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Oxytocin-induced desensitization of the oxytocin receptor
Christopher Robinson1, Ralph Schumann, Peisheng Zhang
1Department of Obstetrics and Gynecology, Medical University of South Carolina, USA.
Objective:
The purpose of this study was to characterize the oxytocin-induced desensitization of oxytocin-stimulated rises of intracellular calcium in cultured human myocytes.
Study Design:
Culture lines were begun from biopsy specimens of myometrium that had been obtained from women who underwent low transverse cesarean deliveries. Fluorescence changes of calcium green-1 were used to demonstrate the rises of intracellular free calcium. Cells were exposed to 10 nmol/L oxytocin for 1 to 6 hours before the experimentation, allowed to rest for 10 minutes, and then tested for the fluorescence increases that resulted from exposure to 10 nmol/L oxytocin and micromol/L prostaglandin F(2)(alpha). Subpopulations were defined as type 1 (responded to both oxytocin and prostaglandin F(2)(alpha)), type 2 (responded only to oxytocin), type 3 (responded only to prostaglandin F(2)(alpha)), or type 4 (responded to neither). The distribution of the subpopulations of cells was assessed by the determination of the response of every cell in every experimental run.
Results:
Pretreatment with oxytocin resulted in a decrease in the percentage of cells that responded to subsequent oxytocin exposure. The decrease was dependent on the duration of oxytocin exposure and was well fit with the Boltzmann sigmoid function. The duration of oxytocin exposure that yielded half-inactivation was 4.2 hours. Without oxytocin pretreatment, the distribution of subpopulations were 37.0% +/- 18.0% (type 1), 23.1% +/- 11.5% (type 2), 12.6% +/- 8.0% (type 3), and 27.3% +/- 22.9% (type 4). After 6 hours of oxytocin pretreatment, the percentage of type 1 and type 2 cells decreased to 2.4% +/- 3.8% and 2.6% +/- 2.4%, respectively, although the percentage of type 3 and type 4 cells increased to 20.4% +/- 18.9% and 74.6% +/- 22.1%, respectively.
Conclusion:
Oxytocin-induced desensitization of myocytes to oxytocin stimulation occurred over a clinically relevant time frame (4.2 hours). Continued responsiveness of the cells to prostaglandin F(2)(alpha) stimulation after 6 hours of oxytocin pretreatment indicated that postreceptor signaling pathways were maintained, which indicates that the oxytocin receptor likely is involved in the mechanism of myocyte desensitization to oxytocin stimulation.
Insights
Oxytocin exposure desensitizes human myocytes to further oxytocin stimulation, with half-inactivation occurring at 4.2 hours. This suggests the oxytocin receptor plays a key role in myocyte desensitization during labor.
Area of Science:
- Reproductive biology
- Cell signaling
- Pharmacology
Background:
- Oxytocin is crucial for uterine contractions during labor.
- Understanding oxytocin's effects on myometrial cells is vital for managing labor and delivery.
- Desensitization mechanisms can impact the efficacy of oxytocin during labor.
Purpose of the Study:
- To characterize oxytocin-induced desensitization in cultured human myometrial cells.
- To investigate the time course and cellular response changes associated with oxytocin desensitization.
- To determine the potential involvement of the oxytocin receptor in this desensitization process.
Main Methods:
- Human myometrial cells were cultured from biopsy specimens.
- Intracellular calcium rises were measured using calcium green-1 fluorescence.
- Cells were pretreated with oxytocin (10 nmol/L) for varying durations (1-6 hours) before stimulation.
- Cellular responses to oxytocin and prostaglandin F(2)(alpha) were assessed to define subpopulations.
Main Results:
- Oxytocin pretreatment significantly decreased the percentage of cells responding to subsequent oxytocin stimulation.
- This desensitization effect was duration-dependent, with a half-inactivation time of 4.2 hours.
- After 6 hours of oxytocin pretreatment, responsive cell subpopulations (Type 1 and 2) decreased dramatically, while unresponsive subpopulations (Type 3 and 4) increased.
Conclusions:
- Oxytocin-induced myocyte desensitization occurs within a clinically relevant timeframe (4.2 hours).
- The maintained responsiveness to prostaglandin F(2)(alpha) suggests that post-receptor signaling pathways remain intact.
- These findings implicate the oxytocin receptor in the mechanism of myocyte desensitization to oxytocin stimulation.