It is well established that GABAergic inputs to the paraventricular nucleus of the hypothalamus (PVN) tonically suppress heart rate and the activity of several sympathetic nerves. However, whether GABA similarly inhibits PVN control of baroreflex function has not been previously investigated. To test this hypothesis, it was determined whether microinjection of the GABA A antagonist, bicuculline, into the PVN enhances the baroreflex in anesthetized female virgin rats. In addition, because GABAergic inhibition of PVN preautonomic neurons is decreased during pregnancy, it was also determined whether the effects of PVN bicuculline administration on baroreflex function were less in pregnant animals. In virgin rats, PVN microinjection of bicuculline increased (P Ͻ 0.05) baroreflex gain and maximum levels of heart rate (gain, from 1.6 Ϯ 0.6 to 3.8 Ϯ 1.3 bpm/mmHg; maximum, from 406 Ϯ 18 to 475 Ϯ 14 bpm) and of lumbar sympathetic nerve activity (gain from 2.6 Ϯ 0.7 to 4.8 Ϯ 1.6%/ mmHg; maximum, 149 Ϯ 32 to 273 Ϯ 48%), indicating that PVN GABA normally suppresses baroreflex function. Pregnancy decreased heart rate baroreflex gain (pregnant, 0.9 Ϯ 0.3 bpm/mmHg; virgin, 1.9 Ϯ 0.2 bpm/mmHg; P Ͻ 0.05). Following PVN bicuculline administration in pregnant rats, smaller (P Ͻ 0.01) increments in baroreflex gain (pregnant, 0.6 Ϯ 0.1 bpm/mmHg; virgin, 2.4 Ϯ 0.9 bpm/mmHg) and maximum (pregnant, 33 Ϯ 7 bpm; virgin, 75 Ϯ 12 bpm; P Ͻ 0.05) were produced. Collectively, these data suggest that the PVN normally inhibits the baroreflex via tonic GABAergic inputs and that this inhibition is less during pregnancy. heart rate; baroreceptor reflex; lumbar sympathetic nervous system; ␥-aminobutyric acid THE PARAVENTRICULAR NUCLEUS (PVN) of the hypothalamus integrates multiple forebrain and brain stem inputs to regulate the autonomic nervous system via outputs that ultimately converge with focal brain stem nuclei, such as the rostral ventrolateral medulla, as well as preganglionic sympathetic neurons in the spinal cord (7,27,29,32). While the contribution of the PVN and its connections to basal sympathetic tone at rest in normal animals is minimal, it appears to drive increased sympathetic activity in such pathophysiological states as hypertension, heart failure, and water deprivation (7,27). Moreover, the PVN mediates, in part, autonomic responses to diverse homeostatic challenges, such as changes in food intake, blood volume, stress, and body temperature (29). However, whether and how the PVN can also influence the regulation of the baroreceptor reflex is currently unclear.Of the PVN neurotransmitters and neuromodulators that effect these many functions, the tonically active inhibitory GABAergic inputs to preautonomic neurons are dominant (10, 28). Indeed, local pharmacological blockade of PVN GABA A receptors elicits profound increases in arterial pressure, heart rate (HR), and sympathetic activity and excites neurons that project to the brain stem or spinal cord (15,18,20,22). Therefore, one aim of the present study was to test the hypothes...

Pregnancy (P) decreases baroreflex gain (BRG) via a mechanism that includes reduced actions of insulin in the hypothalamus. However, specific brain sites and mechanisms are unclear. The paraventricular nucleus (PVN) influences BRG and contains numerous insulin receptors (IR). Because insulin is inhibitory, we hypothesized that PVN insulin increases BRG by suppression of inhibitory GABA inputs and that loss of this action during P leads to enhanced GABAergic inhibition of BRG. To test this hypothesis, we determined if PVN microinjection of bicuculline (BIC, 60 pmol), to block GABA receptors, increases BRG more in late P than in virgin (V) urethane‐anesthetized rats. P decreased (P<0.05) BRG (in bpm/mmHg: 1.9±0.2, V, n=12; 0.9±0.2, P, n=8) and AP (in mmHg: 98±4, V; 81±5, P). In both V and P rats, PVN BIC increased (P<0.05) AP (in mmHg: by 13±2, V; by 11±3, P) and BRG (in bpm/mmHg: by 2.4±0.9, V; by 0.6±0.1, P); however, the increment in BRG was less in P rats (P<0.05). Use of immunocytochemistry, to further test the hypothesis that insulin acts via inhibition of GABAergic inputs, revealed that IR are in both magnocellular and parvocellular neuronal soma in PVN regions that also contain GABAergic (GAD67) terminals. However, no evidence of colocalization of IR in GABAergic terminals was obtained. Together, these results do not support the hypothesis that P impairs BRG by reducing insulin's action to inhibit PVN GABAergic inputs.

Pregnancy (P) decreases baroreflex gain (BRG). Our recent studies in rabbits suggest that decreases in insulin sensitivity (IS) contribute to the BRG impairment: BRG falls in parallel with IS at end gestation, and treatment with the insulin sensitizing drug, rosiglitazone, normalizes BRG. In rats, IS falls at midgestation (days 11‐12 of 21 day gestation), rises to normal by day 15, and then decreases again just before delivery. However, whether BRG exhibits a similar pattern, or whether IS and BRG increase in parallel postpartum (PP), is unknown. To test these hypotheses, BRG was measured in conscious virgin (V) rats, during P [days 11‐12 (P12), 17‐18 (P18), and 19‐20 (P20)], and on PP days 3‐4 (PP3) from a 4 parameter sigmoidal fit of heart rate responses to slow (3‐5 min) ramp changes in arterial pressure. In addition, we measured IS using the hyperinsulinemic‐euglycemic clamp method in V, P20 and PP3 rats. Compared to V rats (4.5±0.5 bpm/mmHg, n=10), BRG was decreased (P<0.05) on P12 (2.8±0.1 bpm/mmHg, n=7) and P20 (2.3±0.4 bpm/mmHg, n=8); however, BRG on P18 (3.8±0.1 bpm/mmHg, n=5) and PP3 (5.9±0.2 bpm/mmHg, n=3) were not different from V. Similarly, IS was decreased on P20 (V, 32±2 mg/kg•min, n=6; P20, 14±1 mg/kg•min, n=3; P<0.05) but normalized by PP3 (30±2 mg/kg•min, n=8). In conclusion, BRG and IS change in parallel during and following rat gestation, suggesting a mechanistic link. Supported by AHA, NIH HL088552.