The tachykinin receptors inducing contractile responses of canine ileum circular muscle

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.

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Neurokinin receptors subserving bronchoconstriction

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y95-127 ◽

1995 ◽

Vol 73 (7) ◽

pp. 923-926 ◽

Cited By ~ 1

Author(s):

James L. Ellis

Keyword(s):

Substance P ◽

Mammalian Species ◽

Receptor Subtypes ◽

Neurokinin A ◽

Endogenous Ligands ◽

Neurokinin Receptors ◽

Tachykinin Receptor ◽

Selective Antagonists ◽

Modified Peptides ◽

Selective Agonists

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.

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Characterization of tachykinin receptors in ferret trachea by peptide agonists and nonpeptide antagonists

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1993.265.2.l164 ◽

1993 ◽

Vol 265 (2) ◽

pp. L164-L169 ◽

Cited By ~ 3

Author(s):

P. Geppetti ◽

C. Bertrand ◽

E. Bacci ◽

O. Huber ◽

J. A. Nadel

Keyword(s):

Smooth Muscle ◽

Muscle Contraction ◽

Receptor Antagonist ◽

Smooth Muscle Contraction ◽

Neurokinin A ◽

Dependent Manner ◽

Nk1 Receptor ◽

Tachykinin Receptors ◽

Selective Agonists

The tachykinin receptors mediating mucus secretion and smooth muscle contraction were studied in the ferret trachea in vitro. Substance P (SP) and the selective agonist for NK1 receptor ([Sar9,Met(O2)11]SP), but not selective agonists for NK2 ([Ala5,beta-Ala8]neurokinin A-(4–10)) and NK3 ([MePhe7]neurokinin B) receptors, induced secretion of macromolecules in a concentration-dependent fashion. The nonpeptide NK1 receptor antagonist, CP-96,345, but not the nonpeptide NK2 receptor antagonist, SR-48968, inhibited SP-induced secretion. Both neurokinin A (NKA) and [Ala5,beta-Ala8]NKA-(4-10), but not NK1 and NK3 selective agonists, evoked a concentration-dependent smooth muscle contraction. SR-48968, but not CP-96,345, inhibited in a concentration-dependent manner the response to NKA. CP-96,345 and SR-48968 did not affect the concentration-dependent increase in macromolecule secretion or smooth muscle contraction by carbachol. These findings indicate that NK1 receptors mediate secretion of macromolecules and NK2 receptors mediate smooth muscle contraction, in response to tachykinins in the ferret trachea in vitro.

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Regulation of colonic propulsion by enteric excitatory and inhibitory neurotransmitters

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1996.271.3.g433 ◽

1996 ◽

Vol 271 (3) ◽

pp. G433-G437 ◽

Cited By ~ 11

Author(s):

A. E. Foxx-Orenstein ◽

J. R. Grider

Keyword(s):

Nitric Oxide ◽

Circular Muscle ◽

Neurokinin A ◽

Maximal Inhibition ◽

Nitric Oxide Synthase Inhibitor ◽

Inhibitory Neurotransmitters ◽

Peristaltic Reflex ◽

In Series ◽

Synthase Inhibitor ◽

Oxide Synthase

The contribution of excitatory and inhibitory motor neurotransmitters to colonic propulsion was examined in isolated segments of guinea pig colon. Synthetic fecal pellets were inserted at the proximal end of the segment, and the velocity of pellet propulsion across a fixed distance was measured in the presence and absence of selective neurotransmitter antagonists. The control velocity (0.97 +/- 0.02 mm/s) was inhibited in a concentration-dependent fashion by atropine and the neurokinin (NK)-2a antagonist MEN-10,376 [half-maximal inhibitory concentration (IC50), 1 microM; maximal inhibition, 98 +/- 1%]. The NK-1 antagonist GR-82,334 (10 microM) also inhibited velocity by 65 +/- 9%, consistent with involvement of acetylcholine, neurokinin A (NK-2 agonist), and substance P (NK-1 agonist) in the contractile components of the peristaltic reflex. Velocity was also inhibited in a concentration-dependent fashion by the nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NNA; IC50, 1 microM; maximal inhibition, 96 +/- 2%) and by the vasoactive intestinal peptide (VIP) antagonist VIP-(10-28) (IC50, 30 nM; maximal inhibition, 64 +/- 6%), consistent with involvement of both nitric oxide and VIP in descending relaxation of circular muscle and contraction of longitudinal muscle. A combination of threshold concentrations of L-NNA and the NK-2a antagonist was synergistic (53 +/- 7% inhibition). The potentiation implied that the ascending and descending phases were functionally coupled in series. We conclude that blockade of neurotransmitters that mediate either phase of the peristaltic reflex inhibits colonic propulsive activity. Serial coupling of the phases leads to synergism between inhibitors, a condition of potential therapeutic importance.

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Chronic rejection causes early destruction of the intrinsic nervous system in rat intestinal transplants

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1997.273.2.g413 ◽

1997 ◽

Vol 273 (2) ◽

pp. G413-G421 ◽

Cited By ~ 1

Author(s):

P. F. Heeckt ◽

W. Halfter ◽

W. H. Schraut ◽

A. J. Bauer

Keyword(s):

Nervous System ◽

Chronic Rejection ◽

Circular Muscle ◽

Electrical Field Stimulation ◽

Functional Changes ◽

Diaphorase Activity ◽

Enteric Nerves ◽

Mucosal Changes ◽

Oxide Synthase ◽

Muscularis Externa

Chronic rejection is the major cause of late intestinal allograft dysfunction. We have previously shown that chronic rejection alters the muscularis externa of the graft. This study determined structural and functional changes to the enteric nerves during chronic rejection. Chronic rejection was achieved in orthotopic intestinal transplants (ACI to Lewis) by limited immunosuppression. Syngeneic transplants (ACI to ACI) and unoperated ACI rats served as controls. Animals were clinically healthy and showed no significant alterations in the mucosal architecture on postoperative day 90. Staining for NADPH diaphorase activity (nitric oxide synthase-containing neurons) and with neurofilament antibody RT-97 revealed that chronic rejection decreased the number of jejunal myenteric ganglia by approximately 50%. Inhibitory junction potentials (IJPs) to circular muscle cells were determined by electrical field stimulation (EFS). In controls and syngeneic grafts, EFS caused a stimulus-dependent increase in IJP amplitude, with a maximal amplitude of 9 +/- 0.4 and 10 +/- 0.8 mV, respectively. Chronic rejection in allografts markedly increased the threshold for IJP initiation and decreased the maximal IJP amplitude (5 +/- 0.8 mV). Our data indicate that chronic rejection severely damages the muscularis and the enteric nervous system before mucosal changes become evident.

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Multiple tachykinin receptors in guinea pig brain. High densities of substance K (neurokinin a) binding sites in the substantia nigra

Neuropeptides ◽

10.1016/0143-4179(85)90090-3 ◽

1985 ◽

Vol 6 (3) ◽

pp. 191-204 ◽

Cited By ~ 73

Author(s):

Rémi Quirion ◽

Than-Vinh Dam

Keyword(s):

Substantia Nigra ◽

Guinea Pig ◽

Binding Sites ◽

Neurokinin A ◽

Tachykinin Receptors ◽

Pig Brain ◽

Substance K ◽

Guinea Pig Brain

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Effects of ageing on regional differences in the contractile responses to acetylcholine and neurokinin A in rabbit airway

General Pharmacology The Vascular System ◽

10.1016/0306-3623(94)90246-1 ◽

1994 ◽

Vol 25 (4) ◽

pp. 685-689

Author(s):

Norio Funayama ◽

Michiko Shinkai ◽

Sachiko Ebisawa ◽

Taichi Abe ◽

Issei Takayanagi

Keyword(s):

Regional Differences ◽

Neurokinin A ◽

Contractile Responses

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Impaired pulmonary artery contractile responses in a rat model of microgravity: role of nitric oxide

Journal of Applied Physiology ◽

10.1152/jappl.2002.92.1.33 ◽

2002 ◽

Vol 92 (1) ◽

pp. 33-40 ◽

Cited By ~ 15

Author(s):

Daniel Nyhan ◽

Soonyul Kim ◽

Stacey Dunbar ◽

Dechun Li ◽

Artin Shoukas ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Pulmonary Artery ◽

Lung Tissue ◽

Rat Model ◽

Orthostatic Intolerance ◽

Volume Distribution ◽

Contractile Responses ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Vascular contractile hyporesponsiveness is an important mechanism underlying orthostatic intolerance after microgravity. Baroreceptor reflexes can modulate both pulmonary resistance and capacitance function and thus cardiac output. We hypothesized, therefore, that pulmonary vasoreactivity is impaired in the hindlimb-unweighted (HLU) rat model of microgravity. Pulmonary artery (PA) contractile responses to phenylephrine (PE) and U-46619 (U4) were significantly decreased in the PAs from HLU vs. control (C) animals. N G-nitro-l-arginine methyl ester (10−5 M) enhanced the contractile responses in the PA rings from both C and HLU animals and completely abolished the differential responses to PE and U4 in HLU vs. C animals. Vasorelaxant responses to ACh were significantly enhanced in PA rings from HLU rats compared with C. Moreover, vasorelaxant responses to sodium nitroprusside were also significantly enhanced. Endothelial nitric oxide synthase (eNOS) and soluble guanlyl cyclase expression were significantly enhanced in PA and lung tissue from HLU rats. In marked contrast, the expression of inducible nitric oxide synthase was unchanged in lung tissue. These data support the hypothesis that vascular contractile responsiveness is attenuated in PAs from HLU rats and that this hyporesponsiveness is due at least in part to increased nitric oxide synthase activity resulting from enhanced eNOS expression. These findings may have important implications for blood volume distribution and attenuated stroke volume responses to orthostatic stress after microgravity exposure.

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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.

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