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.

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.

Role of cGMP in relaxation of vascular and other smooth muscle

1989 ◽  
Vol 67 (4) ◽  
pp. 251-262 ◽  
Author(s):  
Kanji Nakatsu ◽  
Jack Diamond
Keyword(s):  
Smooth Muscle ◽  
Muscle Relaxation ◽  
Smooth Muscles ◽  
Phosphodiesterase Inhibitors ◽  
Current Evidence ◽  
Smooth Muscle Relaxation ◽  
Drug Induced ◽  
Intracellular Cgmp ◽  
Tissue Content

The hypothesis that the relaxant action of many drugs on vascular and other smooth muscle is mediated by increases in intracellular cGMP, the "cGMP hypothesis," is gaining wide acceptance. While much information supporting this idea can be found in the literature, there is also a significant amount of information indicating that an elevation in the tissue content of cGMP is by itself insufficient to cause smooth muscle relaxation. The literature is reviewed with reference to the criteria that need to be fulfilled to consider cGMP as the second messenger mediating relaxation of smooth muscle by a drug; i.e., activation of guanylate cyclase, elevation of tissue content of cGMP, potentiation by phosphodiesterase inhibitors, antagonism by inhibitors of cGMP synthesis, and production of relaxation by cGMP analogues. For each criterion, key observations supporting the hypothesis are considered, followed by examples of important observations not consistent with the hypothesis. It is concluded that in some smooth muscles, for example, rat myometrium and vas deferens, cGMP is not a mediator of drug-induced relaxation. In other smooth muscles, including vascular smooth muscle, cGMP appears to play an important role in the relaxation process; but current evidence suggests that other factors are also important and that the cGMP hypothesis may need to be modified.Key words: cGMP, vascular relaxation, smooth muscle relaxation, vasodilators.

scholarly journals Effects of Aqueous Extract of Curcuma Longa Rhizome On Motility of Isolated Rabbit Jejunum

2019 ◽  
Vol 2 (1) ◽  
pp. 13-22
Author(s):  
B Umaru
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Aqueous Extract ◽  
Curcuma Longa ◽  
Muscle Relaxation ◽  
Soxhlet Extraction ◽  
Smooth Muscle Contraction ◽  
Smooth Muscle Relaxation ◽  
Rabbit Jejunum

Turmeric (curcuma longa) is a rhizomatous herbaceous perennial plant of the ginger family and the order Zingerberales. It is widely cultivated and used in the treatment of various ailments. In this study, the effect of aqueous extract of C. longa on isolated rabbit jejunum was investigated in vitro using Physiograph (Meditech, India). The rhizome of Curcumin was extracted using Soxhlet extraction method and distilled water was used as a solvent. The elemental analysis was determined using AAS and the result revealed the presence of Potassium, Magnesium, Iron and Nitrogen. The percentage concentrations of trace elements in the aqueous Curcumin rhizome were within the WHO standard limit. The aqueous extract at concentration tested (100 mg/ml) significantly decreased (p<0.05) jejunum smooth muscle contraction. Addition of Atropine (1mM) or Propranolol (1mM) further decreased the amplitude of jejunum smooth muscle contraction. Curcumin rhizome (100 mg/ml) blocked contraction induced by Ach (0.001μg/ml). The result of this work has shown that rhizome of C. longa produced jejunum smooth muscle relaxation, plant extract with antispasmodic activity may reduce gastrointestinal motility thereby delay gastric emptying and may be important in treatment of disease ailments like diarrhoea and colic.

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 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.

Roles of CaM kinase II and phospholamban in SNP-induced relaxation of murine gastric fundus smooth muscles

2006 ◽  
Vol 291 (2) ◽  
pp. C337-C347 ◽  
Author(s):  
Minkyung Kim ◽  
In Soo Han ◽  
Sang Don Koh ◽  
Brian A. Perrino
Keyword(s):  
Smooth Muscle ◽  
Soluble Guanylate Cyclase ◽  
Muscle Relaxation ◽  
Smooth Muscles ◽  
Cyclopiazonic Acid ◽  
Gastric Fundus ◽  
Smooth Muscle Relaxation ◽  
Cam Kinase Ii ◽  
Cam Kinase ◽  
No Donor

The mechanisms by which nitric oxide (NO) relaxes smooth muscles are unclear. The NO donor sodium nitroprusside (SNP) has been reported to increase the Ca2+ release frequency (Ca2+ sparks) through ryanodine receptors (RyRs) and activate spontaneous transient outward currents (STOCs), resulting in smooth muscle relaxation. Our findings that caffeine relaxes and hyperpolarizes murine gastric fundus smooth muscles and increases phospholamban (PLB) phosphorylation by Ca2+/calmodulin (CaM)-dependent protein kinase II (CaM kinase II) suggest that PLB phosphorylation by CaM kinase II participates in smooth muscle relaxation by increasing sarcoplasmic reticulum (SR) Ca2+ uptake and the frequencies of SR Ca2+ release events and STOCs. Thus, in the present study, we investigated the roles of CaM kinase II and PLB in SNP-induced relaxation of murine gastric fundus smooth muscles. SNP hyperpolarized and relaxed gastric fundus circular smooth muscles and activated CaM kinase II. SNP-induced CaM kinase II activation was prevented by KN-93. Ryanodine, tetracaine, 2-aminoethoxydiphenylborate, and cyclopiazonic acid inhibited SNP-induced fundus smooth muscle relaxation and CaM kinase II activation. The Ca2+-activated K+ channel blockers iberiotoxin and apamin inhibited SNP-induced hyperpolarization and relaxation. The soluble guanylate cyclase inhibitor 1 H-[1,2,4]oxadiazolo-[4,3-α]quinoxalin-1-one inhibited SNP-induced relaxation and CaM kinase II activation. The membrane-permeable cGMP analog 8-bromo-cGMP relaxed gastric fundus smooth muscles and activated CaM kinase II. SNP increased phosphorylation of PLB at Ser16 and Thr17. Thr17 phosphorylation of PLB was inhibited by cyclopiazonic acid and KN-93. Ser16 and Thr17 phosphorylation of PLB was sensitive to 1 H-[1,2,4]oxadiazolo-[4,3-α]quinoxalin-1-one. These results demonstrate a novel pathway linking the NO-soluble guanylyl cyclase-cGMP pathway, SR Ca2+ release, PLB, and CaM kinase II to relaxation in gastric fundus smooth muscles.

Change in intramural strain distribution in rat aorta due to smooth muscle contraction and relaxation

1996 ◽  
Vol 271 (4) ◽  
pp. H1711-H1716 ◽  
Author(s):  
T. Matsumoto ◽  
M. Tsuchida ◽  
M. Sato
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Residual Strain ◽  
Strain Distribution ◽  
Muscle Relaxation ◽  
Vessel Diameter ◽  
Smooth Muscle Contraction ◽  
Smooth Muscle Relaxation ◽  
Opening Angle ◽  
Contraction And Relaxation

Effect of smooth muscle contraction on intramural strain distribution in rat thoracic aorta was investigated with residual strain considered. Short segments sliced from the aortas were cut radially to release residual strain in an aerated Krebs-Ringer solution (37 degrees C). Each segment opened up immediately to form an arc. Opening angle was measured at this point and after smooth muscle contraction and relaxation. The angle increased from 97 +/- 11 degrees (means +/- SE, n = 14) to 153 +/- 14 degrees with the contraction and decreased to 68 +/- 9 degrees with the relaxation, indicating increase in residual strain with smooth muscle contraction. Intramural strain distribution at various pressures was calculated from the opening angle and pressure-diameter relations of the aortas. Strain distribution was almost uniform at 55 mmHg under smooth muscle relaxation, whereas this pressure exceeded 200 mmHg because of the increase in residual strain and decrease in vessel diameter under smooth muscle contraction. These results suggest aortic smooth muscle may change its contractile state through myogenic response to keep intramural strain distribution uniform against temporary change in blood pressure and thus maintain mechanical homeostasis in the aortic wall.

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.

Functional characteristics of urinary tract smooth muscles in mice lacking cGMP protein kinase type I

2000 ◽  
Vol 279 (3) ◽  
pp. R1112-R1120 ◽  
Author(s):  
Katarina Persson ◽  
Raj Kumar Pandita ◽  
Attila Aszòdi ◽  
Marianne Ahmad ◽  
Alexander Pfeifer ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Urinary Tract ◽  
Protein Kinase ◽  
Smooth Muscles ◽  
Smooth Muscle Relaxation ◽  
Type I ◽  
Wild Type ◽  
No Donor

Nitric oxide (NO)-mediated smooth muscle relaxation is mediated by cGMP through activation of cGMP-dependent protein kinase I (cGKI). We studied the importance of cGKI for lower urinary tract function in mice lacking the gene for cGKI (cGKI−/−) and in litter-matched wild-type mice (cGKI+/+) in vitro and in vivo. cGKI deficiency did not result in any changes in bladder gross morphology or weight. Urethral strips from cGKI−/− mice showed an impaired relaxant response to nerve-derived NO. The cGMP analog 8-bromo-cGMP (8-BrcGMP) and the NO-donor SIN-1 relaxed the wild-type urethra (50–60%) but had only marginal effects in the cGKI-deficient urethra. Bladder strips from cGKI−/− mice responded normally to electrical field stimulation and to carbachol but not to 8-BrcGMP. In vivo, the cGKI-deficient mice showed bladder hyperactivity characterized by decreased intercontraction intervals and nonvoiding bladder contractions. Loss of cGKI abolishes NO-cGMP-dependent relaxations of urethral smooth muscle and results in hyperactive voiding. These data suggest that certain voiding disturbances may be associated with impaired NO-cGKI signaling.

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