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

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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Neural control of vascular permeability: interactions between primary afferents, mast cells, and sympathetic efferents

Journal of Neurophysiology ◽

10.1152/jn.1989.62.1.48 ◽

1989 ◽

Vol 62 (1) ◽

pp. 48-58 ◽

Cited By ~ 142

Author(s):

T. J. Coderre ◽

A. I. Basbaum ◽

J. D. Levine

Keyword(s):

Blood Pressure ◽

Mast Cells ◽

Vascular Permeability ◽

Neural Control ◽

Primary Afferents ◽

Sympathetic Chain ◽

Blue Dye ◽

Base Line ◽

Plasma Extravasation ◽

Sympathetic Efferents

1. This study addressed the contribution of primary afferents, mast cells, and sympathetic efferents to the control of vascular permeability in synovial joints. Extravasation of Evans blue dye into the synovial space was measured by perfusion of the knee joint in the adult rat. Plasma extravasation (PE) was evoked by pharmacologic activation of either unmyelinated primary afferents, mast cells, or sympathetic postganglionic nerve (SPGN) terminals with acute injection of either capsaicin, compound 48/80, or 6-hydroxydopamine (6-OHDA), respectively. In otherwise untreated control rats, acute infusion of capsaicin or compound 48/80 produced a brief increase in vascular permeability; infusion of 6-OHDA produced a larger and more prolonged increase. 2. To evaluate the contribution of an interaction of different cellular elements in the joint to PE, we repeated these experiments in rats pretreated with capsaicin, compound 48/80, or 6-OHDA; administered quercetin; or surgically sympathectomized by excision of the lumbar sympathetic chain. Eliminating unmyelinated afferent nerve terminals by neonatal treatment with capsaicin only reduced the increase in PE produced by acute infusion of capsaicin. Degranulating mast cells by pretreatment with compound 48/80, or preventing the degranulation of mast cells by treatment with quercetin, reduced the increase in PE evoked by infusion of either capsaicin or compound 48/80. Finally, sympathectomy, produced by excision of the lumbar sympathetic chain or by pretreatment with 6-OHDA, significantly reduced PE elicited by acute infusion of capsaicin, compound 48/80, or 6-OHDA. 3. Neither infusing substances normally localized to sympathetic efferents nor inducing changes in blood pressure could mimic the profound increase in PE evoked by activation of sympathetic postganglionic neurons with acute infusion of 6-OHDA. Thus norepinephrine produced a significant decrease in PE, adenosine triphosphate produced only a brief increase, neuropeptide Y had no effect, and manipulating blood pressure (either up or down) had no effect on either base-line or 6-OHDA-induced PE. 4. Indomethacin treatment significantly reduced the increase in PE produced by 6-OHDA. This effect of indomethacin was reversed by the addition of prostaglandin E2 (PGE2) to the 6-OHDA in the perfusion fluid. This finding implicates prostaglandins (i.e., cyclooxygenase products of arachidonic acid metabolism) in SPGN-dependent generation of PE.(ABSTRACT TRUNCATED AT 400 WORDS)

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Plasma extravasation induced in rat trachea by 6-OHDA is mediated by sensory nerves, not by sympathetic nerves

Journal of Applied Physiology ◽

10.1152/jappl.1994.76.2.701 ◽

1994 ◽

Vol 76 (2) ◽

pp. 701-707 ◽

Cited By ~ 11

Author(s):

I. Sulakvelidze ◽

P. Baluk ◽

D. M. McDonald

Keyword(s):

Tyrosine Hydroxylase ◽

Substance P ◽

Knee Joint ◽

Vascular Permeability ◽

Sympathetic Nerves ◽

Sensory Nerves ◽

Plasma Extravasation ◽

Chemical Sympathectomy ◽

6 Hydroxydopamine ◽

Rat Trachea

6-Hydroxydopamine (6-OHDA) stimulates the release of catecholamines from sympathetic nerves. This stimulation has been proposed as the basis of the 6-OHDA-induced increase in vascular permeability in the rat knee joint. We sought to determine whether 6-OHDA increases vascular permeability in the rat trachea through a similar mechanism. We also sought to determine whether sympathetic nerves contribute to the plasma extravasation caused by stimulating sensory nerves with capsaicin. In anesthetized rats, an intratracheal infusion of 6-OHDA caused more Monastral blue extravasation than did an infusion of vehicle (area density, 23 +/- 3% vs. 9 +/- 1%). Chemical sympathectomy, which reduced the number of tyrosine hydroxylase-immunoreactive nerves by 98%, did not reduce the amount of extravasation induced by 6-OHDA. However, pretreatment with capsaicin, which reduced the number of substance P-immunoreactive nerves by 95%, reduced the Monastral blue extravasation induced by 6-OHDA by 98%. Extravasation induced by stimulating sensory nerves with capsaicin was not significantly different in tracheae with or without sympathetic nerves. We conclude that in the rat trachea infusion of 6-OHDA causes plasma extravasation by stimulating sensory nerves, not by stimulating sympathetic nerves. Furthermore, sympathetic nerves are not essential for the plasma extravasation induced by capsaicin.

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Human urotensin-II enhances plasma extravasation in specific vascular districts in Wistar rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y03-122 ◽

2004 ◽

Vol 82 (1) ◽

pp. 16-21 ◽

Cited By ~ 22

Author(s):

Gabrielle Gendron ◽

Bryan Simard ◽

Fernand Gobeil, Jr. ◽

Pierre Sirois ◽

Pedro D'Orléans-Juste ◽

...

Keyword(s):

Vascular Permeability ◽

Evans Blue ◽

Wistar Rats ◽

Platelet Activating Factor ◽

Optimal Dose ◽

Blue Dye ◽

Plasma Extravasation ◽

Urotensin Ii ◽

Evans Blue Dye

Plasma extravasation (PE) was measured in adult Wistar rats by injecting Evans blue dye (EB) (20 mg kg–1) intravenously in the absence or presence of human urotensin II (U-II) (0.1–10 nmol kg–1). A consistent increase of PE was observed in specific organs (e.g., aorta, from 28.1 ± 2.4 to 74.6 ± 3.6 µg EB g–1 dry tissue; P < 0.001) after an administration of 4.0 nmol kg–1 (a preselected optimal dose) of U-II. The effects of U-II (4.0 nmol kg–1) were compared with those of endothelin-1 (ET-1) (1.0 nmol kg–1). In the thoracic aorta and pancreas, U-II was active, while ET-1 was not. The two agents were equivalent in the heart and kidney, whereas, in the duodenum, ET-1 was more active than U-II. Increases of plasma extravasation induced by U-II, but not by ET-1, were reduced after treatment with [Orn8]U-II (0.3 µmol kg–1). This latter antagonist did not show any significant residual agonistic activity in vivo in the rat. Other specific receptor antagonists for ET-1, such as BQ-123 (endothelin type A (ETA) receptor) and BQ-788 (endothelin type B (ETB) receptor), and for the platelet activating factor (PAF), such as BN50730, failed to modify the action of U-II. The present study is the first report describing the modulator roles of U-II on vascular permeability in specific organs. Moreover, the action of U-II appears specific, since it is independent of the ET-1 and PAF signalling pathways.Key words: urotensin-II, receptors antagonists, Evans blue dye, vascular permeability, rats.

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GR 73,632 and [Glu(OBzl)11]substance P are selective agonists for the septide-sensitive tachykinin NK1 receptor in the rat urinary bladder

Neuropeptides ◽

10.1016/0143-4179(95)90081-0 ◽

1995 ◽

Vol 28 (2) ◽

pp. 99-106 ◽

Cited By ~ 4

Author(s):

S Meini ◽

R Patacchini ◽

A Lecci ◽

C Poulos ◽

P Rovero ◽

...

Keyword(s):

Substance P ◽

Urinary Bladder ◽

Nk1 Receptor ◽

Rat Urinary Bladder ◽

Selective Agonists

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Effect of platelet-activating factor on airway vascular permeability: possible mechanisms

Journal of Applied Physiology ◽

10.1152/jappl.1987.63.2.479 ◽

1987 ◽

Vol 63 (2) ◽

pp. 479-484 ◽

Cited By ~ 129

Author(s):

T. W. Evans ◽

K. F. Chung ◽

D. F. Rogers ◽

P. J. Barnes

Keyword(s):

Vascular Permeability ◽

Evans Blue ◽

Platelet Activating Factor ◽

Blue Dye ◽

Base Line ◽

Plasma Extravasation ◽

Dependent Manner ◽

Lipoxygenase Inhibitor ◽

Dose Dependent ◽

Evans Blue Extravasation

We studied the effects of the potent inflammatory mediator, platelet-activating factor (PAF), on vascular permeability in airways (and other tissues) of guinea pigs by measuring extravasation of circulating Evans blue dye. PAF caused a dose-dependent increase in vascular permeability. At 1 ng/kg iv, PAF caused an increase in Evans blue extravasation of 220% (P less than 0.05) in the trachea, with the greatest effect at a dose of 100 ng/kg (858%; P less than 0.01). Histamine (150 micrograms/kg iv) caused a 320% increase over base line in the trachea and 200% in main bronchi; this effect was equivalent to that induced by 10 ng/kg PAF in the trachea and 1 ng/kg in main bronchi. The duration of effect of PAF was greatest in main bronchi (less than 10 min). Platelet depletion with a cytotoxic antibody, or the cyclooxygenase inhibitor, indomethacin, or the cyclooxygenase-lipoxygenase inhibitor, BW 7556, did not affect the vascular permeability response to PAF. The PAF-receptor antagonist, BN 52063, inhibited Evans blue extravasation in the airways in a dose-dependent manner, with complete inhibition at 5 mg/kg. Thus PAF-induced airway vascular leakage is mediated by specific receptors but not by products of arachidonic acid metabolism or by platelets. Increased airway microvascular leakage induced by PAF may lead to plasma extravasation and airway edema, factors that may contribute to the airway narrowing and hyperresponsiveness induced by PAF.

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Neuropeptide Y inhibits neurogenic inflammation in guinea pig airways

Journal of Applied Physiology ◽

10.1152/jappl.1993.75.1.103 ◽

1993 ◽

Vol 75 (1) ◽

pp. 103-107 ◽

Cited By ~ 16

Author(s):

T. Takahashi ◽

M. Ichinose ◽

H. Yamauchi ◽

M. Miura ◽

N. Nakajima ◽

...

Keyword(s):

Substance P ◽

Neuropeptide Y ◽

Evans Blue ◽

Neurogenic Inflammation ◽

Sensory Nerve ◽

Blue Dye ◽

Plasma Extravasation ◽

Dependent Manner ◽

Evans Blue Dye ◽

Exogenous Substance

We examined the effect of neuropeptide Y (NPY) on neurogenic airway microvascular leakage. Male Dunkin-Hartley guinea pigs (250–350 g) were anesthetized with urethan (2 g/kg ip). The cervical artery and vein were cannulated for monitoring blood pressure and injecting drugs, respectively. Atropine and propranolol (each 1 mg/kg i.v.) were administered 30 min before the experiment. After pretreatment with saline (vehicle for NPY) or NPY (1–100 micrograms/kg i.v.), Evans blue dye (30 mg/kg iv) was administered. Then, bilateral vagal nerves were electrically stimulated (5 V, 7 Hz, 5-ms duration for 3 min) to induce airway plasma leakage. Airways were divided into four sections [trachea (Tr), main bronchi, central intrapulmonary airways (IPA), and peripheral IPA] and incubated in formamide (37 degrees C for 16 h). The concentration of Evans blue dye was measured by spectrophotometer. Furthermore, we examined the effect of NPY on exogenous substance P- (0.3 microgram/kg i.v.) induced plasma extravasation. Bilateral vagal stimulation significantly increased leakage of dye in Tr to peripheral IPA. NPY did not affect basal leakage but did significantly inhibit neurogenic plasma extravasation in a dose-dependent manner with maximal inhibitions of 42.3 (Tr), 67.7 (main bronchi), 38.2 (central IPA), and 26.3% (peripheral IPA) at 30 micrograms/kg. Exogenous substance P-induced plasma extravasation was not inhibited by NPY. We conclude that NPY inhibits neurogenic inflammation by prejunctional inhibition of neuropeptide release from airway sensory nerve terminals.

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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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