Beta adrenergic receptor activation attenuates the generation of inositol phosphates in the pregnant rat myometrium. Correlation with inhibition of Ca++ influx, a cAMP-independent mechanism.

Jan 1, 1996The Journal of pharmacology and experimental therapeutics

Activating beta adrenergic receptors reduces signaling molecules in pregnant rat uterus by blocking calcium entry through a pathway independent of cAMP

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Abstract

An averaged 30% of inositol phosphate accumulation in pregnant rat myometrium was inhibited by oxodipine.

The generation of inositol phosphates is partially dependent on calcium influx through voltage-gated calcium channels.
Carbachol and oxytocin elicited a two-phase calcium response, with an initial peak of about 700 nM followed by a sustained level of about 120 nM.
Oxodipine reduced the calcium peak by 40% and the sustained phase by 50%, indicating its role in calcium influx.
Isoproterenol produced a similar reduction in inositol phosphate response as oxodipine, with a 40% decrease in the calcium peak and a 70% decrease in the plateau phase.
The effects of isoproterenol on inositol phosphate accumulation and calcium increase were reversed by pertussis toxin, suggesting a specific signaling pathway.
Forskolin did not influence inositol phosphate accumulation or the calcium peak induced by oxytocin.

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In the pregnant rat myometrium, an averaged 30% of inositol phosphate accumulation induced by carbachol and oxytocin was inhibited by oxodipine indicating that a part of receptor-mediated generation of inositol phosphates depended on Ca++ influx through voltage-gated Ca++ channels. In fura-2-loaded cells, carbachol and oxytocin caused a two-phase [Ca++]i response, made up of a transient [Ca++]i peak of about 700 nM followed by a sustained phase of about 120 nM. Oxodipine reduced the [Ca++]i peak by 40% and the plateau phase by 50%, pointing to a contribution of Ca++ influx in both the [Ca++]i peak and sustained phase. Isoproterenol reduced inositol phosphate response to carbachol and oxytocin to an amount equivalent to that elicited by oxodipine. No additional reduction could be obtained in a combination of isoproterenol and oxodipine. Isoproterenol decreased by 40% the [Ca++]i peak and by 70% the [Ca++]i plateau phase. Differently from isoproterenol, forskolin did not affect inositol phosphate accumulation induced by oxytocin and failed to attenuate the [Ca++]i peak. The inhibitory effect of isoproterenol on both inositol phosphate accumulation and [Ca++]i increase induced by oxytocin was abolished by pertussis toxin. These data suggest that beta adrenergic receptor activation is linked via a cAMP-independent, pertussis toxin-sensitive process to an activation of K+ channels, as revealed by use of selective K+ channel antagonists, with the consequent closure of voltage-gated Ca++ channels, resulting in the inhibition of the Ca(++)-associated generation of inositol phosphates.

Beta adrenergic receptor activation attenuates the generation of inositol phosphates in the pregnant rat myometrium. Correlation with inhibition of Ca++ influx, a cAMP-independent mechanism.

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