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)

Pharmacological studies were performed with neurokinin alpha and beta, new tachykinins isolated from porcine spinal cord, on smooth muscle preparations exhibiting two subtypes of substance P receptor (SP-P and SP-E receptors). The results showed that both neurokinin alpha and beta possessed the typical tachykinin activities and they exhibited SP-E-type ligand characteristics. The potency studies of SP6-11 and (Val8)SP6-11 have revealed that (VAL8)SP6-11 was comparable to SP6-11 in contracting the guinea-pig ileum (SP-P system), but greater than SP6-11 and also substance P in potentiating nerve stimulation-induced contraction of the rat vas deferens (SP-E system). The contractile response of the rat duodenum to neurokinin alpha was slow at onset and long-lasting compared with those to neurokinin beta and substance P. The residual immunoreactivity of each tachykinin in the organ bath decreased in parallel with the fading of the contractile response. The order of the half-life of each immunoreactive peptide was as follows: neurokinin alpha greater than neurokinin beta greater than substance P. The results were discussed from the viewpoints of structural significance in manifestation of pharmacological properties and in inactivation process, as well as the physiological roles of these novel mammalian tachykinins.
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PMID:Pharmacological characterization of novel mammalian tachykinins, neurokinin alpha and neurokinin beta. 608 51

Two novel neuropeptides, neurokinin alpha and beta isolated from porcine spinal cord, were announced. We have synthesized neurokinin alpha as Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2, which were 98-99% pure by HPLC. Assays on the isolated guinea pig ilium showed neurokinin alpha to have 81% and neurokinin beta to have 65% of the activity of Substance P. Knowledge of these three related peptides having a common activity opens new considerations of their intrinsic physiological roles in neurotransmission versus pharmacological activities, and reappraisal of the diverse activities of Substance P including that in the inflammatory response of the eye.
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PMID:Synthesis and biological activities of neurokinin alpha and beta. 632 48

Two classes of structurally different tachykinin neurokinin3 (NK3) antagonists were used to evaluate species difference in antagonist binding between human and rat NK3 receptors. In competition binding experiments with [125I-MePhe7]NKB as radioligand, PD 154740, PD 157672, SR 48968, and SR 142801 displayed lower Ki values for the human NK3 receptor (40 +/- 4, 12 +/- 1,350 +/- 50, and 0.40 +/- 0.05 nM, respectively) than for the rat NK3 receptor (2450 +/- 130, 288 +/- 25, > 10,000, and 11.0 +/- 0.5 nM, respectively). Data from in vitro functional assay showed similar species preference as observed with the competition binding assay. It was shown previously that substitution of only two amino acid residues in the rat receptor to their human counterparts could change the species selectivity of SR 48968, a weak NK3 antagonist. In the double-substituted rat mutant, all three antagonists (PD 154740, PD 157672, and SR 142801) displayed Ki values (76 +/- 8, 16 +/- 2, and 0.50 +/- 0.05 nM, respectively) very similar to the Ki values for the wild-type human NK3 receptor. Thus, in addition to their previously reported effects on SR 48968, these two amino acid residues are responsible for the species selectivity of these three additional NK3 antagonists. Because PD 154740 and PD 157672 are very different structurally from SR 48968 and SR 142801, our results indicate that the two identified residues may be involved in adopting a receptor conformation that favors the binding of NK3 antagonists that display species preference for the human NK3 receptor.
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PMID:Two classes of structurally different antagonists display similar species preference for the human tachykinin neurokinin3 receptor. 747 98

The distribution of neurokinin receptors in rat kidney, renal artery, renal vein, and proximal ureter was evaluated by autoradiography after in vitro labeling of NK1 sites with [125I]Bolton-Hunter substance P (BHSP) or NK3 sites with [125I][MePhe7]neurokinin B ([MePhe7]NKB). Film autoradiography using [125I][MePhe7]NKB revealed specific binding sites associated with the renal vein and its large branches, the renal pelvis, the inner strip of outer renal medulla, and the proximal ureter. High-resolution autoradiograms demonstrated that these sites were localized to the smooth muscle layer in the veins, pelvis, and ureter. Neither the renal arterial system nor the renal cortex contained specific [125I][MePhe7]NKB binding sites although a high level of nonspecific binding was associated with the renal artery. Specific binding of [125I]BHSP was associated with the renal artery and renal pelvis but not the renal veins. Arterial NK1 receptors appeared to be localized to the adventitia. The results indicate that at least two types of tachykinin receptor are present in the rat kidney. The distinct localization observed for most of the NK1 and NK3 receptors suggests that they have different functions.
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PMID:Autoradiographic localization of NK1 and NK3 tachykinin receptors in rat kidney. 747 2

The pharmacological effects of substance P (SP), neurokinin A (NKA), an amino terminal fragment of SP and related tachykinin receptor agonists on renal resistance vessels were assessed in isolated rat kidney perfused at constant rate (3 ml min-1 g-1 of tissue) with a modified Krebs-Ringer bicarbonate buffer. At a basal perfusion pressure (PP) of 75 +/- 6 mm Hg (n = 5), bolus injections of SP (1-33.3 nmol) had no significant vasoactive effect. After a sustained increase in base-line PP (134 +/- 10 mm Hg) produced by 1 microM phenylephrine, SP evoked a dose-dependent increase in PP. The largest dose of SP increased PP by 60 +/- 5 mm Hg. Physalaemin and kassinin had similar effects as SP but caused a smaller increase in PP at the largest dose. NKA was less potent than the other tachykinins. The vasoconstrictor response to SP was not blocked by 1 microM phentolamine when angiotensin II (0.22-0.26 microM) was used to increase basal tone (n = 5). Thus, the response to SP is not mediated by norepinephrine. The N-terminal SP fragment, SP(1-7), had no effect on PP, which suggested that the pressor response to SP is C-terminal dependent and tachykinin receptor mediated. The selective NK-1 receptor agonist, [Sar9,Met(O2)11]SP, had no significant effect on PP. By contrast, the selective NK-2 and NK-3 receptor agonists, GR64349 and [MePhe7]NKB, produced concentration-dependent pressor responses and were more potent than SP (116 +/- 8 and 134 +/- 15 mm Hg increases in PP at 33.3 nmol, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological characterization of the pressor response to tachykinins in isolated perfused rat kidney. 750 28

Intracerebroventricular (i.c.v.) injections of senktide (0.01-10 nmol), a tachykinin NK-3 agonist, had an antidiuretic action in water-loaded rats (4.5% body wt.). Pretreatment with OPC-31260 (1 mg/kg, i.v.), a non-peptide vasopressin V2 antagonist, inhibited the antidiuretic action induced by exogenous arginine vasopressin (AVP, 0.1 micrograms/kg, i.v.) and senktide (0.1 nmol, i.c.v.). In addition, senktide (11.8 nmol, i.c.v.) caused a marked increase of the plasma AVP level in conscious rats. These results suggest that the central NKB analogue senktide has an antidiuretic effect by stimulating AVP secretion from the pituitary gland through the NK-3 receptor in the hypothalamus.
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PMID:Central administration of senktide, a tachykinin NK-3 agonist, has an antidiuretic action by stimulating AVP release in water-loaded rats. 750 13

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

Using intracellular current clamp recording from motoneurones of the neonatal rat spinal cord in vitro, the action of tachykinin receptor agonists was investigated. Test drugs included the endogenously occurring neuropeptide substance P and synthetic compounds, such as substance P methylester (SPMeO), [beta Ala8]neurokinin A4-10 ([Ala]NKA), [MePhe7]neurokinin B ([MePhe]NKB) and senktide. SPMeO and [Ala]NKA were used as selective agonists at NK1 and NK2 receptors, respectively, while [MePhe]NKB or senktide were employed to activate NK3 receptors. In control solution, all compounds produced sustained depolarization with increase in input resistance although at comparable levels of membrane depolarization different patterns of motoneuronal firing were observed dependent on the type of agonist tested. In tetrodotoxin (TTX; 1 microM) solution, the depolarization caused by substance P or SPMeO largely persisted while in the majority of cells the effect of [Ala]NKA, [MePhe]NKB or senktide was blocked. It is suggested that NK1 receptors primarily mediated the actions of substance P on spinal motoneurones and that activation of NK2 or NK3 receptors, predominantly found on interneurones, induced motoneuronal depolarization with different firing patterns.
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PMID:Multiple types of tachykinin receptor mediate a slow excitation of rat spinal motoneurones in vitro. 751 26

The tachykinin receptor type that mediates tachykinin-induced plasma extravasation in the rat knee joint was identified by using selective antagonists as well as natural or synthetic agonists. Substance P (SP) and neurokinin (NK) A induced plasma extravasation with almost the same potency and the maximum response was obtained at 5 nmol/knee. NKB was about ten times less potent than SP or NKA. The NK1 selective agonist, [Sar9, Met(O2)11]-SP, was about ten times more potent than SP, and the NK2 selective agonist, [Nle10]-NKA4-10, was about fifty times less potent than NK1 agonist. The NK3 agonist, Senktide, was totally ineffective at 0.5-50 nmol/knee. All responses induced by SP (5 nmol/knee), NKA (5 nmol/knee), NKB (50 nmol/knee), NK1 agonist (0.5 nmol/knee) or NK2 agonist (25 nmol/knee) were significantly and profoundly inhibited by the NK1 selective antagonist, RP67580, but not by the NK2 selective antagonist, SR48968. Taken together, we conclude that tachykinin-induced plasma extravasation in the rat knee joint is mediated via NK1 receptors.
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PMID:NK1 receptors mediate tachykinin-induced plasma extravasation in the rat knee joint. 751 17

1. The effects of intracerebroventricular (i.c.v.) injection of selective and potent NK1 (RP 67580), NK2 (SR 48968) and NK3 (R 486, [Trp7, beta-Ala8]NKA(4-10)) receptor antagonists were assessed on the cardiovascular and behavioural responses elicited by the i.c.v. injection of substance P (SP), neurokinin A (NKA) or [MePhe7]neurokinin B ([MePhe7]NKB) in the conscious freely moving rat. 2. SP, NKA and [MePhe7]NKB (5-650 pmol) evoked dose-dependent increases in mean arterial blood pressure (MAP) and heart rate (HR) with the rank order of potency SP > NKA > [MePhe7]NKB. The cardiovascular responses were accompanied by excessive face washing, grooming and wet dog shakes. 3. The cardiovascular effects and face washing behaviour induced by SP (25 pmol) were significantly reduced by the pre-injection (i.c.v., 5 min earlier) of RP 67580 (6.5 nmol). However, this antagonist failed to affect the central effects of 25 pmol NKA or [MePhe7]NKB. 4. The cardiovascular and behavioural responses (except for wet dog shakes) elicited by NKA (25 pmol) were significantly reduced by 6.5 nmol SR 48968. However, the latter antagonist had no effect on the SP or [MePhe7]NKB-mediated responses. 5. Both cardiovascular and behavioural effects produced by either SP or NKA (25 pmol) were completely abolished when rats were pretreated with a combination of RP 67580 (6.5 nmol) and SR 48968 (6.5 nmol), yet this combination of antagonists failed to modify the central effects of [MePhe7]NKB. 6. R 486 (6.5 nmol) inhibited the cardiovascular effects as well as wet dog shakes produced by [MePhe7]NKB, but it was inactive against the responses induced by either SP or NKA. 7. None of the tachykinin receptor antagonists or agonists caused motor impairment or respiratory distress. All antagonists blocked in a reversible manner and were devoid of intrinsic activity except R486 (6.5 nmol) which produced a transient increase of MAP and HR.8. These results suggest that the central effects of SP, NKA and [MePhe7]NKB are primarily mediated by central NK1, NK2 and NK3 receptors, respectively. However, a minor activation of NK2 receptors bySP and NK1 receptors by NKA was seen during blockade of both receptors. This study therefore supports the existence of functional NK1, NK2 and NK3 receptors in the adult rat brain.
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PMID:Cardiovascular and behavioural effects of centrally administered tachykinins in the rat: characterization of receptors with selective antagonists. 751 4


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