Pregnancy impairs baroreflex control of heart rate in rats: role of insulin sensitivity

Abstract

Recent studies in rabbits suggest that insulin resistance and reduced brain insulin contribute to impaired baroreflex control of heart rate (HR) during pregnancy; however, the mechanisms are unknown. The rat model is ideal to investigate these mechanisms because much is known about rat brain baroreflex neurocircuitry and insulin receptor locations. However, it is unclear in rats whether pregnancy impairs the HR baroreflex or whether insulin resistance is involved. Therefore, this study tested the hypothesis that in rats pregnancy decreases HR baroreflex sensitivity (BRS) and that this decrease is related to concurrent decreases in insulin sensitivity (IS). BRS was quantified before, during, and after pregnancy using complementary methods: 1) spontaneous BRS (sBRS) derived from sequence method analysis of telemetric, continuous arterial pressure recordings; and 2) maximal BRS of complete sigmoidal baroreflex relationships. IS was measured (hyperinsulinemic euglycemic clamp) to determine whether BRS and IS change in parallel. sBRS was reduced at midgestation [pregnancy day 10 (P10)], returned to nonpregnant (NP) levels on P18, and fell again at late gestation (P20) (sBRS in ms/mmHg: NP, 1.66 + or - 0.04; P10, 1.17 + or - 0.11; P18, 1.55 + or - 0.12; P20, 1.31 + or - 0.05; n = 5; P < 0.05). Similar triphasic patterns were observed for both maximal BRS [in beats x min(-1) x mmHg(-1): NP, 4.45 + or - 0.52 (n = 10); P11-12, 2.76 + or - 0.11 (n = 7); P17-18, 3.79 + or - 0.14 (n = 5); P19-20, 2.32 + or - 0.40 (n = 8); P < 0.0001] and previous and current measurements of IS (in mg glucose x kg(-1) x min(-1): NP, 32 + or - 2; P19-20, 15 + or - 1; P < 0.0005). Furthermore, during pregnancy, the standard deviation (SD) of MAP increased, and the SD of HR decreased, indirectly suggesting baroreflex impairment. sBRS increased transiently during parturition, and sBRS, maximal BRS, and IS normalized 3-4 days postpartum. In conclusion, pregnancy decreases HR BRS in rats. The parallel temporal changes in BRS and IS suggest a mechanistic link.

Fig. 1.

During rat pregnancy, baroreflex sensitivity (BRS) and mean arterial pressure (MAP) decreased and heart rate increased. These variables normalized during the early postpartum period. ○, Daily averages from the 12-h light phase; •, daily averages from the 12-h dark phase. Gray shading delineates the period of pregnancy. NP, nonpregnant; P10-P20, gestational days 10–20; PP2-PP7, postpartum days 2–7. Days P18-P20 identify the 3 days prior to delivery, which was on P21 or P22. Left: in the group studied during gestation (n = 5), 2-way ANOVA of BRS revealed a significant effect of time (P < 0.0001) and a time by diurnal (light vs. dark) interaction (P < 0.01); no overall diurnal difference was detected (P > 0.25). Two-way ANOVA of heart rate indicated a significant diurnal effect (P < 0.0001) as well as a significant time effect (P < 0.001) and a significant time by diurnal interaction (P < 0.05). Two-way ANOVA of MAP revealed a diurnal effect (P < 0.001), an effect of time (P < 0.0001); the time by diurnal interaction was not quite significant (P = 0.06). Right: in the group studied during the postpartum period [n = 6 (5 rats were also studied during pregnancy, left)], 2-way ANOVA of BRS revealed a significant effect of time (P < 0.0001), but not a significant diurnal effect or a time by diurnal (light vs. dark) interaction. Two-way ANOVA of heart rate revealed a diurnal effect (P < 0.0001), an effect of time (P < 0.0001), and a significant time by diurnal interaction (P < 0.05). Two-way ANOVA of MAP indicated significant diurnal (P < 0.0001) and time (P < 0.001) effects, but not a significant time by diurnal interaction. *P < 0.05 compared with NP within the light or dark phase.

Fig. 2.

Pregnancy decreased the standard deviation (SD) of MAP and increased the SD of heart rate (HR). White bars, daily averages from the 12-h light phase; black bars, daily averages from the 12-h dark phase. Gray shading delineates the period of pregnancy. P12–14, pregnancy days 12–14; P18–20, end gestation; PP2–4, postpartum days 2–4; PP5–7, postpartum days 5–7. Two-way ANOVA of MAP SD revealed a significant diurnal effect (P < 0.005), a significant time effect (P < 0.005), and a significant diurnal by time interaction (P < 0.005). Two-way ANOVA of HR SD revealed a significant time effect only (P < 0.005). *P < 0.05 compared with NP within the light or dark phase of the daily cycle. †P < 0.05, compared with P18–20; n = 5.

Fig. 3.

Maximal baroreflex gain fluctuates during rat gestation. Top: sigmoidal baroreflex curves constructed from the means of Boltzman parameters (Table 1) derived from fits of relationships between arterial pressure and heart rate. Points represent the means ± SE of the maximum and minimum baroreflex parameters, as well as the basal MAP and HR values. Bottom: absolute values of maximal baroreflex gain. NP, n = 10; P12, rats studied on pregnancy days 11 or 12 (n = 7); P18, rats studied on gestational days 17 or 18 (n = 5); P20, rats studied on gestational days 19 or 20 (n = 8); PP3, rats studied on postpartum days 3 or 4 (n = 5). One-way ANOVA revealed significant differences in gain between reproductive days (P < 0.0001). *P < 0.05 compared with NP.

Fig. 4.

Insulin sensitivity was reduced in rats at late gestation (P20, n = 4), compared with NP rats (n = 6) and was normalized in rats on postpartum days 3–4 (PP3, n = 8). One-way ANOVA revealed a significant between-group difference (P = 0.0001). *P < 0.05 compared with NP and PP3.