pituitrin and senktide

Central administration of neurokinin B (NKB) agonists stimulates immediate early gene expression in the hypothalamus and increases the secretion of vasopressin from the posterior pituitary through a mechanism that depends on the activation of neurokinin receptor 3 receptors (NK3R). The present study reports that, in the rat, immunoreactivity for NK3R is expressed in magnocellular vasopressin and oxytocin neurones in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus, and that NKB immunoreactivity is expressed in fibres in close juxtaposition with vasopressin neurones at both of these sites. Retrograde tracing in the rat shows that some NKB-expressing neurones in the arcuate nucleus project to the SON and, in mice, using an anterograde tracing approach, it is found that kisspeptin-expressing neurones of the arcuate nucleus, which are known to co-express NKB, project to the SON and PVN. Finally, i.c.v. injection of the NK3R agonist senktide is shown to potently increase the electrical activity of vasopressin neurones in the SON in vivo with no significant effect detected on oxytocin neurones. The results suggest that NKB-containing neurones in the arcuate nucleus regulate the secretion of vasopressin from magnocellular neurones in rodents, and the possible significance of this is discussed.

Topics: Action Potentials; Animals; Arcuate Nucleus of Hypothalamus; Infusions, Intraventricular; Kisspeptins; Male; Mice; Mice, Transgenic; Neuroanatomical Tract-Tracing Techniques; Neurokinin B; Neurons; Oxytocin; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Rats; Receptors, Neurokinin-3; Substance P; Supraoptic Nucleus; Vasopressins

Neurokinin 3 receptors (NK3-Rs) are expressed in the supraoptic nucleus (SON), and SON is innervated by substance P (SP)-expressing A1 neurons in the medulla. Because SP stimulates vasopressin (VP) and oxytocin release from explants of the hypothalamo-neurohypophyseal system (HNS), two hypotheses were tested: (1) SP-stimulated VP release is mediated by NK3-Rs, and (2) stimulation of the A1 pathway by hypotension activates SON NK3-Rs. Senktide, an NK3-R agonist, stimulated VP release from HNS explants, but neither a neurokinin 1 receptor antagonist [L732,138 (N-acetyl-L-tryptophan 3,5-bis(tri-fluoromethyl)benzyl ester)] nor two NK3-R antagonists (SB222200 and SB235375) prevented SP-stimulated VP release. Because the affinity of these antagonists for rat NK-Rs may limit their efficacy, NK3-R internalization was used to assess the ability of SP to activate SON NK3-Rs. Senktide, SP, or vehicle was microinjected above SON. The brain was perfused 5 min after injection and stained for NK3-R immunoreactivity. Using confocal microscopy, the number of NK3-R-immunoreactive (-IR) endosomes was counted in a 5.6(2) mu region of cytoplasm in SON neurons. Senktide, but not SP or vehicle, significantly increased the number of NK3-R-IR endosomes in the cytoplasm. When hypotension was induced with hydralazine, NK3-R internalization was observed within 5 min (p < 0.005). A decrease in cytoplasmic NK3-R immunoreactivity was observed within 15 min of hypotension. Unexpectedly, both senktide and hypotension resulted in translocation of NK3-R-IR immunoreactivity to the nucleus. Thus, although these studies do not identify SP as the NK3-R ligand, they do provide evidence for hypotension-induced release of an endogenous tachykinin in SON and evidence suggesting a role for NK3-Rs in transcription regulation.

Topics: Acetates; Animals; Catecholamines; Cell Compartmentation; Cell Nucleus; Cytoplasm; Endosomes; Hydralazine; Hypotension; Hypothalamo-Hypophyseal System; Hypothalamus, Anterior; Male; Microinjections; Microscopy, Confocal; Neurons; Oxytocin; Peptide Fragments; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Neurokinin-1; Receptors, Neurokinin-3; Substance P; Tachykinins; Transcription, Genetic; Tryptophan; Vasopressins

Intracerebroventricular injection of senktide, a selective agonist for neurokinin B receptor (NK3), induced Fos expression in many neurons of the rat hypothalamus. Fos-positive neurons were predominantly present in the supraoptic and paraventricular hypothalamic nuclei, and some of them were seen in the lateral preoptic area, lateral hypothalamic area, arcuate nucleus, perifornical region, posterior hypothalamic area, circular nucleus, and along relatively large blood vessels (lateral hypothalamic perivascular nucleus) in the anterior hypothalamus. A double labeling study was performed to examine if vasopressin-containing neurons in the hypothalamus could be activated by the treatment. Neurons with both Fos-like immunoreactivity (-LI) and vasopressin-LI were found in the paraventricular nucleus, supraoptic nucleus, circular nucleus and lateral hypothalamic perivascular nucleus. In the supraoptic nucleus, about 87% of vasopressin-containing neurons exhibited Fos-LI, which corresponded to about 64% of Fos-positive neurons in the nucleus. In the paraventricular nucleus, about 80% of vasopressin-like immunoreactive neurons exhibited Fos-LI, which constituted about 51% of the total population of Fos-positive neurons in the region. The results suggest that NK3 receptor may be involved in the modulation of release of vasopressin from the hypothalamus in the rat.

Topics: Animals; Hypothalamus; Male; Neurons; Peptide Fragments; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Substance P; Vasopressins

The central pressor actions of the tachykinin NK-3 receptor in the paraventricular nucleus (PVN) of the hypothalamus were examined in anesthetized rats. In forebrain-restricted animals, the selective tachykinin NK-3 receptor agonist senktide (10 micrograms, i.c.v.) increased the blood pressure, and this pressor response was more potent than in control animals. Injection of senktide into the PVN also increased the blood pressure, and this pressor response was inhibited by pretreatment with the vasopressin V1 receptor antagonist (10 micrograms/kg, i.v.). These results suggest that central injection of senktide stimulated the NK-3 receptor in the PVN of the hypothalamus, and increased blood pressure by inducing release of vasopressin from the pituitary gland.

Topics: Animals; Arginine Vasopressin; Blood Pressure; Injections; Male; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Pressoreceptors; Rats; Rats, Wistar; Receptors, Neurotransmitter; Receptors, Tachykinin; Substance P; Vasopressins

The mechanisms of action of tachykinin peptides thought to be involved in central cardiovascular regulation were examined. Intracerebroventricular injections (i.c.v.) of tachykinin peptides caused dose-dependent increases in blood pressure and heart rate. The pressor responses to substance P (SP) (10 micrograms, i.c.v.) and neurokinin A (NKA) (10 micrograms, i.c.v.) were blocked by peripheral administration of pentolinium or phentolamine, and partially attenuated by adrenalectomy. In contrast, the only initial pressor response to the neurokinin B (NKB) analogue senktide (10 micrograms, i.c.v.) was blocked by pentolinium or phentolamine. The pressor response to senktide was inhibited by pretreatment with a vasopressin V1 receptor antagonist (d(CH2)5OMe(Tyr)AVP) (10 micrograms/kg, i.v.), and senktide (10 micrograms, i.c.v.) caused an increase in plasma vasopressin level. However, the vasopressin antagonist did not influence the SP- and NKA-induced pressor responses. These results suggest that central SP and NKA increase the blood pressure and heart rate via sympathetic nerve activity, whereas central NKB increases the blood pressure mainly via release of vasopressin from the hypothalamus.

Topics: Adrenal Glands; Angiotensin II; Animals; Blood Pressure; Heart Rate; Injections, Intraventricular; Male; Peptide Fragments; Rats; Rats, Inbred Strains; Saralasin; Substance P; Sympatholytics; Tachykinins; Vasopressins