Tuberoinfundibular peptide of 39 residues (TIP39) is a recently discovered neuropeptide identified on the basis of its ability to activate the PTH2 receptor, and it is thought to be the brain PTH2 receptor's endogenous ligand. The PTH2 receptor is highly expressed in the hypothalamus, suggesting a role in the modulation of neuroendocrinological functions. PTHrP, which also belongs to the PTH-related peptides family, stimulates arginine vasopressin (AVP) release. In the present study, therefore, we investigated the effect of centrally administered TIP39 on AVP release in conscious rats. Intracerebroventricular administration of TIP39 (10-500 pmol/rat) significantly suppressed the plasma AVP concentration in dehydrated rats, and the maximum effect was obtained 5 min after administration (dehydration with 100 pmol/rat TIP39, 4.32 +/- 1.17 pg/ml; vs. control, 8.21 +/- 0.70 pg/ml). The plasma AVP increase in response to either hyperosmolality [ip injection of hypertonic saline (HS), 600 mosmol/kg] or hypovolemia [ip injection of polyethylene glycol (PEG)] was also significantly attenuated by an intracerebroventricular injection of TIP39 (HS with 100 pmol/rat TIP39, 2.65 +/- 0.52 pg/ml; vs. HS alone, 4.69 +/- 0.80 pg/ml; PEG with 100 pmol/rat TIP39, 4.10 +/- 0.79 pg/ml; vs. PEG alone, 6.19 +/- 0.34 pg/ml). Treatment with naloxone [1.5 mg/rat, sc injection], a nonselective opioid receptor antagonist, significantly reversed the inhibitory effects of TIP39 on AVP release. These results suggest that central TIP39 plays an inhibitory role in the osmoregulation and baroregulation of AVP release and that intrinsic opioid systems are involved in its mechanism.
GH secretagogue (GHS) is a small, synthetic compound that has the potential to stimulate GH release via its specific receptors (GHS-R). Ghrelin is a novel 28-amino acid peptide recently isolated from human and rat stomach, and it is thought to be the endogenous ligand for GHS-R. Ghrelin has a variety of physiological functions such as the stimulation of GH release or the increase of food intake by activating NPY neurons. In the present study, we investigated the effects of ghrelin on AVP release in conscious rats. Intracerebroventricular (icv) administration of ghrelin increased the plasma AVP concentration in a dose-dependent manner (1-1000 pmol/rat), and its effect was observed as late as 60 min after the administration. Icv injection of ghrelin caused no significant change in plasma osmolality, plasma volume, or arterial blood pressure. Iv administration of ghrelin (10 nmol/rat) also increased the plasma AVP concentration, which was accompanied by a significant decrease in arterial blood pressure. Pretreatment with antiserum against NPY significantly reduced the plasma AVP increase induced by icv administration of ghrelin. These results suggest that ghrelin plays a stimulatory role in AVP release, which is possibly mediated by NPY neurons.
Arginine vasopressin (AVP) is a major antidiuretic hormone, the overproduction of which causes diluting hyponatremia in humans and is called the syndrome of inappropriate antidiuresis (SIAD). To study physiological changes resulting from AVP overproduction and to develop an animal model of hyponatremia, the human AVP gene was expressed under the control of the metallothionein promoter in transgenic (Tg) rats. Analyses of AVP immunoreactivity (irAVP) in the tissues revealed that the transgene is expressed mainly in the central nervous system. Gel filtration showed that irAVP in the brain and plasma was properly processed AVP. AVP purified from the brains of both Tg and control rats also exerted equal bioactivity to generate cAMP in LLC-PK1 cells. The founder rats did not show any physical or anatomical abnormalities. Under basal conditions, Tg rats had high plasma AVP levels (Tg 13·8 2·5 pg/ml; control 2·7 1·2 pg/ml; n=6 in both groups; means S.E.M.), decreased urine volume, and normal plasma [Na + ]. Hypertonic saline injected i.p. did not affect AVP secretion in Tg rats. In response to a zinc-supplemented liquid diet, plasma AVP decreased in control rats, but increased in Tg rats (Tg 32·7 2·7 pg/ml; control 1·0 0·1 pg/ml; n=6), resulting in hyponatremia (Tg 135·2 2·5 mEq/l; control 140·8 0·4 mEq/l; n=6). To our knowledge, this is the first transgenic animal to show diluting hyponatremia. This transgenic rat may therefore provide a useful model in which to investigate various physiological alterations resulting from the oversecretion of AVP which involve SIAD, stress response, behavior, and blood pressure.
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