Pregnancy and the endocrine regulation of the baroreceptor reflex

Abstract

The purpose of this review is to delineate the general features of endocrine regulation of the baroreceptor reflex, as well as specific contributions during pregnancy. In contrast to the programmed changes in baroreflex function that occur in situations initiated by central command (e.g., exercise or stress), the complex endocrine milieu often associated with physiological and pathophysiological states can influence the central baroreflex neuronal circuitry via multiple sites and mechanisms, thereby producing varied changes in baroreflex function. During pregnancy, baroreflex gain is markedly attenuated, and at least two hormonal mechanisms contribute, each at different brain sites: increased levels of the neurosteroid 3alpha-hydroxy-dihydroprogesterone (3alpha-OH-DHP), acting in the rostral ventrolateral medulla (RVLM), and reduced actions of insulin in the forebrain. 3alpha-OH-DHP appears to potentiate baroreflex-independent GABAergic inhibition of premotor neurons in the RVLM, which decreases the range of sympathetic nerve activity that can be elicited by changes in arterial pressure. In contrast, reductions in the levels or actions of insulin in the brain blunt baroreflex efferent responses to increments or decrements in arterial pressure. Although plasma levels of angiotensin II are increased in pregnancy, this is not responsible for the reduction in baroreflex gain, although it may contribute to the increased level of sympathetic nerve activity in this condition. How these different hormonal effects are integrated within the brain, as well as possible interactions with additional potential neuromodulators that influence baroreflex function during pregnancy and other physiological and pathophysiological states, remains to be clearly delineated.

Fig. 1.

Pregnancy impairs baroreflex control of heart rate (bpm, beats per min) and renal sympathetic nerve activity (RSNA) in conscious rats. Arterial pressure was increased and decreased by infusion of increasing doses of phenylephrine or nitroprusside, respectively, while continuously recording arterial pressure, heart rate, and RSNA. Sigmoidal relationships between arterial pressure and heart rate or RSNA were determined by fitting a 4-parameter equation from which maximal gain was calculated, and parameters were statistically compared between pregnant (P) and nonpregnant (NP) rats (24, 124). In terms of baroreflex control of heart rate, pregnancy decreased the maximum level of heart rate, the heart rate range, and the maximal baroreflex gain and increased the range over which arterial pressure is regulated. Pregnancy also decreased the RSNA range, RSNA maximum, and RSNA minimum; the slope of RSNA responses to decreases in arterial pressure was also decreased. [Adapted from Brooks et al. (24) and Masilamani and Heesch (124).]

Fig. 2.

Schematic diagram showing the essential pathways that subserve the baroreflex control of the sympathetic outflow to the heart and blood vessels and possible sites of action and mechanisms by which changes in the activity of the hormones angiotensin II (ANG II), 3α-hydroxy-dihydroprogesterone (3α-OH-DHP; a metabolite of progesterone), and insulin can alter the baroreflex. Note that in addition to the inhibitory input to rostral ventrolateral medulla (RVLM) sympathetic premotor neurons from barosensitive neurons in the caudal ventrolateral medulla (CVLM), there is a baroreceptor-independent inhibitory input to the RVLM neurons arising from other CVLM neurons that receive excitatory inputs from neurons in unknown brain regions. NTS, nucleus tractus solitarii; AP, area postrema; PVN, paraventricular nucleus; SFO, subfornical organ. + indicates an excitatory effect, and − indicates an inhibitory effect.

Fig. 3.

Insulin sensitivity and baroreflex gain decreased in parallel during pregnancy in rabbits, and the changes were well correlated (r² = 0.65 ± 0.08, n = 5). [From Daubert et al. (47).]

Fig. 4.

Local blockade of the paraventricular nucleus (PVN) with bilateral microinjection of muscimol reversed the effect of intracerebroventricular (icv) insulin infusion to increase baroreflex gain (n = 4). In contrast, in control animals not receiving insulin, bilateral PVN muscimol did not alter baroreflex gain (1.1 ± 0.3 bpm/mmHg, control; 1.1 ± 0.3 bpm/mmHg, icv artificial cerebrospinal fluid or no infusion; 1.2 ± 0.3 bpm/mmHg, +PVN muscimol; n = 5; P > 0.05). Experiments were performed in urethane-anesthetized male rats using previously published procedures (65, 161). *P < 0.05 compared with the other 2 treatments (ANOVA for repeated measures and the Newman Keuls post hoc test). Similar results have recently been found in female rats (34).

Fig. 5.

Increased baroreflex-independent GABA_A inhibition of the RVLM in pregnant rats. In sinoaortic denervated rats, increases in mean arterial pressure (ΔMAP) and RSNA (ΔRSNA) in response to bilateral blockade of GABA_A receptors (bicuculline, Bic) into the RVLM was greater in P compared with NP rats. Prior blockade of ANG II AT₁ receptors (L158,809; AT1X) in the RVLM attenuated responses to Bic, but differences between NP and P rats persisted. *P ≤ 0.05, greater than in NP rats. †P ≤ 0.05, main effect of AT1X. [From Kvochina et al. (110)].

Fig. 6.

3α-OH-DHP in the RVLM of NP rats limits maximum baroreflex-mediated sympathoexcitation. Maximum (max) RSNA due to baroreflex unloading was reversibly attenuated following microinjection of 3α-OH-DHP (3α) into the RVLM but not into the CVLM or NTS. C, control; Rec, recovery. *P ≤ 0.05, less than control. †P ≤ 0.05, less than during recovery.