Previous Pregnancies Affect Myometrial Response to Uterotonic Agents at Term, during Labor, and during Involution in Rats

Abstract

ObjectiveOur overall hypothesis is that pregnancy’s mechanical and hormonal stimuli induce permanent changes in the properties of uterine tissue. Our objective here was to quantify the variation in the response to oxytocin, PGE2, and PGF2α of myometrium from pregnant female rats at term, during labor, and during involution.MethodFirst time (Preg1) and second time (Preg2) pregnant female 18 weeks old rats were euthanized either at term (day 22 of gestation, no labor E22), during labor (day 22 of gestation after birth of first pup, E22L), or at involution (2 days after parturition, INV). For each group, 8 rats were used. Six 3×10 mm myometrial strips were suspended in a tissue bath containing Krebs solution (in mM, NaCl 117, KCl 4.7, NaHCO3 25, MgCl2 1.2, KH2PO4 1.2, CaCl2 2.5, glucose 11, pH= 7.4) at 37°C and bubbled with 95% O2 and 5% CO2. Separate dose responses curves to the endogenous uterotonics oxytocin, PGE2, and PGF2 were generated by incremental additions of each drug to the tissue bath (10E‐10 to 10E‐5 M in all cases).ResultsIn E22 tissue, the affinity of oxytocin for its receptor changes somewhat significantly (P= 0.042) between Preg1 (log EC50 −8.53 ± 0.07) and Preg2 (log EC50 −8.72 ± 0.07), while the maximal response to the drug was essentially the same (P<0.05). In E22L tissue, oxytocin log EC50 is similar in Preg1 and Preg2, while maximal response was higher in Preg1 than in Preg2 tissue, (Max for Preg1= 0.97 ± 0.03; Max for Preg2= 0.73 ± 0.06 AUC/AUC KCl, P<0.001). During INV, no differences in log EC50 or Max response were detected (P<0.05). For PGE2, in E22, no significant difference was detected in log EC50 between Preg1 and Preg2. However, maximal response was higher in Preg1 than Preg2 (Max for Preg1= 0.37 ± 0.02; Max for Preg2= 0.28 ± 0.01 AUC/AUC KCl, P=0.012). The same is true for E22L (Max for Preg1= 0.43 ± 0.03; Max for Preg2= 0.33 ± 0.02 AUC/AUC KCl, P=0.018). In INV, instead, the log EC50 was higher for Preg1 than Preg2 (log EC50 for Preg1 −7.52 ± 0.4; log EC50 for Preg1 −6.35 ± 0.1; P=0.006), while the maximal response was stronger in Preg2 than in Preg1 (Max for Preg1= 0.12 ± 0.02; Max for Preg2= 0.28 ± 0.01 AUC/AUC KCl; P<0.001). For PGF2, in E22, logEC50 is similar in Preg1 and Preg2, while Preg2 showed a stronger response than Preg1 (Max for Preg1= 0.48 ± 0.02; Max for Preg2= 0.61 ± 0.02 AUC/AUC KCl; P<0.001) A similar pattern was demonstrated in E22L (Max for Preg1= 0.30 ± 0.01; Max for Preg2= 0.35 ± 0.01 AUC/AUC KCl; P=0.019). Finally, in INV, log EC50 was higher in Preg1 than Preg2 (log EC50 for Preg1= −7.01± 0.09; log EC50 for Preg1 −6.22 ± 0.0.09; P<0.001), but the maximal response was moderately stronger in Preg2 than in Preg1 (Max for Preg1= 0.44 ± 0.01; Max for Preg2= 0.48 ± 0.01 AUC/AUC KCl; P=0.03).ConclusionsIn the past, we demonstrated alteration in the response of never before pregnant and proven breeder myometrial tissues to endogenous uterotonic agents in the non‐pregnant and pregnant state. Our current results show that also at term, during labor, and during involution these responses are modified in smooth muscle that has experienced a previous pregnancy.Support or Funding InformationThis study was funded by an MWU intramural research grant to MP.