scholarly journals Modulation of lymphatic muscle contractility by the neuropeptide substance P

2008 ◽  
Vol 295 (2) ◽  
pp. H587-H597 ◽  
Author(s):  
Michael J. Davis ◽  
Megan M. Lane ◽  
Ann M. Davis ◽  
David Durtschi ◽  
David C. Zawieja ◽  
...  
Keyword(s):  
Substance P ◽  
Capillary Permeability ◽  
Lymphatic Vessels ◽  
Sensory Innervation ◽  
Pump Efficiency ◽  
Lymphatic Function ◽  
Low Concentrations ◽  
Chronotropic Effects ◽  
Spontaneous Contractions ◽  
Lymphatic Pumping

Substance P (SP) is a neuropeptide associated with sensory innervation of lymphoid tissue and a suspected modulator of lymphatic function in inflammation. Only a few studies have examined the effects of SP on lymphatic contraction, and it is not clear to what extent SP acts directly on the lymphatic muscle and/or endothelium or indirectly through changes in intraluminal filling pressure secondary to increases in capillary permeability/filtration. We tested the effects of SP on the spontaneous contractions of rat isolated mesenteric lymphatic vessels under isometric and isobaric conditions, hypothesizing that low concentrations would stimulate lymphatic pumping by enhancing lymphatic muscle contraction in a manner complementary to the effect of increased preload. Under isometric conditions, SP (10 nM) dramatically enhanced lymphatic chronotropy and inotropy. Unlike guinea pig lymphatics, SP actions were not blocked by cyclooxygenase or PLA2inhibition. In the absence of SP, ramp increases in isometric preload resulted in ×∼1.6 increases in contraction amplitude (Amp) and ×∼1.7 increases in frequency (Freq). SP increased Freq by ×∼2.4, Amp by ×∼1.9, and the Amp-Freq product (AFP) by ×∼3.5. Under isobaric conditions, the pressure elevation from 0.5 to 10 cmH2O in the absence of SP decreased Amp by ×∼0.6 and increased Freq by ×∼1.8. SP caused a modest increase in Amp, a robust increase in Freq at all pressures, and shifted the AFP-pressure relationship upward and leftward. Therefore, SP has substantial positive inotropic and chronotropic effects on rat lymphatic muscle, improving pump efficiency independent of the effects of preload and broadening of the working range of the lymphatic pump.

scholarly journals Impairments in the intrinsic contractility of mesenteric collecting lymphatics in a rat model of metabolic syndrome

2012 ◽  
Vol 302 (3) ◽  
pp. H643-H653 ◽  
Author(s):  
Scott D. Zawieja ◽  
Wei Wang ◽  
Xin Wu ◽  
Zhanna V. Nepiyushchikh ◽  
David C. Zawieja ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Serum Insulin ◽  
Lymphatic Vessels ◽  
Lymphatic Function ◽  
Cell Coverage ◽  
High Fructose ◽  
Contractile Parameters ◽  
Generating Capacity ◽  
Chronotropic Effects ◽  
Lymphatic Pumping

Numerous studies on metabolic syndrome (MetSyn), a cluster of metabolic abnormalities, have demonstrated its profound impact on cardiovascular and blood microvascular health; however, the effects of MetSyn on lymphatic function are not well understood. We hypothesized that MetSyn would modulate lymphatic muscle activity and alter muscularized lymphatic function similar to the impairment of blood vessel function associated with MetSyn, particularly given the direct proximity of the lymphatics to the chronically inflamed adipose depots. To test this hypothesis, rats were placed on a high-fructose diet (60%) for 7 wk, and their progression to MetSyn was assessed through serum insulin and triglyceride levels in addition to the expression of metabolic and inflammatory genes in the liver. Mesenteric lymphatic vessels were isolated and subjected to different transmural pressures while lymphatic pumping and contractile parameters were evaluated. Lymphatics from MetSyn rats had significant negative chronotropic effects at all pressures that effectively reduced the intrinsic flow-generating capacity of these vessels by ∼50%. Furthermore, lymphatics were remodeled to a significantly smaller diameter in the animals with MetSyn. Wire myograph experiments demonstrated that permeabilized lymphatics from the MetSyn group exhibited a significant decrease in force generation and were less sensitive to Ca2+, although there were no significant changes in lymphatic muscle cell coverage or morphology. Thus, our data provide the first evidence that MetSyn induces a remodeling of collecting lymphatics, thereby effectively reducing their potential load capabilities and impairing the intrinsic contractility required for proper lymph flow.

Decreased lymphatic pumping after intravenous endotoxin administration in sheep

1987 ◽  
Vol 253 (6) ◽  
pp. H1349-H1357 ◽  
Author(s):  
R. M. Elias ◽  
M. G. Johnston ◽  
A. Hayashi ◽  
W. Nelson
Keyword(s):  
Contractile Activity ◽  
Lymphatic Vessels ◽  
Transmural Pressure ◽  
Sheep Model ◽  
Endotoxin Administration ◽  
Maximum Inhibition ◽  
Spontaneous Contractions ◽  
Lymphatic Pumping ◽  
Pumping Activity

The effects of endotoxin on the ability of lymphatic vessels to pump fluid in vivo have been assessed with the use of a sheep model system that permits analysis of lymph pumping in sheep without the complication of variable lymph inputs. This involved the isolation of intestinal lymphatic vessels from all lymph input, with saline or lymph provided from a reservoir. The blood and nerve supplies to the vessel were left intact. With no net driving pressure, but with a transmural pressure applied to the vessel to initiate spontaneous contractions and fluid pumping, the intravenous administration of endotoxin (3.3 micrograms/kg in anesthetized sheep and 33 micrograms/kg in nonanesthetized animals) reduced fluid propulsion in both groups of animals (P less than 0.02 and P less than 0.03, respectively). Comparisons with animals that did not receive endotoxin revealed maximum inhibition greater than 90% in anesthetized and 50% in nonanesthetized sheep. Normal pulsatile lymphatic pressures (produced from lymphatic contractions) were reduced in frequency and amplitude after endotoxin administration. Endotoxin itself had no effect on the vessels when added to the fluid in the reservoir, suggesting that the inhibition of the "lymph pump" was mediated through the interaction of endotoxin with cellular or humoral elements in the host. In addition to suppression of lymphatic contractile activity, the intravenous injection of endotoxin enhanced lymph formation as indicated by the 3- to 10-fold increases in lymph flow rates in the two groups. We conclude that, for a given transmural pressure, the systemic administration of endotoxin reduces lymphatic pumping activity. We speculate that this effect may be important in the pathogenesis of the edema associated with sepsis.

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

2013 ◽  
Vol 304 (8) ◽  
pp. R675-R682 ◽  
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.

Abstract 27: ApoA-I Improves Lymphatic Function Through a Platelet-Dependent Mechanism in Atherosclerotic Mice

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Andreea Milasan ◽  
François Dallaire ◽  
Gabriel Jean ◽  
Jean-Claude Tardif ◽  
Yahye Merhi ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Ex Vivo ◽  
Lymphatic Vessels ◽  
Lymphatic Transport ◽  
Lv Function ◽  
Experimental Conditions ◽  
Lymphatic Function ◽  
Beneficial Effects ◽  
Dependent Mechanism

Rationale: Lymphatic vessels (LVs) are now recognized as prerequisite players in the modulation of cholesterol removal from the artery wall in experimental conditions of plaque regression, and a particular attention has been brought on the role of the collecting LVs in early atherosclerosis-related lymphatic dysfunction. Whereas recent findings revealed that apoA-I restores the neovascularization capacity of the lymphatic system during tumor necrosis factor-induced inflammation, the effect of apoA-I on collecting LV function during atherosclerosis has not been tested. Objective: In the present study, we address whether and how apoA-I can enhance collecting LV function in atherosclerosis-associated lymphatic dysfunction. Methods and Results: A 6-week systemic treatment with lipid-free apoA-I enhanced lymphatic transport and abrogated collecting lymphatic vessel permeability in atherosclerotic Ldlr –/– mice when compared to control. As injection of apoA-I has been shown to protect wild-type mice against flow restriction-induced thrombosis, and that platelets are identified as key elements in the maintenance of lymphatic vessel integrity via their interaction with lymphatic endothelial cells (LECs), we have tested whether the effects of apoA-I could be mediated through a platelet-dependent mechanism. Our in vivo results show that apoA-I kinetics in lymph reflected that of blood. Ex vivo experiments performed with washed platelets isolated from mouse blood reveal that apoA-I decreased thrombin-induced but not podoplanin-induced platelet aggregation. Whereas this result suggests that apoA-I limits platelet thrombotic potential in blood but not in lymph, we demonstrate that treatment of human LECs with apoA-I increases the adhesion of bridge-like platelets on human LECs. Conclusions: Our results suggest that apoA-I can mediate beneficial effects on lymphatic function by promoting platelet adhesion to the lymphatic endothelium and consequently restore collecting LV integrity. Altogether, we bring forward a new pleiotropic role for apoA-I in lymphatic function and unveil new potential therapeutic targets for the prevention and treatment of atherosclerosis.

SPONTANEOUS CONTRACTIONS OF LYMPHATIC VESSELS IN MAN

The Lancet ◽  
1963 ◽  
Vol 281 (7296) ◽  
pp. 1425 ◽  
Author(s):  
J.B. Kinmonth ◽  
E.P. Sharpey-Schafer ◽  
G.W. Taylor
Keyword(s):  
Lymphatic Vessels ◽  
Spontaneous Contractions

Aortic Reactivity of Rats with Genetic and Experimental Renal Hypertension

1972 ◽  
Vol 50 (11) ◽  
pp. 1072-1079 ◽  
Author(s):  
F. P. Field ◽  
R. A. Janis ◽  
D. J. Triggle
Keyword(s):  
Smooth Muscle ◽  
Renal Hypertension ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Aortic Smooth Muscle ◽  
Low Concentrations ◽  
Experimental Renal Hypertension ◽  
Altered Cell ◽  
Specific Alteration ◽  
Spontaneous Contractions

The isometric tensions produced by low concentrations of norepinephrine (1 × 10−10 and 3 × 10−10M) or potassium (10 mM) were greater in aortic rings from mature rats with hypertension produced by bilateral renal encapsulation and from rats with genetic hypertension than from Car-worth normotensive Wistar rats. This hyper-reactivity was not associated with a hypersensitivity to low calcium concentrations in the presence of 80 mM KCl. Similarly the loss of maximum response to KCl with time in calcium-free solution was the same for aortic smooth muscle from normotensive and hypertensive rats. However, the rate of relaxation after 80 mM KCl was washed from the bath with normal Krebs solution was much faster for aortic smooth muscle from normotensive than from hypertensive animals. Spontaneous contractions were observed in aortic rings obtained from eight of 12 renal hypertensive rats but were not observed in rings from either spontaneously hypertensive or normotensive rats. An elevated thyroid activity was not associated with the increase in systolic blood pressure to 185 mm Hg in the renal encapsulated rats. The results suggest that the hypersensitivity to norepinephrine of the aortic smooth muscle is due to an altered cell membrane rather than a specific alteration of the adrenergic α-receptors.

scholarly journals Interactions between neutral endopeptidase (EC 3.4.24.11) and the substance P (NK1) receptor expressed in mammalian cells

1994 ◽  
Vol 299 (3) ◽  
pp. 683-693 ◽  
Author(s):  
A Okamoto ◽  
M Lovett ◽  
D G Payan ◽  
N W Bunnett
Keyword(s):  
Substance P ◽  
Epithelial Cells ◽  
Mammalian Cells ◽  
Neutral Endopeptidase ◽  
Nk1 Receptor ◽  
Endopeptidase 24.11 ◽  
Low Concentrations ◽  
Substance P Receptor ◽  
Maximal Binding ◽  
Fold Excess

Interactions between neutral endopeptidase-24.11 (NEP) and the substance P receptor (SPR; NK1) were investigated by examining substance P (SP) degradation, SP binding and SP-induced Ca2+ mobilization in epithelial cells transfected with cDNA encoding the rat SPR and rat NEP. Expression of NEP accelerated the degradation of SP by intact epithelial cells and by membrane preparations, and degradation was reduced by the NEP inhibitor thiorphan. In cells expressing SPR alone, specific 125I-SP binding after 20 min incubation at 37 degrees C was 92.2 +/- 3.1% of maximal binding and was unaffected by thiorphan. Coexpression of NEP in the same cells as the SPR markedly reduced SP binding to 13.9 +/- 0.5% of maximal, and binding was increased to 82.7 +/- 2.4% of maximal with thiorphan. Coexpression of NEP in the same cells as the SPR also reduced to undetectable the increase in intracellular Ca2+ in response to low concentrations of SP (0.3 and 0.5 nM), and significantly reduced the response to higher concentrations (1 and 3 nM). The Ca2+ response was restored to control values by inhibition of NEP with thiorphan. In contrast, SP binding and SP-induced Ca2+ mobilization were only slightly reduced when cells expressing SPR alone were mixed with a 3- to 24-fold excess of cells expressing NEP alone. Therefore, in this system, NEP markedly down-regulates SP binding and SP-induced Ca2+ mobilization only when coexpressed in the same cells as the SPR.

scholarly journals Lipopolysaccharide modulates neutrophil recruitment and macrophage polarization on lymphatic vessels and impairs lymphatic function in rat mesentery

2015 ◽  
Vol 309 (12) ◽  
pp. H2042-H2057 ◽  
Author(s):  
Sanjukta Chakraborty ◽  
Scott D. Zawieja ◽  
Wei Wang ◽  
Yang Lee ◽  
Yuan J. Wang ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Contractile Activity ◽  
Macrophage Polarization ◽  
Lymphatic Vessels ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Lymphatic Function ◽  
Inflammatory Conditions ◽  
Rat Mesentery

Impairment of the lymphatic system is apparent in multiple inflammatory pathologies connected to elevated endotoxins such as LPS. However, the direct mechanisms by which LPS influences the lymphatic contractility are not well understood. We hypothesized that a dynamic modulation of innate immune cell populations in mesentery under inflammatory conditions perturbs tissue cytokine/chemokine homeostasis and subsequently influences lymphatic function. We used rats that were intraperitoneally injected with LPS (10 mg/kg) to determine the changes in the profiles of innate immune cells in the mesentery and in the stretch-mediated contractile responses of isolated lymphatic preparations. Results demonstrated a reduction in the phasic contractile activity of mesenteric lymphatic vessels from LPS-injected rats and a severe impairment of lymphatic pump function and flow. There was a significant reduction in the number of neutrophils and an increase in monocytes/macrophages present on the lymphatic vessels and in the clear mesentery of the LPS group. This population of monocytes and macrophages established a robust M2 phenotype, with the majority showing high expression of CD163 and CD206. Several cytokines and chemoattractants for neutrophils and macrophages were significantly changed in the mesentery of LPS-injected rats. Treatment of lymphatic muscle cells (LMCs) with LPS showed significant changes in the expression of adhesion molecules, VCAM1, ICAM1, CXCR2, and galectin-9. LPS-TLR4-mediated regulation of pAKT, pERK pI-κB, and pMLC20 in LMCs promoted both contractile and inflammatory pathways. Thus, our data provide the first evidence connecting the dynamic changes in innate immune cells on or near the lymphatics and complex cytokine milieu during inflammation with lymphatic dysfunction.

Modulation of lymphatic pumping by lymph-borne factors after endotoxin administration in sheep

1990 ◽  
Vol 68 (1) ◽  
pp. 199-208 ◽  
Author(s):  
R. M. Elias ◽  
M. G. Johnston
Keyword(s):  
Potent Inhibitor ◽  
Lymphatic Vessels ◽  
Transmural Pressure ◽  
Test Animal ◽  
Indwelling Catheter ◽  
Endotoxin Administration ◽  
Lymphatic Pumping ◽  
Pumping Activity

The purpose of this study was to test the hypothesis that endotoxin administration to sheep results in host-derived lymph-borne factors that modulate lymphatic pumping activity. To achieve this, two sheep were used for each experiment. In the test animal, a segment of intestinal lymphatic was isolated from all lymph input and provided with lymph from a reservoir. Pumping activity was initiated with a fixed transmural pressure applied to the test vessel, and the only input to this duct was provided by lymph from an indwelling catheter in a second donor sheep. The intravenous administration of endotoxin to the donor animals (33 micrograms/kg) generally resulted in increased pumping in the test vessels over the 1st h, but this was followed by reductions in pumping until flow stopped in all preparations. In control experiments (no endotoxin administered) pumping was unaffected. Further investigation revealed that these activities were relatively unstable and, in the case of the inhibitory material, appeared to act by decreasing the sensitivity of the vessel to changes in transmural pressure, because flow could be reestablished in the test vessels by elevating transmural pressures above the level originally chosen for the experiment. Endotoxin itself had no direct effect on sheep lymphatics in vivo or on bovine lymphatic vessels in vitro. However, the appearance of erythrocyte hemolysate (erythrolysate) in lymph was regularly observed after endotoxin infusion, and we demonstrated that erythrolysate (diluted to contain 10(-5) M hemoglobin) was a potent inhibitor of lymphatic pumping in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiology and pharmacology of the oviducts of Raja and Scyliorhinus

1995 ◽  
Vol 350 (1332) ◽  
pp. 143-151 ◽  
Keyword(s):  
Substance P ◽  
Rhythmic Activity ◽  
Egg Laying ◽  
High Concentration ◽  
M 12 ◽  
Egg Case ◽  
Spontaneous Contractions ◽  
Large Contraction ◽  
Rhythmical Contractions

1. In oviparous elasmobranchs the oviducts vary in structure and physiology according to how they carry the sperm upwards and the eggs down. The sperm are accompanied by a large volume of fluid secreted by the siphon. In some species this contains much 5-hydroxytryptamine (5HT), produced by a gland. The muscles of the oviducts are very sensitive to 5HT in Raja , which has such a gland, but not in Scyliorhinus , which has none. 2. The female Scyliorhinus draws the egg case down the duct by attaching tendrils to a rock or weeds and swimming round and round (Dodd 1983); the muscles of the lower oviduct and vagina are weak. 3. In Raja the egg case is buried in the sand or mud and there are powerful muscles in the lower oviduct and vagina. 4. In-vitro isolated strips of longitudinal or circular muscles of the lower oviduct of Raja give slow rhythmical contractions. 5-HT 10 -8 m increased the amplitude and frequency of contraction. The same response was induced by 8-OH-DPAT 5 x 10 -6 m (a 5-HT 1A receptor agonist) but not by 5 x 10 -6 m 2-methyl-5-HT (a 5-HT 3 agonist) or by 5 x 10 -6 m x-methyl-5-HT (a 5-HT 2 agonist). The response to 5-HT was partly blocked by methysergide 10 -6 m (a 5-HT 2 antagonist) but not by ketanserin 10 -5 m (a 5-HT 2 antagonist) or granisetron (BRL 43694) 10 -5 m (a5-HT 3 and 5-H T 4 antagonist). The receptor involved may therefore be of the 5-HT 1 or perhaps 5-HT 2 type. 5. Spontaneous contractions of the oviduct in Raja were inhibited by adrenalin 10 -6 m, and less strongly by noradrenaline 10 -6 m . 6. Substance P 10 -8 m produced increased amplitude and frequency of contraction. 7. Acetylcholine produced contraction only above a dose of 10 -6 m. 8. Strips of lower oviduct or vagina of Scyliorhinus canicula showed long periods of slight rhythmic activity punctuated by large rapid contractions at intervals of 10—40 min. 9. Similar large contractions occurred after addition of 5-HT at 10 -6 m but only in half the experiments and at high concentration, and with long delay. 10. Adrenalin produced large rapid contractions but only at a dose of 10 -7 M and above, and often after a long delay. 11. Substance P and acetylcholine also produced contraction, but the latter only at 10 -6 m . 12. Strips of the oviduct or vagina of either Raja or Scyliorhinus responded to a sudden stretch by a large contraction. 13. These findings are discussed in the light of the differences in sperm transport and egg laying in the two species.

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