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

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.

Impaired baroreflex gain during pregnancy in conscious rats: role of brain insulin.

Pregnancy impairs baroreflex gain, but the mechanism is incompletely understood. To test the hypothesis that reductions in brain insulin contribute, we determined whether pregnant rats exhibit lower cerebrospinal fluid (CSF) insulin concentrations and whether intracerebroventricular infusion of insulin normalizes gain of baroreflex control of heart rate in conscious pregnant rats. CSF insulin was lower in pregnant (68 ± 21 pg/mL) compared to virgin (169 ± 25 pg/mL) rats (P < 0.05). Pregnancy reduced baroreflex gain (pregnant 2.4 ± 0.2 bpm/mm Hg, virgin 4.6 ± 0.3 bpm/mm Hg; P < 0.0001) and the maximum heart rate elicited by hypotension (pregnant 455 ± 15 bpm, virgin 507 ± 12 bpm; P = 0.01). Infusion of insulin (100 µU/min) intracerebroventricularly increased baroreflex gain in pregnant (2.4 ± 0.4 to 3.9 ± 0.5 bpm/mm Hg; P < 0.01) but not virgin (4.6 ± 0.4 to 4.2 ± 0.4 bpm/mm Hg; NS) rats. Maximum heart rate was not altered by intracerebroventricular insulin in either group. Interestingly, while in pregnant rats the baroreflex was unchanged by intracerebroventricular infusion of the artificial CSF vehicle, in virgin rats, vehicle infusion lowered baroreflex gain (4.7 ± 0.3 to 3.9 ± 0.3 bpm/mm Hg; P < 0.05) and the maximum baroreflex heart rate (495 ± 19 to 444 ± 21 bpm; P < 0.05). These data support the hypothesis that brain insulin is required to support optimal baroreflex function and that a decrease in brain insulin contributes to the fall in baroreflex gain during pregnancy.

Baroreflex sensitivity varies during the rat estrous cycle: role of gonadal steroids.

Baroreflex sensitivity (BRS) increases in women during the luteal phase of the menstrual cycle, when gonadal hormones are elevated, but whether a similar cycle-dependent variation in BRS occurs in rats is unknown. In addition, whether cyclic BRS changes depend on gonadal steroids has not been previously investigated. To test these hypotheses, BRS was determined in cycling female rats using two approaches: 1) baroreflex control of renal sympathetic nerve activity (RSNA) in anesthetized rats; 2) cardiovagal spontaneous BRS (sBRS) in conscious rats instrumented for continuous telemetric measurements of mean arterial pressure (MAP) and heart rate (HR). MAP, HR, and sBRS were also measured in rats 2-3 and 5-6 wk following ovariectomy (OVX), to eliminate gonadal steroids. In anesthetized rats, RSNA BRS gain was increased (P < 0.01) during proestrus (-4.8+/-0.5% control/mmHg) compared with diestrus/estrus (-2.8 +/- 0.3% control/mmHg). Similarly, a proestrous peak in sBRS was observed in conscious rats (1.66 +/- 0.07 ms/mmHg, proestrus; 1.48 +/- 0.06 ms/mmHg, diestrus/estrus; P < 0.001). OVX eliminated estrous cycle-induced variation in sBRS. In addition, OVX reduced (P < 0.05) diurnal variations in MAP (5.9 +/- 0.3 vs. 3.9 +/- 0.5 mmHg) and HR [54 +/- 4 vs. 39 +/- 3 beats per minute (bpm)], and abolished diurnal variations in sBRS. Finally, while MAP, HR, and sBRS were decreased 2-3 wk following OVX, approximately 3 wk later, MAP and sBRS increased, and HR decreased further. No changes in MAP, HR, or sBRS were seen with time in sham OVX controls. In summary, RSNA and cardiovagal sBRS vary during the rat estrous cycle, and this variation is abolished by OVX. We conclude that sex steroid hormones are required for both cyclic and diurnal changes in BRS in rats.