Neurokinin receptors subserving bronchoconstriction

Tachykinin receptor subtypes were initially defined using agonist potency ratios for the endogenous ligands substance P (SP), neurokinin (NK) A, and NKB. On this basis it was suggested that there are three tachykinin receptor subtypes. These subtypes were designated NK1, NK2, and NK3, where SP is most potent at NK1 receptors, NKA is most potent at NK2 receptors, and NKB is most potent at NK3 receptors. Recently analogs of the endogenous ligands that show greater selectivity (about 1000-fold) for the different receptor subtypes have been developed. In addition selective antagonists, which are either nonpeptides or modified peptides, for the receptor subtypes have been developed. This minireview concentrates on the wealth of new knowledge concerning the tachykinin receptor subtypes subserving bronchoconstriction in several mammalian species, including man, provided by the use of these selective agonists and antagonists.Key words: neurokinins, bronchoconstriction, substance P, neurokinin A, receptor subtypes.

Download Full-text

The tachykinin receptors inducing contractile responses of canine ileum circular muscle

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1995.268.1.g161 ◽

1995 ◽

Vol 268 (1) ◽

pp. G161-G170 ◽

Cited By ~ 1

Author(s):

E. E. Daniel ◽

M. B. Parrish ◽

E. G. Watson ◽

J. E. Fox-Threlkeld ◽

D. Regoli ◽

...

Keyword(s):

Circular Muscle ◽

Neurokinin A ◽

Neurokinin Receptors ◽

Contractile Responses ◽

Tachykinin Receptors ◽

Selective Antagonists ◽

Nk3 Receptor ◽

Nk1 Antagonist ◽

Selective Agonists ◽

Oxide Synthase

This study sought to determine which tachykinin receptors were involved in contractile responses of circular muscle to tachykinins infused into isolated segments of canine ileum. Selective agonists for neurokinin receptors NK1 and NK2 as well as for substance P (SP) and neurokinin A (NKA) were infused, and selective antagonists against NK1, NK2, and NK3 receptors were tested. The responses to a submaximal concentration of NKA were reduced by a selective NK2 antagonist, SR-48968, and abolished by a combination of this antagonist with an NK1 antagonist, either CP-96,345 or RP-67580. The selective NK2 agonist, [Nle10]NKA-(4-10), had low potency. We concluded that NKA acted on typical NK2 receptors and that is action was potentiated by its additional action on NK1 receptors. Neither the contractile responses to SP nor those to [Sar9,Met(O2)11]SP given in submaximal concentrations were inhibited by CP-96,345 or RP-67580, either alone or together with SR-48968. Indeed, the two NK1-selective antagonists potentiated responses to the selective NK1 agonist, [Sar9,Met(O2)11]SP, an effect attributed to previously demonstrated prejunctional inhibitory action of the agonist. The selective NK3 agonist, succinyl-[Asp6,N-Me-Phe8]SP-(6-11), was not effective as a contractile agent, even after block of nitric oxide synthase with N omega-nitro-L-arginine. The selective NK3 antagonist, R-487, was also ineffective in blocking responses to SP. Studies with an antagonist to H1 histamine receptors suggested that contractile actions of SP did not involve histamine release from mast cells. We concluded that, in addition to typical NK1 and NK2 receptors activated by NKA and a prejunctional inhibitory receptor activated by SP and [Sar9,Met(O2)11]SP, another tachykinin receptor existed on canine ileum to initiate contractions. It is not a typical NK1, NK2, or NK3 receptor.

Download Full-text

Plasma extravasation induced by neurokinins in conscious rats: receptor characterization with agonists and antagonists

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y93-034 ◽

1993 ◽

Vol 71 (3-4) ◽

pp. 217-221 ◽

Cited By ~ 26

Author(s):

Mauro Nicolau ◽

Martin G. Sirois ◽

Michel Bui ◽

Gérard E. Plante ◽

Pierre Sirois ◽

...

Keyword(s):

Substance P ◽

Urinary Bladder ◽

Vascular Permeability ◽

Blue Dye ◽

Receptor Subtype ◽

Plasma Extravasation ◽

Functional Sites ◽

Conscious Rats ◽

Selective Antagonists ◽

Selective Agonists

The purpose of the present experiments was to study the effects of various neurokinin related peptides, such as substance P, [βAla8]NKA(4–10), and [MePhe7]NKB, which are selective for NK-1, NK-2, and NK-3 functional sites, respectively, to induce plasma extravasation in rats and the effectiveness of RP 67580 and CP-96,345 (two nonpeptide NK-1 receptor selective antagonists) and SR 48968 (a nonpeptide NK-2 receptor selective antagonist) to prevent such an effect. Bolus intravenous injection of substance P (1.0 nmol/kg) into conscious rats induced extravasation of Evans blue dye (EB), a selective marker of albumin vascular permeability, in the duodenum, the stomach, the pancreas, and the urinary bladder by 50, 40, 58, and 312%, respectively; a slight increment occurred also in the ileum and the kidney but was not significant. [βAla8]NKA(4–10) (1.0 nmol/kg) increased EB extravasation in the stomach and the urinary bladder by 52 and 99%, respectively, while [MePhe7]NKB (1.0 nmol/kg) did the same in the stomach, the ileum, and the urinary bladder by 58, 50, and 79%. Pretreatment with RP 67580 (250 nmol/kg) blocked the albumin extravasation mediated by substance P in the duodenum, the pancreas, and the urinary bladder by 100, 100, and 78%, respectively. CP-96,345 (250 nmol/kg) also inhibited EB extravasation mediated by substance P in the duodenum and the pancreas by 100 and 100%, respectively, but was ineffective in the urinary bladder. Neither RP 67580 nor CP-96,345 prevented the substance P mediated extravasation in the stomach. RP 67580 and CP-96,345 did not antagonize the effects of NK-2 and NK-3 selective agonists. SR 48968 (500 nmol/kg) was inactive against substance P as well as against the NK-2 or NK-3 selective agonists. RP 67580 (250 nmol/kg), CP-96,345 (250 nmol/kg), and SR 48968 (500 nmol/kg) per se did not induce any plasma extravasation, except in the urinary bladder, where CP-96,345 and SR 48968 increased EB concentrations in the tissue. These results suggest that the effects of neurokinins on vascular permeability vary from one tissue to another. The blockade of substance P by the NK-1 receptor selective antagonists, RP 67580 and CP-96,345, suggests that NK-1 receptors play an important role in the plasma extravasation induced by substance P. However, the effects of NK-2 and NK-3 receptor selective agonists appear to be independent of activation of NK-1 receptors since they are not blocked by RP 67580 or CP-96,345. Furthermore, because the effect of [βAla8]NKA(4–10), the NK-2 selective agonist, was not abolished by SR 48968, it is suggested that it might be mediated by the NK-2 receptor subtype NK-2B, which is less sensitive to SR 48968 than is NK-2A. The contribution of NK-3 receptors to plasma extravasation could not be adequately demonstrated in the present study because NK-3 antagonists sufficiently active in vivo are not available.Key words: neurokinins, RP 67580, CP-96,345, SR 48968, vascular permeability.

Download Full-text

Selective agonists for substance P and neurokinin receptors

Neuropeptides ◽

10.1016/0143-4179(87)90088-6 ◽

1987 ◽

Vol 10 (1) ◽

pp. 43-54 ◽

Cited By ~ 209

Author(s):

G. Drapeau ◽

P. D'Orléans-Juste ◽

S. Dion ◽

N.-E. Rhaleb ◽

N.-E. Rouissi ◽

...

Keyword(s):

Substance P ◽

Neurokinin Receptors ◽

Selective Agonists

Download Full-text

DESIGN, SYNTHESIS AND BIOLOGICAL ACTIVITY OF SELECTIVE AGONISTS FOR TACHYKININ RECEPTOR SUBTYPES

Porto Carras, Chalkidiki, Greece, Aug. 31–Sept. 5, 1986 ◽

10.1515/9783110864243-092 ◽

1987 ◽

pp. 397-400 ◽

Cited By ~ 1

Author(s):

M. Chorev ◽

R. Laufer ◽

D. Ron ◽

J. Frey ◽

U. Wormser ◽

...

Keyword(s):

Biological Activity ◽

Receptor Subtypes ◽

Design Synthesis ◽

Tachykinin Receptor ◽

Selective Agonists

Download Full-text

Calcitonin Gene-Related Peptide and Cerebral Blood Vessels: Distribution and Vasomotor Effects

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1987.126 ◽

1987 ◽

Vol 7 (6) ◽

pp. 720-728 ◽

Cited By ~ 224

Author(s):

L. Edvinsson ◽

R. Ekman ◽

I. Jansen ◽

J. McCulloch ◽

R. Uddman

Keyword(s):

Substance P ◽

Guinea Pig ◽

Blood Vessels ◽

Mammalian Species ◽

Cerebral Arteries ◽

Nerve Fibers ◽

Neurokinin A ◽

Cerebral Blood Vessels ◽

Calcitonin Gene ◽

Basilar Arteries

The innervation of cerebral blood vessels by nerve fibers containing calcitonin gene-related peptide (CGRP) and the vasomotor effects of this peptide are described for a number of different mammalian species. CGRP-immunoreactive nerve fibers were present in the adventitia of cerebral arteries in all species examined (guinea pig, cat, rabbit, rat, and mouse). Numerous perikarya containing CGRP immunoreactivity are demonstrable in the trigeminal ganglion of all species. In the cerebral perivascular nerve fibers and in trigeminal perikarya, CGRP is often colocalized with substance P and neurokinin A. Marked interspecies differences exist both in the density of CGRP-immunoreactive nerve fibers and in the cerebrovascular levels measured with radioimmunoassay. The highest concentrations were observed in cerebral vessels from guinea pigs, the lowest concentration in rabbit vessels, and intermediate levels in the feline and human cerebral vasculature. CGRP is a potent dilator of cerebral arteries in all species examined (human pial, feline middle cerebral, rabbit, guinea pig and rat basilar arteries). The concentration of CGRP eliciting half-maximal responses ranged from 0.4 n M (human pial artery) to 3 n M (rat and rabbit basilar arteries). Pretreatment of cerebral arteries with low concentrations of either substance P (0.1 n M) or neurokinin A (3 n M) attenuated slightly the CGRP-induced relaxations of guinea pig basilar arteries. Calcitonin was found to be a very weak dilator of cerebral arteries from human and guinea pig. Thus, cardiovascular nerve fibers containing CGRP appear to be present in all mammalian species (although to varying degrees) and CGRP is invariably a potent dilator of the cerebral arteries for all species.

Download Full-text

Identification in the NK1 tachykinin receptor of a domain involved in recognition of neurokinin A and septide but not of substance P

FEBS Letters ◽

10.1016/s0014-5793(99)00298-7 ◽

1999 ◽

Vol 447 (2-3) ◽

pp. 155-159 ◽

Cited By ~ 33

Author(s):

Anne Wijkhuisen ◽

Marie-Astrid Sagot ◽

Yveline Frobert ◽

Christophe Créminon ◽

Jacques Grassi ◽

...

Keyword(s):

Substance P ◽

Neurokinin A ◽

Tachykinin Receptor

Download Full-text

Prostacyclin release induced by neurokinins in cultured human endothelial cells

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y89-026 ◽

1989 ◽

Vol 67 (2) ◽

pp. 159-162 ◽

Cited By ~ 20

Author(s):

François Marceau ◽

Brigitte Tremblay ◽

Réjean Couture ◽

Domenico Regoli

Keyword(s):

Endothelial Cells ◽

Substance P ◽

Rank Order ◽

Receptor Subtypes ◽

Human Endothelial Cells ◽

Basal Secretion ◽

Selective Agonist ◽

Prostaglandin F ◽

Selective Agonists ◽

Substance P Fragments

The effects of neurokinins (NK) and related peptides on the secretion of 6-keto-prostaglandin F1α, a stable metabolite of prostacyclin, were measured. These peptides enhanced three- to five-fold the basal secretion rate with the following rank order of potency (based on threshold concentrations for a significant output): substance P (SP) ≥ NKA > SP 4–11 ≥ [pGlu6]SP 6–11 = SP7–11. NKB and SP 1–9 were inactive. Ac[Arg6, Sar9, Met(O2)11]SP, a NK1 receptor selective agonist, was more potent than other selective agonists for the NK2 and NK3 receptor subtypes. These results suggest that the NK receptors, which mediate the release of prostacyclin from human endothelial cells, belong to the NK1 subtype.Key words: neurokinins, substance P fragments, selective agonists, prostacyclin release, human endothelial cells.

Download Full-text

Neurokinin receptors subserving plasma extravasation in guinea pig airways

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y95-128 ◽

1995 ◽

Vol 73 (7) ◽

pp. 927-931 ◽

Cited By ~ 11

Author(s):

Ian W. Rodger ◽

Christine Tousignant ◽

Donna Young ◽

Chantal Savoie ◽

Chi-Chung Chan

Keyword(s):

Substance P ◽

Guinea Pig ◽

Sensory Nerve ◽

Neurokinin A ◽

Plasma Extravasation ◽

Contrast Extravasation ◽

Human Fibrinogen ◽

Neurokinin Receptors ◽

Airway Function ◽

Nk Receptor

In the respiratory system the tachykinins substance P and neurokinin A exhibit a variety of effects on airway function that include bronchoconstriction, vasodilatation, and plasma extravasation. Increased microvascular permeability with accompanying plasma extravasation is a principal cause of tissue edema observed in asthma. In guinea pig airways it has been suggested that neurogenic plasma extravasation is mediated by tachykinins, released from sensory nerve terminals, acting via neurokinin (NK) receptors. We have characterized NK receptor mediated plasma extravasation in guinea pig airways, using 125I-labelled human fibrinogen as a marker for leakage. Extravasation was induced using selective NK1 and NK2 receptor agonists, capsaicin, or nonadrenergic, noncholinergic nerve stimulation. The inhibitory effects of the selective nonpeptide NK receptor antagonists (CP 99,994 for NK1 and. SR 48,968 for NK2) were also examined. Results from our studies demonstrate conclusively that only NK1 receptors subserve plasma extravasation in the trachea and large airways of the guinea pig. In stark contrast, extravasation in the lower airways (secondary bronchi and intraparenchymal airways) of the guinea pig is mediated by both NK1 and NK2 receptors.Key words: tachykinins, substance P, neurokinin A, plasma extravasation, neurokinin receptors, asthma.

Download Full-text

Tachykinin receptors in guinea-pig airways: characterization using selective ligands

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y95-126 ◽

1995 ◽

Vol 73 (7) ◽

pp. 915-922 ◽

Cited By ~ 2

Author(s):

Elizabeth Burcher ◽

Xiang-Ping Zeng ◽

John Strigas ◽

Dominic P. Geraghty ◽

Solange Lavielle

Keyword(s):

Substance P ◽

Guinea Pig ◽

Radioligand Binding ◽

Neurokinin A ◽

Tachykinin Receptors ◽

Tachykinin Receptor ◽

High Affinity ◽

Selective Ligands ◽

Dose Dependent ◽

Potency Order

Tachykinin receptors in guinea-pig airways were examined using radioligand binding techniques in lung homogenates, and using isolated bronchial segments. Binding of the NK1 selective radioligand 125I-labelled Bolton–Hunter [Sar9,Met(O2)11]substance P ([125I]BHSarSP) was saturable and of high affinity (KD, 0.26 nM). The rank potency order of competitors for [125I]BHSarSP binding was [Pro9]SP > CP 96345 [Formula: see text] septide > [pGlu6]SP(6–11) > RP 67580 ≥ [DPro9, [Formula: see text],Trp11]SP > [DPro9,[Formula: see text],Trp11]physalaemin ≥ GR 82334 ≥ 127I Bolton–Hunter neurokinin A (BHNKA). Septide had higher affinity than expected, and it was the only ligand to bind to two sites. Agonists interacting with NK2 receptors were more potent contractile agents than NK1 receptor agonists. Responses to BHNKA (pD2 8.4) were antagonized by MDL 29913 and MEN 10207, with pKB values 6.42 and 6.79, and also by SR 48968 and GR 94800, although this was not dose dependent. This agonist was also weakly inhibited by CP 96345 and RP 67580. These data demonstrate that BHNKA can interact with both NK1 and NK2 receptors. There was no relationship between the binding affinity of NK1 ligands in lung homogenates, with GR 82334 being notably weak, and their agonist or antagonist potency in bronchial smooth muscle.Key words: tachykinin receptor, radioligand binding, septide, guinea-pig bronchus, 127I Bolton–Hunter neurokinin A.

Download Full-text