Contributions of arachidonic acid derivatives and substance P to the sensitization of cutaneous nociceptors

1990 ◽  
Vol 64 (2) ◽  
pp. 457-464 ◽  
Author(s):  
R. H. Cohen ◽  
E. R. Perl
Keyword(s):  
Arachidonic Acid ◽  
Substance P ◽  
Receptive Fields ◽  
Lipoxygenase Inhibitor ◽  
Arterial Perfusion ◽  
Mediators Of Inflammation ◽  
Rabbit Ear ◽  
C Fiber

1. The role of presumed chemical mediators of inflammation in the heat-induced sensitization of cutaneous C-polymodal nociceptors (CPNs) was examined in a rabbit ear preparation maintained in vitro by intra-arterial perfusion with a solution free of protein and cellular elements. 2. In this preparation, CPNs consistently showed enhanced responsiveness after repeated exposure of their receptive fields to noxious levels of heat. The average magnitude of sensitization was quantitatively similar to that observed in vivo, suggesting that blood-born factors are not essential for development of sensitization. 3. Sensitization in one-half of randomly selected CPNs was blocked or reduced when the perfusate contained a cyclooxygenase inhibitor, indomethacin or dipyrone, or the dual cyclooxygenase/lipoxygenase inhibitor, BW755C, even though initial responsiveness to heat and pressure was unaltered. These observations suggest that arachidonic acid breakdown products, possibly prostaglandins, are intermediaries in the sensitization of some, but not all, C-fiber nociceptors of the skin. In addition, heat-induced sensitization for some C-fiber cutaneous nociceptors is the result of processes that are at least partially independent of those involved in excitation. 4. Substance P (SP) or the putative SP antagonists, [D-Pro2, D-Trp7.9]-SP or [D-Pro2, D-Phe7, D-Trip9]-SP, produced no significant effect on heat-responsiveness or sensitization, although ongoing activity may have marginally increased over control levels after repeated heat stimulations. We conclude that SP in an in vitro preparation is not involved in the enhancement of cutaneous C-fiber nociceptor responsiveness after repeated thermal insults.

scholarly journals α-Conotoxins Enhance both the In Vivo Suppression of Ehrlich carcinoma Growth and In Vitro Reduction in Cell Viability Elicited by Cyclooxygenase and Lipoxygenase Inhibitors

Marine Drugs ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 193
Author(s):  
Alexey V. Osipov ◽  
Tatiana I. Terpinskaya ◽  
Tatsiana Yanchanka ◽  
Tatjana Balashevich ◽  
Maxim N. Zhmak ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Antitumor Effect ◽  
Nordihydroguaiaretic Acid ◽  
Ehrlich Carcinoma ◽  
Arachidonic Acid Cascade ◽  
Lipoxygenase Inhibitor ◽  
Lipoxygenase Inhibitors ◽  
Combined Application

Several biochemical mechanisms, including the arachidonic acid cascade and activation of nicotinic acetylcholine receptors (nAChRs), are involved in increased tumor survival. Combined application of inhibitors acting on these two pathways may result in a more pronounced antitumor effect. Here, we show that baicalein (selective 12-lipoxygenase inhibitor), nordihydroguaiaretic acid (non-selective lipoxygenase inhibitor), and indomethacin (non-selective cyclooxygenase inhibitor) are cytotoxic to Ehrlich carcinoma cells in vitro. Marine snail α-conotoxins PnIA, RgIA and ArIB11L16D, blockers of α3β2/α6β2, α9α10 and α7 nAChR subtypes, respectively, as well as α-cobratoxin, a blocker of α7 and muscle subtype nAChRs, exhibit low cytotoxicity, but enhance the antitumor effect of baicalein 1.4-fold after 24 h and that of nordihydroguaiaretic acid 1.8–3.9-fold after 48 h of cell cultivation. α-Conotoxin MII, a blocker of α6-containing and α3β2 nAChR subtypes, increases the cytotoxic effect of indomethacin 1.9-fold after 48 h of cultivation. In vivo, baicalein, α-conotoxins MII and PnIA inhibit Ehrlich carcinoma growth and increase mouse survival; these effects are greatly enhanced by the combined application of α-conotoxin MII with indomethacin or conotoxin PnIA with baicalein. Thus, we show, for the first time, antitumor synergism of α-conotoxins and arachidonic acid cascade inhibitors.

Warm-Sensitive Afferent Splanchnic C-Fiber Units In Vitro

1997 ◽  
Vol 77 (6) ◽  
pp. 2989-3002 ◽  
Author(s):  
David W. Adelson ◽  
Jen Yu Wei ◽  
Lawrence Kruger
Keyword(s):  
Receptive Fields ◽  
Sense Organ ◽  
Cardiovascular Responses ◽  
Peak Temperature ◽  
Mechanical Stimuli ◽  
Tonic Component ◽  
Brown Adipose ◽  
C Fiber

Adelson, David W., Jen Yu Wei, and Lawrence Kruger. Warm-sensitive afferent splanchnic C-fiber units in vitro. J. Neurophysiol. 77: 2989–3002, 1997. Receptive fields of 41 slowly conducting sensory fibers were located using a thermal (warm) search stimulus in an in vitro splanchnic nerve-mesentery preparation. Warm-sensitive receptive fields were punctate and were densest in the region surrounding the prevertebral ganglia, an area with prominent deposits of brown adipose tissue, where the abdominal aorta branches into the major trunks supplying the abdominal viscera. Impulse activity was recorded while applying a warm stimulus to identified receptive fields (RFs). The warm stimulus consisted of a warming ramp (10–15°C in 1–2 s to a 42–49°C peak temperature) followed by a 10- to 30-s period during which the RF was maintained at this peak temperature (plateau phase). Eighty percent (33/41) of warm-sensitive units responded to warming with discharge comprising both a phasic and a tonic component (slowly adapting warm-sensitive, or SA-W, units). The remainder (8/41) responded with only phasic discharge (rapidly adapting warm-sensitive, or RA-W, units). Units' adaptation characteristics were consistent from trial to trial and when applying stimuli from different positions. Fifty percent of SA-W units (8/16) and 17% of RA-W units (1/6) were activated by transient exposure to 9–90 nM bradykinin (BK). Twenty-seven percent (9/33) of SA-W units and 12%(1/8) of RA-W units were activated by probing their RF with von Frey hairs with bending forces <10 mN (∼1 g equivalent mass). An additional five SA-W units tested were activated by strong mechanical stimuli (compression with a metal probe or firm stretching). No BK-responsive warm-sensitive units were activated by von Frey probing <10 mN, but two (both SA-W) responded to strong mechanical stimuli. In six SA-W units and one RA-W unit, the number of impulses evoked by warming ∼5 min after exposure to BK was >2 SD greater than the mean pre-BK response, indicating sensitization. This sensitization was transient, the response to warming returning to within one standard deviation of the pretrial mean or less over the course of the next 5–10 min. Changes in background activity, mechanical sensitivity, BK sensitivity, and BK-induced sensitization were noted in various splanchnic units over the course of prolonged observations, suggesting that these indices may not reliably distinguish unit type, but instead may indicate the functional state of the sense organ. Splanchnic neurons responsive to the intense warming used in the present in vitro experiments may participate in the cardiovascular responses observed in vivo in heat-stressed rats. The dense distribution of warm-receptive fields in the vicinity of the celiac-superior mesenteric ganglionic complex is consistent with the localization of splanchnic thermosensitive units previously noted in vivo in the rabbit.

Paradoxical effect of salbutamol in a model of acute organophosphates intoxication in guinea pigs: role of substance P release

2007 ◽  
Vol 292 (4) ◽  
pp. L915-L923 ◽  
Author(s):  
Jaime Chávez ◽  
Patricia Segura ◽  
Mario H. Vargas ◽  
José Luis Arreola ◽  
Edgar Flores-Soto ◽  
...  
Keyword(s):  
Substance P ◽  
Guinea Pigs ◽  
Smooth Muscle Contraction ◽  
In Vivo Experiments ◽  
Intracellular Ca ◽  
Neurokinin 1 ◽  
Substance P Release

Organophosphates induce bronchoobstruction in guinea pigs, and salbutamol only transiently reverses this effect, suggesting that it triggers additional obstructive mechanisms. To further explore this phenomenon, in vivo (barometric plethysmography) and in vitro (organ baths, including ACh and substance P concentration measurement by HPLC and immunoassay, respectively; intracellular Ca2+ measurement in single myocytes) experiments were performed. In in vivo experiments, parathion caused a progressive bronchoobstruction until a plateau was reached. Administration of salbutamol during this plateau decreased bronchoobstruction up to 22% in the first 5 min, but thereafter airway obstruction rose again as to reach the same intensity as before salbutamol. Aminophylline caused a sustained decrement (71%) of the parathion-induced bronchoobstruction. In in vitro studies, paraoxon produced a sustained contraction of tracheal rings, which was fully blocked by atropine but not by TTX, ω-conotoxin (CTX), or epithelium removal. During the paraoxon-induced contraction, salbutamol caused a temporary relaxation of ∼50%, followed by a partial recontraction. This paradoxical recontraction was avoided by the M2- or neurokinin-1 (NK1)-receptor antagonists (methoctramine or AF-DX 116, and L-732138, respectively), accompanied by a long-lasting relaxation. Forskolin caused full relaxation of the paraoxon response. Substance P and, to a lesser extent, ACh released from tracheal rings during 60-min incubation with paraoxon or physostigmine, respectively, were significantly increased when salbutamol was administered in the second half of this period. In myocytes, paraoxon did not produce any change in the intracellular Ca2+ basal levels. Our results suggested that: 1) organophosphates caused smooth muscle contraction by accumulation of ACh released through a TTX- and CTX-resistant mechanism; 2) during such contraction, salbutamol relaxation is functionally antagonized by the stimulation of M2 receptors; and 3) after this transient salbutamol-induced relaxation, a paradoxical contraction ensues due to the subsequent release of substance P.

P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function

2002 ◽  
Vol 82 (1) ◽  
pp. 131-185 ◽  
Author(s):  
Richard J. Roman
Keyword(s):  
Arachidonic Acid ◽  
Angiotensin Ii ◽  
Vascular Tone ◽  
Mesangial Cells ◽  
Cardiovascular Function ◽  
Tubuloglomerular Feedback ◽  
Peripheral Vasculature ◽  
Therapeutic Benefits

Recent studies have indicated that arachidonic acid is primarily metabolized by cytochrome P-450 (CYP) enzymes in the brain, lung, kidney, and peripheral vasculature to 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) and that these compounds play critical roles in the regulation of renal, pulmonary, and cardiac function and vascular tone. EETs are endothelium-derived vasodilators that hyperpolarize vascular smooth muscle (VSM) cells by activating K+channels. 20-HETE is a vasoconstrictor produced in VSM cells that reduces the open-state probability of Ca2+-activated K+channels. Inhibitors of the formation of 20-HETE block the myogenic response of renal, cerebral, and skeletal muscle arterioles in vitro and autoregulation of renal and cerebral blood flow in vivo. They also block tubuloglomerular feedback responses in vivo and the vasoconstrictor response to elevations in tissue Po2both in vivo and in vitro. The formation of 20-HETE in VSM is stimulated by angiotensin II and endothelin and is inhibited by nitric oxide (NO) and carbon monoxide (CO). Blockade of the formation of 20-HETE attenuates the vascular responses to angiotensin II, endothelin, norepinephrine, NO, and CO. In the kidney, EETs and 20-HETE are produced in the proximal tubule and the thick ascending loop of Henle. They regulate Na+transport in these nephron segments. 20-HETE also contributes to the mitogenic effects of a variety of growth factors in VSM, renal epithelial, and mesangial cells. The production of EETs and 20-HETE is altered in experimental and genetic models of hypertension, diabetes, uremia, toxemia of pregnancy, and hepatorenal syndrome. Given the importance of this pathway in the control of cardiovascular function, it is likely that CYP metabolites of arachidonic acid contribute to the changes in renal function and vascular tone associated with some of these conditions and that drugs that modify the formation and/or actions of EETs and 20-HETE may have therapeutic benefits.

Effect of inhibition of 5-lipoxygenase metabolism of arachidonic acid on response to endotoxemia in sheep

1988 ◽  
Vol 65 (3) ◽  
pp. 1351-1359 ◽  
Author(s):  
J. W. Coggeshall ◽  
B. W. Christman ◽  
P. L. Lefferts ◽  
W. E. Serafin ◽  
I. A. Blair ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Whole Blood ◽  
Ex Vivo ◽  
Calcium Ionophore ◽  
Lung Mechanics ◽  
Gas Chromatography Mass Spectrometry ◽  
Lipoxygenase Inhibitor ◽  
Pulmonary Hemodynamics ◽  
Lung Lymph

We studied the effects of a 5-lipoxygenase inhibitor, L-651,192, on the pulmonary dysfunction caused by endotoxemia in chronically instrumented unanesthetized sheep. The efficacy and selectivity of L-651,392 were tested by measuring in vivo production of leukotriene B4 (LTB4) and cyclooxygenase products of arachidonic acid after endotoxemia before and after pretreatment with L-651,392 and ex vivo from granulocytes and whole blood stimulated with calcium ionophore from sheep before and 24 h after pretreatment with L-651,392. A novel assay for LTB4 by high-performance liquid chromatography/gas chromatography/mass spectrometry techniques was developed as a measure of 5-lipoxygenase metabolism of arachidonic acid. L-651,392 proved to be an effective in vivo 5-lipoxygenase inhibitor in sheep. L-651,392 blocked the increase in LTB4 observed in lung lymph after endotoxemia in vivo in sheep as well as inhibited by 80% the ex vivo production of LTB4 by granulocytes removed from sheep treated 24 h earlier with L-651,392. Although L-651,392 blocked the increase in cyclooxygenase products of arachidonic acid observed in lung lymph after endotoxemia in vivo in sheep, the drug probably did not function directly as a cyclooxygenase inhibitor. L-651,392 did not attenuate the ex vivo production of thromboxane B2 by whole blood from sheep treated 24 h earlier with the drug. L-651,392 attenuated the alterations in pulmonary hemodynamics, lung mechanics, oxygenation, and lung fluid and solute exchange observed after endotoxemia in sheep. We speculate that 5-lipoxygenase products are a major stimulus for cyclooxygenase metabolism of arachidonic acid after endotoxemia in sheep.

Abstract 064: The Lipoxigenase Inhibitor Nordihydroguaiaretic Acid Prevents the Development of Hypoxia-Induced Pulmonary Hypertension in Mice

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Andrea Iorga ◽  
Gabriel Wong ◽  
Denise Mai ◽  
Jingyuan Li ◽  
Salil Sharma ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Actin ◽  
Nordihydroguaiaretic Acid ◽  
Treated Group ◽  
Oxidation Products ◽  
Lipoxygenase Inhibitor ◽  
Human Pulmonary Artery

Pulmonary hypertension (PH) is a chronic lung disease characterized by progressively elevated pulmonary arterial pressures and severe pulmonary vascular remodeling resulting from interactions between oxidized lipoprotein deposition and increased endothelial proliferation. Previously we have shown increased plasma levels of biological oxidation products such as hydroxyoctadecadienoic acids (HODEs) and hydroxyeicosatetraenoic acids (HETEs) in the rat monocrotaline model of PH. Here we investigated the role of HETEs and HODEs in the development of PH and whether their inhibition with the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) attenuates the progression of PH. Mice were placed in a hypoxic chamber with O2 concentrations of ≤10% for 21 days and either left untreated to develop PH (n=7) or treated with NDGA daily (10mg/kg/day, i.p., n=4) from day 1. Direct RV catheterization was terminally performed to record RV pressure (RVP). Pulmonary arteriolar thickening and oxidized lipid deposition were assessed by staining lung sections with Masson’s Trichrome or with α-smooth muscle actin and E-06 (marker for oxidized low-density lipoproteins). In vitro, human pulmonary artery smooth muscle cell (hPASMC) proliferation was assessed by MTT assays in the absence or presence of 12-HETE (100ng/ml), 9-HODE (1µg/ml) and 13-HODE (1µg/ml) alone or together with NDGA (10, 25 and 50µM). In-vitro, HETE/HODE treatment increased hPASMC proliferation ~ 2-fold when compared to untreated cells and NDGA significantly inhibited the proliferative effects of all three oxidized lipids. In-vivo, NDGA treatment prevented the development of PH. RVP was lower in the NDGA-treated group vs. the PH group (24.01±1.39mmHg vs. 36.91±5.74mmHg, p<0.05) and was comparable to control normoxic mice (20.93±2.52mmHg). RV hypertrophy index was significantly elevated in the PH mice versus control mice (0.38±0.03 vs. 0.28±0.02 (p<0.001), while NDGA treatment completely prevented the development of RV hypertrophy (0.28±0.04). Lung sections demonstrated arteriolar thickening and E-06 positive deposits in the PH group, which was prevented by NDGA therapy. We conclude that oxidized fatty acid deposition and accumulation might play a role in the development of PH.

Abstract 5: Neovascularization By Substance-p- Mobilized Epc And Msc In Vitro And In Vivo

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Hyun Sook Hong ◽  
Suna Kim ◽  
Youngsook Son
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Substance P ◽  
Network Formation ◽  
Skin Wound ◽  
Hematopoietic Stem ◽  
Vessel Structure

Bone marrow stem cells, especially, endothelial precursor cells (EPC), mesenchymal stem cells (MSC) or hematopoietic stem cell (HSC) are expected as reparative cells for the repair of a variety of tissue damages such as stroke and myocardial infarction, even though their role in the repair is not demonstrated. This report was investigated to find a role of Substance-p (SP) as a reparative agent in the tissue repair requiring EPC and MSC. In order to examine EPC (EPC SP ) and MSC (MSC SP ) mobilized by SP, we injected SP intravenously for consecutive 2 days and saline was injected as a vehicle. At 3 post injection, peripheral blood (PB) was collected.To get mesenchymal stem cells or endothelial progenitor cells, MNCs were incubated in MSCGM or EGM-2 respectively for 10 days. Functional characteristics of the EPC SP were proven by the capacity to form endothelial tubule network in the matrigel in vitro and in the matrigel plug assay in vivo. In contrast, MSC SP did not form a tube-like structure but formed a pellet-structure on matrigel. However, when both cells were premixed before the matrigel assay, much longer and branched tubular network was formed, in which a-SMA expressing MSC SP were decorating outside of the endothelial tube, especially enriched at the bifurcating point. MSC SP may contribute and reinforce elaborate vascular network formation in vivo by working as pericyte-like cells. Thus, the EPC SP and MSC SP were labeled with PKH green and PKH red respectively and their tubular network was examined. Well organized tubular network was formed, which was covered by PKH green labeled cells and was decorated in a punctate pattern by PKH red labeled cells. In order to investigate the role of EPC SP and MSC SP specifically in vivo, rabbit EPC SP and MSC SP were transplanted to full thickness skin wound. The vessel of EPC SP -transplanted groups was UEA-lectin+, which was not covered with a-SMA+ pericytes but EPC SP + MSC SP -transplanted groups showed, in part, a-SMA+ pericyte-encircled UEA-lectin+ vessels. This proved the specific role of MSC SP as pericytes. From these data, we have postulated that the collaboration of MSC and EPC is essential for normal vessel structure and furthermore, accelerated wound healing as ischemia diseases, which can be stimulated through by SP injection.

scholarly journals Prostacyclin as a potent effector of adipose-cell differentiation

1989 ◽  
Vol 257 (2) ◽  
pp. 399-405 ◽  
Author(s):  
R Négrel ◽  
D Gaillard ◽  
G Ailhaud
Keyword(s):  
Arachidonic Acid ◽  
Cyclic Amp ◽  
Critical Role ◽  
Terminal Differentiation ◽  
Prostaglandin F2 Alpha ◽  
Adipogenic Effect ◽  
Adipose Cells

The terminal differentiation of Ob1771 pre-adipose cells induced by arachidonic acid in serum-free hormone-supplemented medium containing insulin, transferrin, growth hormone, tri-iodothyronine and fetuin (5F medium) was strongly diminished in the presence of inhibitors of prostaglandin synthesis, namely aspirin or indomethacin. Carbaprostacyclin, a stable analogue of prostacyclin (prostaglandin I2) known to be synthesized by pre-adipocytes and adipocytes, behaved as an efficient activator of cyclic AMP production and was able, when added to 5F medium, to mimic the adipogenic effect of arachidonic acid. Prostaglandins E2, F2 alpha and D2, unable to affect the cyclic AMP production, failed to substitute for carbaprostacyclin. However, prostaglandin F2 alpha, which is another metabolite of arachidonic acid in pre-adipose and adipose cells, able to promote inositol phospholipid breakdown and protein kinase C activation, potentiated the adipogenic effect of carbaprostacyclin. In addition, carbaprostacyclin enhanced both a limited proliferation and terminal differentiation of adipose precursor cells isolated from rodent and human adipose tissues maintained in primary culture. These results demonstrate the critical role of prostacyclin and prostaglandin F2 alpha on adipose conversion in vitro and suggest a paracrine/autocrine role of both prostanoids in the development of adipose tissue in vivo.

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