Voltage-Gated Calcium Channels and the Parity-Dependent Differential Uterine Response to Oxytocin in Rats

The experience of pregnancy affects uterine function well beyond delivery. We previously demonstrated that the response to oxytocin is more robust in the uteri of proven breeder rats. This study investigates the contribution of T-type calcium channels (TTCCs) and L-type calcium channels (LTCCs) to the distinct response of virgin (V) and proven breeder (PB) rat uteri to oxytocin. Dose-inhibition responses to mibefradil (TTCC inhibitor) and verapamil (LTCC inhibitor) were conducted on isolated V and PB uterine strips. These experiments were followed by dose-response curves to oxytocin (10-10 to 10-5 M) in the presence of 10 µM of each inhibitor. Area-under-the-curve (AUC), amplitude, frequency, and duration of contractions were measured. V uteri generally showed a greater dependence on VGCCs, especially TTCCs. However, PB uteri exhibited a stronger frequency response to oxytocin. Blocking TTCCs had a more pronounced impact on the differential oxytocin response, particularly affecting the frequency component of contractions. The stronger frequency response in PB uteri may be due to a higher concentration of TTCCs in their myometrial pacemaker cells. This study provides supporting evidence that pregnancy induces lasting changes in uterine calcium handling. Our findings suggest that TTCCs play a more important role than LTCC in the parity-dependent differential response to oxytocin. The impact of ORAI and TRP channels still needs to be evaluated, to gain a more comprehensive understanding of the relative impact of voltage-gated calcium channels vs. storage-operated calcium entry channels on this phenomenon.