apamin and L-NOARG, the ij.p. was blocked, and EFS produced a pure NANC e.j.p.; ADPPS produced depolarization, action potentials and contraction.8. Suramin (100 microM) blocked the depolarization, action potentials and contractions produced by ADP beta S in the presence of apamin and L-NOARG, without affecting the responses produced by the NK1receptor agonist, [Sar9}SP sulphone.9. We conclude that NK1 and NK2 receptors cooperate in producing NANC excitation and contraction of the circular muscle in the guinea-pig proximal duodenum. Activation of either TK receptor produces membrane depolarization and both receptors contribute to generate action potentials which are essential for producing muscle contraction, via nifedipine-sensitive calcium channels. It appears that endogenous ATP chiefly acts as an inhibitory transmitter but, after blockade of NANC inhibitory mechanism(s),ATP may act as a fast signalling excitatory transmitter.
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PMID:Evidence that tachykinin NK1 and NK2 receptors mediate non-adrenergic non-cholinergic excitation and contraction in the circular muscle of guinea-pig duodenum. 754 17

1. We have investigated the effect of calcitonin gene-related peptide (CGRP) on non-adrenergic, non-cholinergic (NANC) excitatory transmission to the longitudinal muscle of the guinea-pig proximal colon. 2. In the presence of atropine (0.3 microM), guanethidine (5 microM), hexamethonium (100 microM) and indomethacin (3 microM), electrical field stimulation (EFS, 1 Hz, 0.3 ms for 10 s) produced tetrodotoxin-(300 nM)-sensitive contractions which were reduced by the combined administration of FK 888 (10 microM) and MEN 10,376 (0.3 microM), to block tachykinin NK1 and NK2 receptors, respectively. Thus, the EFS-induced NANC contractions are a tachykinin-mediated response. 3. CGRP, at concentrations higher than 0.1 nM, caused an increase in the electrically-evoked, NANC contractions in a concentration-dependent manner and at 10 nM produced a maximal effect (pEC50 = 9.20 +/- 0.17, n = 6). 4. 5-Hydroxytryptamine (5-HT, 1-100 nM) also caused an increase in the EFS-induced NANC contractions in a concentration-dependent manner and at 30 nM produced a maximal effect (pEC50 = 8.06 +/- 0.09, n = 4), but calcitonin (10-100 nM) failed to enhance the EFS-induced NANC responses. Moreover, a 5-HT4 receptor antagonist, DAU 6285 (3 microM) abolished the enhancing action of 5-HT (30 nM). 5. The combined administration of FK 888 (10 microM) plus MEN 10,376 (0.3 microM) abolished the enhancement of EFS-induced NANC contractions by CGRP (10 nM), but DAU 6285 (3 microM) had no effect on the enhancement. 6. Human CGRP8-37 (1 microM), a CGRP1 receptor antagonist had no effect on the submaximal enhancement of the electrically-evoked, NANC contractions by CGRP (1 nM).7. CGRP (30 nM) had no effect on contractions evoked by exogenous substance P (0.3-1 nM).8. These results indicate that in the guinea-pig proximal colon, CGRP produced an enhancement ofNANC contraction induced by EFS through prejunctional mechanisms and that the enhancement is mediated by the stimulation of non-CGRP1 receptors located on intramural tachykininergic neurones.Further, the possible contribution of 5-HT to the enhancing effect of CGRP appeared to be negligible.
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PMID:Calcitonin gene-related peptide (CGRP)-enhanced non-adrenergic non-cholinergic contraction of guinea-pig proximal colon. 758 58

The present study was undertaken to investigate neural control of mouse small intestinal longitudinal muscle. Electrical field stimulation evoked acetylcholine- and neurokinin A-mediated contractile responses, whereas nitric oxide-mediated neurotransmission resulted in relaxation. The inflammatory mediators, histamine and leukotriene D4, contracted the longitudinal muscle preparation. Histamine-evoked contractions resulted from binding to histamine H1 receptors on non-neural cells of the small intestine. Leukotriene D4 played a role in neurokinin A-mediated excitation as the leukotriene D4 receptor antagonist, WY 48,252, reduced the response to nerve stimulation under noncholinergic conditions by almost 80%. In contrast, WY 48,252 had no effect on the response to exogenous neurokinin A, indicating that the response to this neurotransmitter is not mediated by leukotriene D4 release. Subthreshold concentrations of leukotriene D4 did not modify the response to neurokinin A, ruling out a synergistic relationship between these two agonists. Leukotriene D4 did not cause synaptic transmitter release through ganglionic stimulation, because its contractile effect was tetrodotoxin insensitive, and did not contribute to noncholinergic excitation through stimulation of neurokinin A release, as the neurokinin2 receptor antagonist, MEN 10,376, did not alter the response to leukotriene D4. Instead leukotriene D4 may modulate the release of neurokinin A from nerve endings during nerve stimulation.
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PMID:Neural control of mouse small intestinal longitudinal muscle: interactions with inflammatory mediators. 761 50

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