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

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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Renal sensory and sympathetic nerves reinnervate the kidney in a similar time-dependent fashion after renal denervation in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00599.2012 ◽

2013 ◽

Vol 304 (8) ◽

pp. R675-R682 ◽

Cited By ~ 74

Author(s):

Jan Mulder ◽

Tomas Hökfelt ◽

Mark M. Knuepfer ◽

Ulla C. Kopp

Keyword(s):

Substance P ◽

Optical Density ◽

Renal Denervation ◽

Time Course ◽

Sympathetic Nerves ◽

Sensory Nerves ◽

Sensory Innervation ◽

Multiple Time ◽

Sensory Reinnervation ◽

Renal Sympathetic

Efferent renal sympathetic nerves reinnervate the kidney after renal denervation in animals and humans. Therefore, the long-term reduction in arterial pressure following renal denervation in drug-resistant hypertensive patients has been attributed to lack of afferent renal sensory reinnervation. However, afferent sensory reinnervation of any organ, including the kidney, is an understudied question. Therefore, we analyzed the time course of sympathetic and sensory reinnervation at multiple time points (1, 4, and 5 days and 1, 2, 3, 4, 6, 9, and 12 wk) after renal denervation in normal Sprague-Dawley rats. Sympathetic and sensory innervation in the innervated and contralateral denervated kidney was determined as optical density (ImageJ) of the sympathetic and sensory nerves identified by immunohistochemistry using antibodies against markers for sympathetic nerves [neuropeptide Y (NPY) and tyrosine hydroxylase (TH)] and sensory nerves [substance P and calcitonin gene-related peptide (CGRP)]. In denervated kidneys, the optical density of NPY-immunoreactive (ir) fibers in the renal cortex and substance P-ir fibers in the pelvic wall was 6, 39, and 100% and 8, 47, and 100%, respectively, of that in the contralateral innervated kidney at 4 days, 4 wk, and 12 wk after denervation. Linear regression analysis of the optical density of the ratio of the denervated/innervated kidney versus time yielded similar intercept and slope values for NPY-ir, TH-ir, substance P-ir, and CGRP-ir fibers (all R2 > 0.76). In conclusion, in normotensive rats, reinnervation of the renal sensory nerves occurs over the same time course as reinnervation of the renal sympathetic nerves, both being complete at 9 to 12 wk following renal denervation.

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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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Substance P and bradykinin stimulate plasma extravasation in the mouse gastrointestinal tract and pancreas

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1997.272.4.g785 ◽

1997 ◽

Vol 272 (4) ◽

pp. G785-G793 ◽

Cited By ~ 13

Author(s):

M. Figini ◽

C. Emanueli ◽

E. F. Grady ◽

K. Kirkwood ◽

D. G. Payan ◽

...

Keyword(s):

Gastrointestinal Tract ◽

Substance P ◽

Neurogenic Inflammation ◽

Sensory Nerves ◽

Plasma Extravasation ◽

Nk1 Receptor ◽

Nk1 Receptor Antagonist ◽

B2 Receptors ◽

Mediate Inflammation ◽

Small And Large Intestine

Neurogenic inflammation is mediated by release of tachykinins from sensory nerves, which stimulate plasma extravasation from postcapillary venules. Because there are conflicting results regarding the importance of neurogenic inflammation in the gastrointestinal tract, we quantified plasma extravasation using Evans blue and identified sites of the leak using Monastral blue in the mouse. Substance P and bradykinin stimulated extravasation from postcapillary venules in the stomach, small and large intestine, pancreas, urinary bladder, trachea, and skin by two- to sevenfold by interacting with NK1 and B2 receptors, respectively. Stimulation of sensory nerves with capsaicin also induced extravasation. Capsaicin- and bradykinin-stimulated extravasation was attenuated by an NK1-receptor antagonist and is thus mediated by release of tachykinins and activation of the NK1 receptor. We conclude that 1) substance P stimulates extravasation in the gastrointestinal tract and pancreas of mice by interacting with the NK1 receptors, and 2) capsaicin and bradykinin induce plasma extravasation by stimulating tachykinin release from sensory nerves. Thus neurogenic mechanisms mediate inflammation in the gastrointestinal tract and pancreas of the mouse.

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The role of sympathetic nerves in bradykinin (BK)-induced plasma extravasation in the rat knee joint

Neuropeptides ◽

10.1016/0143-4179(94)90303-4 ◽

1994 ◽

Vol 26 ◽

pp. 64 ◽

Cited By ~ 1

Author(s):

H. Cambridge ◽

S.D. Brain

Keyword(s):

Knee Joint ◽

Sympathetic Nerves ◽

Plasma Extravasation

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Presynaptic sympathetic mechanism in the insulinostatic effect of epinephrine in mouse pancreatic islets

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.272.5.r1371 ◽

1997 ◽

Vol 272 (5) ◽

pp. R1371-R1378 ◽

Cited By ~ 3

Author(s):

S. Karlsson ◽

U. Myrsen ◽

A. Nieuwenhuizen ◽

F. Sundler ◽

B. Ahren

Keyword(s):

Insulin Secretion ◽

Tyrosine Hydroxylase ◽

Sympathetic Nerve ◽

Sympathetic Nerves ◽

Nerve Terminals ◽

Relative Contribution ◽

Presynaptic Mechanisms ◽

Mouse Pancreatic Islets ◽

Mouse Islets ◽

6 Hydroxydopamine

The catecholamines inhibit insulin release. It is not established whether presynaptic mechanisms contribute to this effect. We therefore examined the relative contribution of presynaptic and postsynaptic mechanisms to the insulinostatic effects of epinephrine and norepinephrine. Mice were injected with 6-hydroxydopamine (6-OHDA; 0.19 mmol/kg) or its vehicle. Islets were isolated after 48 h. Islets from vehicle-injected control animals contained numerous tyrosine hydroxylase (TH)-immunoreactive nerve terminals (marker for sympathetic nerves). In contrast, TH-immunoreactive nerves were not detected in islets from 6-OHDA-treated animals, indicating sympathetic denervation. Basal (5.6 mmol/l glucose) or glucose-stimulated (16.7 mmol/l) insulin secretion did not differ between incubated islets from vehicle-injected control animals and islets from 6-OHDA-treated animals. The insulinostatic effect of epinephrine, but not that of norepinephrine, was markedly impaired in islets from 6-OHDA-treated animals: the lowest effective insulinostatic concentration of epinephrine was 0.01 nmol/l in islets from vehicle-injected animals and 1 nmol/l in islets from 6-OHDA-treated animals. We conclude that in isolated mouse islets the insulinostatic effect of epinephrine, but not that of norepinephrine, partially depends on sympathetic nerve terminals, suggesting an important role for presynaptic mechanisms in epinephrine-induced inhibition of insulin secretion.

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First Place — Student Research Award 1995: A Mechanism for Sympathectomy-Induced Bone Resorption in the Middle Ear

Otolaryngology ◽

10.1177/019459989511300508 ◽

1995 ◽

Vol 113 (5) ◽

pp. 569-581 ◽

Cited By ~ 1

Author(s):

Bret E. Sherman ◽

Richard A. Chole

Keyword(s):

Substance P ◽

Calcium Release ◽

In Vitro Study ◽

Sensory Nerves ◽

Neonatal Mouse Calvaria ◽

6 Hydroxydopamine ◽

Post Hoc ◽

Stabilization Period

BACKGROUND: Recent investigations have demonstrated a link between sympathectomy and osteoclast-mediated bone resorption. The exact nature of this link, however, is unknown, We hypothesize that substance P, a potent vasoconstrictive neuropeptide found in peripheral sensory fibers, including those innervating bone, is the mediator of this phenomenon. To test this theory, the effects of substance P on in vitro calcium release from cultured neonatal mouse calvaria were assessed. In addition, an in vivo study was conducted whereby gerbils were injected with capsaicin to eliminate substance P-containing fibers before sympathectomy with 6-hydroxydopamine. If the effects of 6-hydroxydopamine were eliminated by prior administration of capsaicin, the role of sensory nerves in sympathectomy-induced resorption would be strongly implicated. IN VITRO STUDY: Substance P at 10−8 mol/L was incubated with eight newborn Swiss-Webster mouse hemicalvarial explants and compared with explants incubated in control media alone. The neonatal mice were euthanized at day 3, and their hemicalvaria were preincubated in 2 ml of stock media without treatment for 24 hours at 36.5° C as a stabilization period. After the stabilization period, the stock media were replaced with 2 ml of fresh control media or media containing substance P at 10−8 mol/L. A similar experiment was performed with the addition of indomethacin at 5 × 10−7. The explants were then incubated for 72 hours with gassing every 12 hours with a mixture of O2, N2, and CO2. At the end of the 72-hour period, the media were analyzed for calcium content by atomic absorption spectrophotometry and compared by one-way analysis of variance with Bonferroni-corrected post hoc tests. IN VSVO STUDY: Forty-eight Mongolian gerbils were placed into four groups: group 1 received intraperitoneal injections of 6-hydroxydopamine at 75 μg/gm body weight on days 1, 2, 6, 7, and 8; group 2 received identical injections of hydroxydopamine, but 12 hours after receiving subdermal injections of capsaicin at 50 μg/gm body weight; group 3 received only subdermal injections of capsaicin; and group 4 received only saline injections to serve as controls. Seven days after treatment, the animals were euthanized, and the ventral wall of each animal's right bulla was resected and quantified for osteoclast number and surface with a computer-based histomor-phometry system. Analysis was then made by one-way analysis of variance with Bonferroni-corrected post hoc tests. RESULTS: The results of the in vitro study revealed that substance P at 10−8 mol/L (11.05 ± 3.37 μg/ml) induced significant calcium release from cultured neonatal mouse calvaria when compared with control bone incubated in base media alone (0.92 ± 2.85 μg/ml, p < 0.01). The process was completely inhibited by 5.0 × 10−7 indomethacin. The results of the in vivo study showed 6-hydroxydopamine treatment significantly increased both the osteoclast number (NOc/TL = 3.14 ± 1.33/mm) and the osteoclast surface (OcS/BS = 16.04% ± 6.95%) of bone when compared with bone from saline-treated controls (NOc/TL = 1,77 ± 0.79/mm, p < 0.01; OcS/BS = 8.88% ± 4.15%, p < 0.01), These 6-hydroxydopamine-induced increases were eliminated, however, in animals pretreated with capsaicin before sympathectomy (NOc/TL = 1.86 ± 0.68/mm, p > 0.05; OcS/BS = 9.92 ± 3.73, p > 0.05), whereas treatment with capsaicin alone had no effect when compared with bone from saline-treated controls (NOc/TL = 2.02 ± 0.50/mm, p > 0.05; OcS/BS = 10.28% ± 2.62%, p > 0.05), Substance P has thus been shown to induce calcium release from membranous bone in vitro, whereas capsaicin, a substance P-specific sensory neurolytic chemical, eliminates the in vivo osteoclast-inductive effects of 6-hydroxydopamine when given 12 hours before treatment. The results indicate that substance P is capable of inducing resorption and that substance P-containing sensory nerves are required for the induction of resorption after sympathectomy in the gerbil.

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The involvement of sympathetic nerves in plasma extravasation induced by prostaglandin E2 and substance P

Brain Research ◽

10.1016/0006-8993(94)91687-x ◽

1994 ◽

Vol 644 (2) ◽

pp. 251-256 ◽

Cited By ~ 9

Author(s):

Ronald Mathison ◽

Joseph S. Davison

Keyword(s):

Substance P ◽

Prostaglandin E2 ◽

Sympathetic Nerves ◽

Plasma Extravasation

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Dopamine type 2 receptor expression and function in rodent sensory neurons projecting to the airways

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00222.2004 ◽

2005 ◽

Vol 289 (1) ◽

pp. L153-L158 ◽

Cited By ~ 17

Author(s):

Christian Peiser ◽

Marcello Trevisani ◽

David A. Groneberg ◽

Q. Thai Dinh ◽

Doerthe Lencer ◽

...

Keyword(s):

Sensory Neurons ◽

Receptor Activation ◽

Receptor Expression ◽

Sensory Nerves ◽

Plasma Extravasation ◽

Rt Pcr ◽

Functional Studies ◽

And Function ◽

Rat Trachea

Agonists of the dopamine receptors have been demonstrated to have bronchodilatory properties in pathologically constricted airways. The mechanism by which these agonists induce bronchodilatation is thought to involve airway sensory nerves. In this study, the expression and function of dopamine D2 receptor were examined in sensory ganglia supplying the airways. Neuronal dopamine D2 receptor mRNA expression was demonstrated by single-cell RT-PCR following laser-assisted microdissection. The projection of the neurons to the airways was confirmed by retrograde neuronal labeling. In functional studies, dopamine D2 receptor agonists (AR-C65116AB and ropinirole) inhibited intraneuronal calcium mobilization in rat capsaicin-sensitive primary sensory neurons and capsaicin-induced plasma extravasation in the rat trachea. Our results provide support to the hypothesis that dopamine D2 receptor activation inhibits neurogenic inflammation and proinflammatory reflex responses.

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