Inhibitory and contractile effects of okadaic acid on rat uterine muscle

Candenas, Luz; Norte, Manuel; González, Rodrigo; Arteche, Elena; Fernández, Javier; Borges, Ricardo; Boada, J; Advenier, C.; Martı́n, Julio D.

doi:10.1016/0014-2999(92)90492-m

Cited by 7 publications

(5 citation statements)

References 9 publications

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“…Candenas and coworkers [20] first reported that OA could inhibit and stimulate uterine contractions at low (100 nM) and high (5 M) concentrations, respectively. Okadaic acid-stimulated uterine contractions are partially inhibited when transmembrane Ca 2ϩ movement was inhibited with Ca 2ϩ -free media plus EDTA [21,22].…”

Section: Discussionmentioning

confidence: 98%

“…Presently, there is a lack of agreement in regard to whether PP1 and/ or PP2A are the primary smooth muscle PP within these tissues. Likewise, OA has been shown to both inhibit and stimulate contractions of rat myometrial strips depending on concentrations used [20][21][22][23]. Low concentrations (100 Tissues were fixed, paraffin embedded, and exposed to microwave antigen retrieval prior to incubation with primary antibodies or NIRS (A1-A3) followed by biotinylated secondary antibody and colorimetric evaluation with avidin-biotin-peroxidase and DAB.…”

Section: Introductionmentioning

confidence: 99%

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Divergence in Murine Myometrium Spontaneous and Oxytocin-Stimulated Contractile Responses to Serine/Threonine Protein Phosphatase-1 Inhibition1

Smith

Liu

Phillippe

2000

Biology of Reproduction

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Reversible phosphorylation is essential in regulating uterine contractions. Identification, characterization, and functional understanding of myometrium protein phosphatase(s) are lacking. Okadaic acid (OA), which inhibits protein phosphatase-1 (PP1) and PP2A, has been shown to alter uterine contractions. Experiments were conducted to determine the 1) identity of the myometrial OA-sensitive PP, 2) influence of OA on spontaneous and oxytocin (OT)-stimulated myometrial contractions, and 3) expression of uterine PPs during sexual development. Western blot analysis indicated the presence of PP1(alpha) and PP2A in immature and mature mice. As determined by immunohistochemistry, gonadotropin-stimulated adult mouse uteri contain PP1(alpha) in longitudinal and circular myometrial layers and endometrial epithelium. Conversely, PP2A was localized to the endometrial stroma. Cumulative addition of OA (n = 9; 10, 100, 250, 500, 1000 nM) did not significantly alter spontaneous contractions of mouse uterine horns in comparison to vehicle-treated controls (n = 9). By the end of the test period OA- and vehicle-treated uteri displayed a comparable decline in uterine contractions to 79.2% and 63.7%, respectively, of basal contractile activity. Pretreatment of uterine tissue with OA (1 microM; n = 7) significantly reduced contractile response to increasing concentrations of OT (8, 16, 32, 64 nM) in comparison to vehicle pretreatment (dimethyl sulfoxide; n = 7). At the end of the OT-administration period, contractile activity was 160.4% and 67.3% of basal contractile activity for vehicle (no OA) and OA-pretreated groups, respectively. During the early prepubertal period PP1(alpha) was expressed in longitudinal myometrium and absent in circular myometrium; whereas, during the transition to sexual maturity PP1(alpha) was observed in both the longitudinal and circular myometrium. In summary, these studies have indicated 1) that PP1 is the primary myometrial OA-sensitive PP; 2) that inhibition of PP1 had no effect on spontaneous contractions, whereas it markedly inhibited OT-stimulated uterine contractions; and 3) that PP1 is differentially expressed in the circular and longitudinal myometrium in relation to sexual development.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Divergence in Murine Myometrium Spontaneous and Oxytocin-Stimulated Contractile Responses to Serine/Threonine Protein Phosphatase-1 Inhibition1

Smith

Liu

Phillippe

2000

Biology of Reproduction

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“…Okadaic acid mediates both vascular and intestinal smooth muscle contraction independent of extracellular calcium (Ozaki et al , 1987; Obara et al , 1989; Hirano et al , 1989) as a consequence of the inhibition of myosin light chain phosphatase (Takai et al , 1987; Ishihara et al , 1989). In other studies, okadaic acid has been shown to induce relaxation of vascular and uterine smooth muscle (Karaki et al , 1989; Candenas et al , 1992), while in human airways both excitatory and inhibitory effects have been observed (Naline et al , 1994). The mechanism underlying the inhibitory effect of okadaic acid on smooth muscle function is not clear but may relate to a reduction in calcium entry (Naline et al , 1994) and/or to an increase in the open probability of calcium‐dependent potassium channels (Kume et al , 1989).…”

Section: Introductionmentioning

confidence: 95%

The effect of okadaic acid on non‐adrenergic non‐cholinergic contraction in guinea‐pig isolated bronchus

Harrison

Spina

Page

1997

British J Pharmacology

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1 We have investigated the role of phosphatases in modulating contractile responses to electrical ®eld stimulation (EFS), methacholine, substance P and capsaicin in guinea-pig isolated main bronchus by use of the phosphatase 1 and 2A inhibitor okadaic acid. 2 Non-adrenergic non-cholinergic (eNANC) contractile responses were elicited by EFS (3 Hz, 20 s, 0.5 ms max. voltage) in the guinea-pig isolated main bronchus in the presence of the non-selective muscarinic antagonist, atropine (1 mM), the non-selective b-adrenoceptor antagonist, propranolol (1 mM), the neutral endopeptidase inhibitor thiorphan (10 mM) and the cyclo-oxygenase inhibitor, indomethacin (5 mM). Okadaic acid signi®cantly attenuated eNANC contractile responses (% inhibition) elicited by EFS (0.01 mM, 15.2+26.9%; 0.03 mM, 30.4+13.9%; 0.01 mM, 39.8+5.1%; 0.3 mM, 59.5+8.7%; 1 mM 77.8+7.8%; P50.05, n=4). In contrast, the inactive analogue 1-Nor okadaone (0.3 mM) failed to attenuate signi®cantly eNANC contractile responses (% inhibition elicited by 1-Nor okadaone, 71.25+8.5% vs dimethylsulphoxide (DMSO), 713.5+21.5%; P40.05, n=4). 3 Cholinergic contractile responses were elicited by EFS (1 ± 30 Hz, 10 s, 0.5 ms max. voltage) in guinea-pig isolated bronchus in the presence of the nitric oxide synthase inhibitor, N o -nitro-L-arginine methyl ester (L-NAME, 30 mM). Okadaic acid failed to attenuate signi®cantly the contractile (% methacholine E max ) response elicited by EFS at all frequencies tested compared with the control (1 Hz, control, 22+7.9% vs okadaic acid, 18+7.7%; 3 Hz, control, 26+6.9% vs okadaic acid, 27+9.1%; 10 Hz, control, 36+7.6% vs okadaic acid, 33+8.9%; 30 Hz, control, 50+7.6% vs okadaic acid, 42+14%; P40.05, n=4). 4 Okadaic acid (0.3 mM) failed to alter signi®cantly the contractile potency (pD 2 ) to capsaicin (okadaic acid, 9.0+0.5, vs DMSO, 9.2+0.4; P40.05 n=6), substance P (okadaic acid, 7.6+0.3 vs DMSO, 8.2+0.2; P40.05 n=7) or methacholine (okadaic acid, 6.4+0.2 vs DMSO, 6.4+0.3; P40.05 n=4). 5 Okadaic acid (0.01 ± 1 mM) did not appear to reverse substance P-induced tone. The maximal relaxant response (% reversal of substance P-induced tone) mediated by okadaic acid (1 mM) was 33+11.7% (n=4), this was not signi®cantly dierent from the DMSO (0.8%) or a time-dependent fall in tone of 34.3+23.1% (n=4) and 33+15.8% (n=4), respectively. Okadaic acid (0.3 mM) failed to augment isoprenaline-induced relaxation repsonses in substance P contracted bronchus (okadaic acid, 6.5+0.4 vs DMSO, 5.9+0.3; P40.05, n=9). 6 These results indicate that protein phosphatases appear to regulate the release of sensory neuropeptides from airway sensory nerves in response to electrical ®eld stimulation.

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“…Depolarizationinduced contractures as well as spontaneous or agonist-induced rhythmic oscillations are strictly dependent o n external Ca2+ and inhibited by Ltype calcium channel blockers (Parkington and Coleman, 1990;Arteche et al, 1995). W e have previously shown that O A induces both inhibitory and contractile effects in estrogen-primed rat myometrium (Candenas et al, 1992(Candenas et al, , 1994. The inhibitory effects appear at concentrations between 0.1 and 1 pM, lower than those needed to evoke a contractile response.…”

Section: Introductionmentioning

confidence: 96%

Inhibitory effects of okadaic acid on rat uterine contractile responses to different spasmogens

Arteche

Ausina

Delgado

et al. 1997

Fundamemntal Clinical Pharma

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In the present study, we examined the effects of okadaic acid, a selective inhibitor of type 1 and 2A protein phosphatases, on the mechanical responses evoked by oxytocin, K(+)- and Na(+)-modified solutions and ouabain in estrogen-primed rat myometrium. Oxytocin elicited a rapid, phasic contraction followed by rhythmic oscillations. The phasic response was partially resistant to the absence of external Ca2+. Okadaic acid (1 microM) and the L-type calcium channel blocker nifedipine (1 microM) abolished the oscillatory component and reduced the initial, phasic response to about 80% of the control response. High K+ (60 mM) solution, ouabain (1 mM), K(+)-free medium and low Na+ (25 mM) solution induced extracellular Ca(2+)-dependent biphasic responses composed by an early rapid (KCl, ouabain and K(+)-free solution) or slower developed (25 mM Na+ solution) phasic contraction followed by a sustained increase in tension. Okadaic acid and nifedipine, alone or in combination, abolished or decreased similarly the contractile response evoked by these stimulants. The okadaic acid- and nifedipine-insensitive responses to ouabain, K(+)-free and low Na+ solution were enhanced by increasing the extracellular concentration of Ca2+ in the medium and were inhibited in a dose-dependent manner by amiloride (0.05-0.5 mM). These data suggest that, in estrogen-primed rat uterus, dephosphorylating mechanisms by OA-sensitive protein phosphatases play an important role in regulating myometrial contractions elicited by Ca2+ entry through voltage-sensitive Ca2+ channels.

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Inhibitory and contractile effects of okadaic acid on rat uterine muscle

Cited by 7 publications

References 9 publications

Divergence in Murine Myometrium Spontaneous and Oxytocin-Stimulated Contractile Responses to Serine/Threonine Protein Phosphatase-1 Inhibition1

Divergence in Murine Myometrium Spontaneous and Oxytocin-Stimulated Contractile Responses to Serine/Threonine Protein Phosphatase-1 Inhibition1

The effect of okadaic acid on non‐adrenergic non‐cholinergic contraction in guinea‐pig isolated bronchus

Inhibitory effects of okadaic acid on rat uterine contractile responses to different spasmogens

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