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

Abstract

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.

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

“…Whereas the initial administration of OA had no significant influence on unstimulated uterine contractions, in relation to baseline and controls, this single OA treatment significantly inhibited the responsiveness of mouse uterine horns to OT-stimulated contractions. This OA-induced suppression of OT-stimulated contractions is similar to that recently described in the estrogen-primed rat myometrial strip system [42].…”

Role of serine-threonine phosphoprotein phosphatases in smooth muscle contractility

“…Hence, PP2A inhibitors are expected to cause smooth muscle contraction. Paradoxically, inhibitor-based studies have shown that Յ1-3 M OA caused relaxation in rat, guinea pig, dog, pig, and bovine vasculature, rat myometrium, and bovine trachea smooth muscles (1,10,11,18,28,29,102,109,211,235). In myometrium, only Ͼ10 M OA produced contraction or temporary contraction and then relaxation, and these contractions were attributed to PP1 inhibition (10,28,29).…”