Modulation of central sodium / osmo-homeostatic mechanisms by novel peptides-Integrative studies

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・Modification of adaptive responses to hypertonic saline (HS) loading by the endogenous vasopressin system: The paraventricular nucleus (PVN) of the hypothalamus consists of the magnocellular and parvicellular divisions. The PVN division that is activated following HS loading and is affected by pretreatment with vasopressin (AVP) V1 receptor antagonist (OPC-21268) was examined using the expression of Fos-like immunoreactivity (FLI). Although both PVN divisions were activated, the parvocellular division, but not the magnocellular division, was enhanced by the pretreatment, indicating the inhibitory action of the AVP system on the sympathetic promotor neurons in the PVN. In addition, the responses of the cardiovascular system and FLI expression to HS loading in conscious vasopressin-overexpressing transgenic (Tg) rats were examined. Central HS loading enhanced arterial blood pressure (ABP) and FLI expression in the PVN, the supraoptic nucleus (SON), the median preoptic nucleus (MnPO), th … More e area postrema (AP), and the organum vasculosum laminae terminalis (OVLT) in Tg rats compared to the control rats. The pretreatment with OPC-21268 blocked the increase in ABP and significantly decreased the FLI expression in the magnocellular division of the PVN induced by HS loading in the Tg rats.・Roles of novel peptides in the regulation of body water balance and the cardiovascular system: The effects of corticotrophin-releasing factor (CRF)and neuromedin U (NMU) on rat PVN neurons were studied using whole-cell patch-clamp recordings. Under current clamp, CRF and NMU increased the neuronal basal firing rate and depolarized neurons in a dose-dependent manner. Under voltage clamp, both peptides significantly increased the hyperpolarization-activated cation current (IH) in a dose-dependent manner. The results showed that CRF and NMU modulate the subpopulation of PVN parovocellular neuronal function by CRF receptor 1 and NMU receptor 2, respectively, via the potentiation of HCN ion channel activity. In addition, intracerebroventricular (i.c.v.)administration of another novel peptide, neuropeptide W (NPW), increased ABP, heart rate, and plasma norepinephrine and epinephrine concentrations in conscious rats. Furthermore, i.c.v. administration of NPW excited 22 and inhibited 7 but did not affect 6 out of 35 PVN neurons tested in conscious, freely moving rats.・Functional analysis of vasopressin V1b receptor knockout (V1b-/-)mice: Daily drinking behavior and renal secretory function were measured in V1b-/- and control (V1b+/+) mice. In addition, body temperature and locomotor activity were measured with a biotelemetry system. The baseline daily water intake and urine volume were larger in V1b-/- mice than in V1b+/+ mice. V1b-/- mice had significantly higher locomotor activity than did wild-type mice, whereas the body temperature and oxygen consumption were lower in V1b-/- than in V1b+/+ mice. Next, the mice were subjected to water deprivation for 48 hr. Under this condition, their body temperature decreased with the time course, and the decrease was significantly greater for V1b-/- than for V1b+/+ mice. The V1b receptor may be, at least in part, involved in body water balance and body temperature regulation. Less