Vasopressinergic Activity of the Suprachiasmatic Nucleus and mRNA Expression of Clock Genes in the Hypothalamus-Pituitary-Gonadal Axis in Female Aging.

The important involvement of the suprachiasmatic nucleus (SCN) and the activity of vasopressinergic neurons in maintaining the rhythmicity of the female reproductive system depends on the mRNA transcription-translation feedback loops. Therefore, circadian clock function, like most physiological processes, is involved in the events that determine reproductive aging. This study describes the change of mRNA expression of clock genes, Per2, Bmal1, and Rev-erbα, in the hypothalamus-pituitary-gonadal axis (HPG) of female rats with regular cycle (RC) and irregular cycle (IC), and the vasopressinergic neurons activity in the SCN and kisspeptin neurons in the arcuate nucleus (ARC) of these animals. Results for gonadotropins and the cFos/AVP-ir neurons in the SCN of IC were higher, but kisspeptin-ir was minor. Change in the temporal synchrony of the clock system in the HPG axis, during the period prior to the cessation of ovulatory cycles, was identified. The analysis of mRNA for Per2, Bmal1, and Rev-erbα in the reproductive axis of adult female rodents shows that the regularity of the estrous cycle is guaranteed by alternation in the amount of expression of Bmal1 and Per2, and Rev-erbα and Bmal1 between light and dark phases, which ceases to occur and contributes to determining reproductive senescence. These results showed that the desynchronization between the central and peripheral circadian clocks contributes to the irregularity of reproductive events. We suggest that the feedback loops of clock genes on the HPG axis modulate the spontaneous transition from regular to irregular cycle and to acyclicity in female rodents.

Oestradiol acts through its beta receptor to increase vasopressin neuronal activation and secretion induced by dehydration.

Vasopressinergic neurones of the supraoptic (SON) and paraventricular (PVN) nuclei express oestrogen receptor (ER)ß and receive afferent projections from osmosensitive neurones that express ERα. However, which subtype of these receptors mediates the effects of oestradiol on vasopressin (AVP) secretion induced by hydromineral challenge has not yet been demonstrated in vivo. Moreover, AVP secretion induced by hyperosmolality is known to involve activation of TRPV1 (transient receptor potential vanilloid, member 1) in magnocellular neurones, although whether oestradiol modulates expression of this receptor is unknown. Thus, the present study aimed to clarify the mechanisms involved in the modulation exerted by oestradiol on AVP secretion, specifically investigating the involvement of ERß, ERα and TRPV1 receptors in response to water deprivation (WD). We observed that treatment with an ERß agonist potentiated AVP secretion and vasopressinergic neuronal activation induced by WD. This increase in AVP secretion induced by WD was reversed by an ERß antagonist. By contrast to ERß, the ERα agonist did not alter plasma AVP concentrations or activation of AVP neurones in the SON and PVN. Additionally, Fos expression in the subfornical organ was not altered by the ERα agonist. TRPV1 mRNA expression was increased by WD in the SON, although this response was not altered by any treatment. The results of the present study suggest that ERß mediates the effects of oestradiol on AVP secretion in response to WD, indicating that the effects of oestradiol occur directly in AVP neurones without affecting TRPV1.

Role of AMPA and NMDA receptors on vasopressin and oxytocin secretion induced by hypertonic extracellular volume expansion.

Vasopressin (AVP) and oxytocin (OT) are essential for the control of extracellular fluid osmolality and volume. Secretion of these hormones is modulated by several mechanisms, including NMDA and AMPA L-glutamate receptors in magnocellular cells of paraventricular (PVN) and supraoptic (SON) hypothalamic nuclei. Thus, to better understand the participation of L-glutamate on the neuroendocrine control of AVP and OT, this work evaluated the effects of intracerebroventricular (icv) NMDA and AMPA receptor antagonists on plasma AVP and OT levels induced by extracellular volume expansion (EVE). Cannulated rats received icv NMDA (AP5) and AMPA (NBQX) antagonists in 10 and 30nmol/5µl/rat doses and were subjected to either isotonic (0.15 M NaCl, 2ml/100g) or hypertonic (0.30 M NaCl, 2ml/100g) EVE. Blood samples were collected for plasma AVP and OT determination. Isotonic EVE did not change plasma AVP and OT levels, but hypertonic EVE increased both AVP and OT plasma levels. AP5 reduced plasma AVP, but it did not change the OT level induced by hypertonic EVE. On the other hand, NBQX reduced plasma OT, but did not alter the AVP plasma level. Our data shows that L-glutamate controls the secretion of neurohypophyseal hormones through the NMDA receptor for AVP release, and through the AMPA receptor for OT release, both in response to hypertonic EVE. This article is protected by copyright. All rights reserved.

Oestradiol effects on neuroendocrine responses induced by water deprivation in rats.

Water deprivation (WD) induces changes in plasma volume and osmolality, which in turn activate several responses, including thirst, the activation of the renin-angiotensin system (RAS) and vasopressin (AVP) and oxytocin (OT) secretion. These systems seem to be influenced by oestradiol, as evidenced by the expression of its receptor in brain areas that control fluid balance. Thus, we investigated the effects of oestradiol treatment on behavioural and neuroendocrine changes of ovariectomized rats in response to WD. We observed that in response to WD, oestradiol treatment attenuated water intake, plasma osmolality and haematocrit but did not change urinary volume or osmolality. Moreover, oestradiol potentiated WD-induced AVP secretion, but did not alter the plasma OT or angiotensin II (Ang II) concentrations. Immunohistochemical data showed that oestradiol potentiated vasopressinergic neuronal activation in the lateral magnocellular PVN (PaLM) and supraoptic (SON) nuclei but did not induce further changes in Fos expression in the median preoptic nucleus (MnPO) or subfornical organ (SFO) or in oxytocinergic neuronal activation in the SON and PVN of WD rats. Regarding mRNA expression, oestradiol increased OT mRNA expression in the SON and PVN under basal conditions and after WD, but did not induce additional changes in the mRNA expression for AVP in the SON or PVN. It also did not affect the mRNA expression of RAS components in the PVN. In conclusion, our results show that oestradiol acts mainly on the vasopressinergic system in response to WD, potentiating vasopressinergic neuronal activation and AVP secretion without altering AVP mRNA expression.

Estradiol potentiates hypothalamic vasopressin and oxytocin neuron activation and hormonal secretion induced by hypovolemic shock.

Estrogen receptors are located in important brain areas that integrate cardiovascular and hydroelectrolytic responses, including the subfornical organ (SFO) and supraoptic (SON) and paraventricular (PVN) nuclei. The aim of this study was to evaluate the influence of estradiol on cardiovascular and neuroendocrine changes induced by hemorrhagic shock in ovariectomized rats. Female Wistar rats (220-280 g) were ovariectomized and treated for 7 days with vehicle or estradiol cypionate (EC, 10 or 40 µg/kg, sc). On the 8th day, animals were subjected to hemorrhage (1.5 ml/100 g for 1 min). Hemorrhage induced acute hypotension and bradycardia in the ovariectomized-oil group, but EC treatment inhibited these responses. We observed increases in plasma angiotensin II concentrations and decreases in plasma atrial natriuretic peptide levels after hemorrhage; EC treatment produced no effects on these responses. There were also increases in plasma vasopressin (AVP), oxytocin (OT), and prolactin levels after the induction of hemorrhage in all groups, and these responses were potentiated by EC administration. SFO neurons and parvocellular and magnocellular AVP and OT neurons in the PVN and SON were activated by hemorrhagic shock. EC treatment enhanced the activation of SFO neurons and AVP and OT magnocellular neurons in the PVN and SON and AVP neurons in the medial parvocellular region of the PVN. These results suggest that estradiol modulates the cardiovascular responses induced by hemorrhage, and this effect is likely mediated by an enhancement of AVP and OT neuron activity in the SON and PVN.