Insulin resistance and impaired baroreflex gain during pregnancy

Abstract

Pregnancy decreases baroreflex gain, but the underlying mechanism is unclear. Insulin resistance, which has been associated with reduced transport of insulin into the brain, is a consistent feature of many conditions exhibiting impaired baroreflex gain, including pregnancy. Therefore, using conscious pregnant and nonpregnant rabbits, we tested the novel hypothesis that the pregnancy-induced impairment in baroreflex gain is due to insulin resistance and reduced brain insulin. Baroreflex gain was determined by quantifying changes in heart rate in response to stepwise steady-state changes in arterial pressure, secondary to infusion of nitroprusside and phenylephrine. We found that insulin sensitivity and baroreflex gain were strongly correlated in nonpregnant and term pregnant rabbits (r2 = 0.59). The decrease in insulin sensitivity and in baroreflex gain exhibited similar time courses throughout pregnancy, reaching significantly lower levels at 3 wk of gestation and remaining reduced at 4 wk (term is 31 days). Treatment of rabbits with the insulin-sensitizing drug rosiglitazone during pregnancy almost completely normalized baroreflex gain. Finally, pregnancy significantly lowered cerebrospinal fluid insulin concentrations. These data identify insulin resistance as a mechanism underlying pregnancy-induced baroreflex impairment and suggest, for the first time in any condition, that decreased brain insulin concentrations may be the link between reductions in peripheral insulin sensitivity and baroreflex gain.

Pregnancy and the endocrine regulation of the baroreceptor reflex

“…In support of this hypothesis, decreases in insulin sensitivity (40,47,100,114,141,167) and baroreflex gain (16,24,47,122) exhibit the same time course during gestation in humans, rabbits (Fig. 3), and rats.…”

“…Interesting, preeclampsia produces further reductions in insulin sensitivity (100, 180) and, as indicated above, is associated with further baroreflex impairment. More importantly, when pregnant rabbits were treated throughout gestation with the insulin-sensitizing drug rosiglitazone, insulin sensitivity improved and, to the same extent, baroreflex gain increased, without altering other aspects of the sigmoidal baroreflex curve (47). Collectively, these data implicate insulin resistance as a factor involved in the baroreflex impairment induced by pregnancy.…”

“…69,163), including infusion of vasoactive drugs to generate complete sigmoidal baroreflex relationships between arterial pressure and heart rate or sympathetic nerve activity. Three aspects of these curves are particularly attenuated: the midpoint of the baroreflex function curve relative to MAP or the "set point," the maximal level of heart rate or sympathetic activity achieved when arterial pressure is lowered, and the maximal gain or sensitivity of the most linear segment of the curve (24,47,89,123,149) (Fig. 1).…”

“…] cin, adipokines such as leptin, and inflammatory factors such as TNF-␣ and IL-6. Longitudinal studies during pregnancy indicate that the depression of baroreflex function does not correlate temporally with hemodynamic changes (e.g., blood volume, blood pressure, or cardiac output), at least in rats (24,178) and rabbits (47,147,162), suggesting that different factors are involved. Moreover, estrogen is likely not an initiating factor, since levels are not increased significantly in some species such as rabbit and sheep, and since several studies have demonstrated that this steroid enhances arterial baroreflex function via an action in the hindbrain (135,155,169).…”

GABA in the paraventricular nucleus tonically suppresses baroreflex function: alterations during pregnancy

“…The present results demonstrating reduced GABA influences in PVN suggest that the effect of 3␣-OH-DHP to enhance GABA actions in the PVN is minimal. Second, pregnancy decreases brain insulin, which contributes to the fall in BRG (1,9). Insulin normally increases baroreflex gain via an action in the hypothalamus (26) and the PVN is involved (3).…”