EP2 receptors mediate airway relaxation to substance P, ATP, and PGE2

2001 ◽  
Vol 281 (2) ◽  
pp. L469-L474 ◽  
Author(s):  
Christopher N. Fortner ◽  
Richard M. Breyer ◽  
Richard J. Paul
Keyword(s):  
Smooth Muscle ◽  
Substance P ◽  
Experimental Evidence ◽  
Airway Epithelium ◽  
Muscle Function ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Wild Type ◽  
Targeted Deletion ◽  
Smooth Muscle Function

Substance P (SP) and ATP evoke transient, epithelium-dependent relaxation of constricted mouse tracheal smooth muscle. Relaxation to either SP or ATP is blocked by indomethacin, but the specific eicosanoid(s) involved have not been definitively identified. SP and ATP are reported to release PGE2 from airway epithelium in other species, suggesting PGE2 as a likely mediator in epithelium-dependent airway relaxation. Using mice homozygous for a gene-targeted deletion of the EP2 receptor [EP2(−/−)], one of the PGE2 receptors, we tested the hypothesis that PGE2 is the primary mediator of relaxation to SP or ATP. Relaxation in response to SP or ATP was significantly reduced in tracheas from EP2(−/−) mice. There were no differences between EP2(−/−) and wild-type tracheas in their physical dimensions, contraction to ACh, or relaxation to isoproterenol, thus ruling out any general alterations of smooth muscle function. There were also no differences between EP2(−/−) and wild-type tracheas in basal or stimulated PGE2 production. Exogenous PGE2 produced significantly less relaxation in EP2(−/−) tracheas compared with the wild type. Taken together, this experimental evidence supports the following two conclusions: EP2 receptors are of primary importance in airway relaxation to PGE2 and relaxation to SP or ATP is mediated through PGE2 acting on EP2 receptors.

scholarly journals The effects of wild-type and mutant SOD1 on smooth muscle contraction

2015 ◽  
Vol 67 (1) ◽  
pp. 187-192 ◽  
Author(s):  
Aleksandra Nikolic-Kokic ◽  
Zorana Orescanin-Dusic ◽  
Ivan Spasojevic ◽  
Dusko Blagojevic ◽  
Zorica Stevic ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Muscle Relaxation ◽  
Smooth Muscles ◽  
Smooth Muscle Contraction ◽  
Smooth Muscle Relaxation ◽  
Transgenic Rat ◽  
Wild Type ◽  
Liver Copper ◽  
Ion Conducting ◽  
G93a Sod1

In this work we compared the mutated liver copper zinc-containing superoxide dismutase (SOD1) protein G93A of the transgenic rat model of familial amyotrophic lateral sclerosis (FALS), to wild-type (WT) rat SOD1. We examined their enzymatic activities and effects on isometric contractions of uteri of healthy virgin rats. G93A SOD1 showed a slightly higher activity than WT SOD1 and, in contrast to WT SOD1, G93A SOD1 did not induce smooth muscle relaxation. This result indicates that effects on smooth muscles are not related to SOD1 enzyme activity and suggest that heterodimers of G93A SOD1 form an ion-conducting pore that diminishes the relaxatory effects of SOD1. We propose that this type of pathogenic feedback affects neurons in FALS.

N-Acetylcysteine Does Not Improve the Endothelial and Smooth Muscle Function in the Human Saphenous Vein

2007 ◽  
Vol 41 (3) ◽  
pp. 239-245 ◽  
Author(s):  
Muhammad Anees Sharif ◽  
Ulvi Bayraktutan ◽  
Ian Stuart Young ◽  
Chee Voon Soong
Keyword(s):  
Smooth Muscle ◽  
Saphenous Vein ◽  
Muscle Function ◽  
Ex Vivo ◽  
Smooth Muscle Relaxation ◽  
Organ Bath ◽  
Human Saphenous Vein ◽  
Vein Segment ◽  
Significant Difference ◽  
Smooth Muscle Function

Oxidative stress can lead to vein graft dysfunction in the saphenous vein. This ex vivo study is aimed to compare the effects of increasing concentrations of the antioxidant N-acetylcysteine (NAC) with heparinized saline (HS) on endothelial and smooth muscle function in the human saphenous vein. Long saphenous vein segment obtained during infrainguinal bypass surgery was divided into 7 rings; 1 immersed in HS and the remaining 6 in increasing NAC concentrations (0.0025%, 0.005%, 0.01%, 0.02%, 0.03%, and 0.04%). Rings were mounted in an organ bath, and relaxant responses to acetylcholine and sodium nitroprusside were assessed through isometric tension studies. Endothelium-dependent relaxations were observed in 77 vein segments from 11 patients. No significant difference was seen in veins treated with either lower NAC concentrations (0.0025%, 0.005%, 0.01%, 0.02%, and 0.03%) or HS. However, HS-treated veins showed significantly better relaxation compared to those treated with maximum (0.04%) NAC ( P < .05). Endothelium-independent relaxations were observed in 91 segments from 13 patients. No difference in relaxation was observed between veins treated with HS or any of the NAC concentrations. In conclusion, lower NAC concentrations do not offer better endothelial protection than HS, whereas the highest NAC concentration has a detrimental effect on endothelium-dependent relaxation. Moreover, NAC did not show beneficial effect on direct smooth muscle relaxation.

scholarly journals Epithelium-dependent regulation of airways smooth muscle function. A histamine-nitric oxide pathway

1998 ◽  
Vol 7 (6) ◽  
pp. 409-411 ◽  
Author(s):  
Konstantinos Gourgoulianis ◽  
Zoe Iliodromitis ◽  
Apostolia Hatziefthimiou ◽  
Paschalis-Adam Molyvdas
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Airway Epithelium ◽  
Muscle Function ◽  
Smooth Muscles ◽  
Airways Smooth Muscle ◽  
Smooth Muscle Function ◽  
No Release ◽  
Nos Inhibitor

The airway epithelium is responsible for the production of a number of arachidonic acid and nonprostanoid inhibitory factors. Epithelium synthesises nitric oxide (NO) which may be important in regulating the function of airways smooth muscles. We studiedin vitrothe effect of histamine (100 nM100 μ M) which increases the NO release on rabbit airway smooth muscles induced by 80 mM KCl in the presence or not of 10-5Methylene blue (MB) (inactivator of guanylate cyclase) or N(G)-monomethyl L-arginine (L-NMMA), a NOS inhibitor. All experiments were done in tracheal muscle strips from 28 rabbits with epithelium and after epithelium removal. The additional use of histamine (1 μ M) on KCl contraction induced a relaxation of 10% of the initial contraction. The additional use of L-NMMA decreased the relaxation to 5% of initial contraction. MB rather than L-NMMA increased the contraction significantly(p<0.01). Epithelium removal increased the contraction induced by KCl (80 mM) and histamine (1 μ M) by about 30%(p<0.001). NO release especially from epithelium regulates the airways smooth muscle functions. Damage to the epithelium may contribute to an increase in airways sensitivity, observed in asthma.

scholarly journals The Effects of Human Wild-Type and Fals Mutant L144P SOD1 on Non-Vascular Smooth Muscle Contractions / EFEKTI HUMANE NORMALNE I FALS MUTIRANE L144P SOD1 NA NEVASKULARNE KONTRAKCIJE GLATKIH MIŠIĆA

2013 ◽  
Vol 32 (4) ◽  
pp. 375-379
Author(s):  
Aleksandra Nikolić-Kokić ◽  
Zorana Oreščanin-Dušić ◽  
Marija Slavić ◽  
Ivan Spasojević ◽  
Zorica Stević ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Muscle Relaxation ◽  
Disease Onset ◽  
Smooth Muscle Relaxation ◽  
Wild Type ◽  
Feedback Effects ◽  
Copper Zinc ◽  
Smooth Muscle Contractions ◽  
Human Sod1

Summary Background: Mutated copper, zinc-containing superoxide dismutase (SOD1) may self-aggregate, an event that could also be an initial cause of motor neuron malfunction leading to disease onset. The effects of human mutated SOD1 pro- tein from the blood of familial amyotrophic lateral sclerosis (FALS) patients bearing Leu144Phe (L144F) mutation were compared to wild-type (WT) human SOD1 derived from healthy examinees, for enzymatic activity and the effects on isometric contractions of non-vascular smooth muscle. Methods: We isolated WT and L144F SOD1 enzymes from eight patients with FALS, L144F mutation in exon 5 and eight healthy controls. We then investigated SOD1 activities in the obtained samples by the adrenaline method and pro- filed them electrophoretically. Finally, we applied WT and L144F SOD1 on the isolated rat uterus. Results: L144F SOD1 showed lower superoxide-dismutating activity compared to WT human SOD1. We found that, in contrast to WT human SOD1, mutated L144F does not induce smooth muscle relaxation. Conclusions: Our data suggest that the lack of relaxation of muscle tonus in the presence of mutated SOD1 may have pathogenic feedback effects in FALS.

Inhibition of sustained smooth muscle contraction by PKA and PKG preferentially mediated by phosphorylation of RhoA

2003 ◽  
Vol 284 (6) ◽  
pp. G1006-G1016 ◽  
Author(s):  
Karnam S. Murthy ◽  
Huiping Zhou ◽  
John R. Grider ◽  
Gabriel M. Makhlouf
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Muscle Relaxation ◽  
Phosphorylation Site ◽  
Rho Kinase ◽  
Muscle Cells ◽  
Smooth Muscle Contraction ◽  
Smooth Muscle Relaxation ◽  
Wild Type ◽  
Constitutively Active

The role of RhoA in myosin light-chain (MLC)20 dephosphorylation and smooth muscle relaxation by PKA and PKG was examined in freshly dispersed and cultured smooth muscle cells expressing wild-type RhoA, constitutively active RhoV14, and phosphorylation site-deficient RhoA188. Activators of PKA (5,6-dichloro-1-β-ribofuranosyl benzimidazole 3′,5′-cyclic monophosphothionate, Sp-isomer; cBIMPS) or PKG [8-(4-chlorophenylthio)guanosine 3′,5′-cyclic monophosphate (8-pCPT-cGMP), sodium nitroprusside (SNP)] or both PKA and PKG (VIP) induced phosphorylation of constitutively active RhoV14 and agonist (ACh)- or GTPγS-stimulated wild-type RhoA but not RhoA188. Phosphorylation was accompanied by translocation of membrane-bound wild-type RhoA and RhoV14 to the cytosol and complete inhibition of ACh-stimulated Rho kinase and phospholipase D activities, RhoA/Rho kinase association, MLC20phosphorylation, and sustained muscle contraction. Each of these events was blocked depending on the agent used, by the PKG inhibitor KT5823 or the PKA inhibitor myristoylated PKI. Inhibitors were used at a concentration (1 μM) previously shown by direct measurement of kinase activity to selectively inhibit the corresponding kinase. In muscle cells overexpressing the active phosphorylation site-deficient mutant RhoA188, MLC20 phosphorylation was partly inhibited by SNP, VIP, cBIMPS, and 8-pCPT-cGMP, suggesting the existence of an independent inhibitory mechanism downstream of RhoA. Results demonstrate that dephosphorylation of MLC20 and smooth muscle relaxation are preferentially mediated by PKG- and PKA-dependent phosphorylation and inactivation of RhoA.

scholarly journals Airway smooth muscle relaxation is impaired in mice lacking the p47phoxsubunit of NAD(P)H oxidase

2008 ◽  
Vol 294 (1) ◽  
pp. L139-L148 ◽  
Author(s):  
Pasquale Chitano ◽  
Lu Wang ◽  
Stanley N. Mason ◽  
Richard L. Auten ◽  
Erin N. Potts ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Relaxation ◽  
Reactive Oxygen ◽  
Smooth Muscle Relaxation ◽  
Oxygen Species ◽  
Wild Type ◽  
Shortening Velocity

NAD(P)H oxidase is one of the critical enzymes mediating cellular production of reactive oxygen species and has a central role in airway smooth muscle (ASM) cell proliferation. Since reactive oxygen species also affect ASM contractile response, we hypothesized a regulatory role of NAD(P)H oxidase in ASM contractility. We therefore studied ASM function in wild-type mice (C57BL/6J) and mice deficient in a component (p47phox) of NAD(P)H oxidase. In histological sections of the trachea, we found that the area occupied by ASM was 17% more in p47phox−/−than in wild-type mice. After correcting for the difference in ASM content, we found that force generation did not vary between the two genotypes. Similarly, their ASM shortening velocity, maximal power, and sensitivity to acetylcholine, as well as airway responsiveness to methacholine in vivo, were not significantly different. The main finding of this study was a significantly reduced ASM relaxation in p47phox−/−compared with wild-type mice both during the stimulus and after the end of stimulation. The tension relaxation attained at the 20th second of electric field stimulation was, respectively, 17.6 ± 2.4 and 9.2 ± 2.3% in null and wild-type mice ( P <0.01 by t-test). Similar significant differences were found in the rate of tension relaxation and the time required to reduce tension by one-half. Our data suggest that NAD(P)H oxidase may have a role in the structural arrangement and mechanical properties of the airway tissue. Most importantly, we report the first evidence that the p47phoxsubunit of NAD(P)H oxidase plays a role in ASM relaxation.

Carbon dioxide enhances substance P-induced epithelium-dependent bronchial smooth muscle relaxation in Sprague–Dawley rats

2011 ◽  
Vol 89 (7) ◽  
pp. 513-520 ◽  
Author(s):  
Tamer Y. El Mays ◽  
Mahmoud Saifeddine ◽  
Parichita Choudhury ◽  
Morley D. Hollenberg ◽  
Francis H.Y. Green
Keyword(s):  
Carbon Dioxide ◽  
Smooth Muscle ◽  
Substance P ◽  
Airway Smooth Muscle ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Sprague Dawley ◽  
Bronchial Smooth Muscle ◽  
Hepes Buffer ◽  
Effects Of Ph

Hypocapnia and hypercapnia constrict and relax airway smooth muscle, respectively, through pH- and calcium (Ca2+)-mediated mechanisms. In this study we explore a potential role for the airway epithelium in these responses to carbon dioxide (CO2). Contractile and relaxant responses of isolated rat bronchial rings were measured under hypocapnic, eucapnic, and hypercapnic conditions. Substance P was added to methacholine precontracted bronchial rings with and without epithelium. The role of Ca2+ was assessed using Ca2+-free solutions and a Ca2+ channel blocker, nifedipine. The effects of pH were assessed in solutions with HEPES buffer. Hypocapnic challenge increased the organ bath’s pH and increased bronchial smooth muscle resting tension. This effect was abolished with HEPES buffer and partially inhibited by nifedipine. Hypocapnic conditions suppressed substance P-induced epithelium-dependent relaxation, whereas hypercapnia augmented the response. The epithelial hypocapnic effect was pH dependent, whereas the hypercapnic effect was pH independent. CO2 had no effect on the epithelial independent smooth muscle agonists methacholine and isoproterenol. In conclusion our data indicate that, in addition to the effects of pH and Ca2+, CO2 affects airway smooth muscle by a pH-independent, epithelium-mediated mechanism. These findings could potentially lead to new treatments for asthma involving CO2-sensing receptors in the airways.

scholarly journals A.122 Vascular effects of propofol: smooth muscle relaxation in human isolated veins and arteries

1996 ◽  
Vol 76 ◽  
pp. 38-39
Author(s):  
Eric Le Pelley ◽  
Pierre Corbi ◽  
Thierry Chataigneau ◽  
Robert Tricoche ◽  
Jacques Fusciardi
Keyword(s):  
Smooth Muscle ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Vascular Effects
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