V.T.Y. Ang

Vasopressin, oxytocin and neurophysins in the human brain and spinal cord

The concentrations of arginine vasopressin, oxytocin, and their related neurophysins were compared in many areas of postmortem human brain and spinal cord using specific radioimmunoassays. In the hypothalamus the ratio of vasopressin to oxytocin was approximately 3:1, and in the extrahypothalamic areas of the brain the greatest amount of both peptides was present in the locus coeruleus, and to a lesser extent the periaqueductal grey. Vasopressin only was found in the substantia nigra, and globus pallidus. In the medulla, including the nucleus of the solitary tract, the dorsal nucleus of the vagus, and the nucleus of the spinal tract of the trigeminal nerve, the amount of oxytocin was greater than that of vasopressin. In the spinal cord oxytocin predominated over vasopressin to an even greater extent, and reached particularly high values in certain segments of the intermediolateral grey column and dorsal horn. Estrogen-stimulated and nicotine-stimulated neurophysins (ESN and NSN) were both found in large amounts in those areas of the brain and spinal cord where the concentrations of the nonapeptides were greatest, but when the molar ratios of ESN to oxytocin and NSN to vasopressin were compared there was an excess of ESN.

Effects of lesions in the hypothalamic paraventricular, supraoptic and suprachiasmatic nuclei on vasopressin and oxytocin in rat brain and spinal cord

The content of arginine vasopressin and oxytocin in various extrahypothalamic sites of the rat brain and spinal cord was determined by specific radioimmunoassays after lesions had been made in either the paraventricular (PVN), supraoptic (SON) or suprachiasmatic nuclei (SCN). In some animals all 3 nuclei were destroyed together. The PVN provided a considerable amount of the vasopressin innervation of the solitary tract nucleus, and most of that in the spinal cord. Oxytocin was removed from some areas after lesions of the PVN and, again, most of this peptide was lost from the spinal cord. Lesions of the SCN did not appear to be followed by significant quantitative changes in either hormone in any of the areas studied. Lesions of the SON resulted in loss of oxytocin, particularly in the periventricular grey and some other areas, suggesting that extrahypothalamic projections from this nucleus may be more important than was previously assumed. Lesions of all 3 nuclei which included destruction of accessory hypothalamic nuclei resulted in a much more widespread loss of vasopressin and oxytocin, but there was preservation of both peptides in the dorsal raphe nucleus and much of those present in the locus coeruleus. It is concluded that the contribution of the classical hypothalamic nuclei to the extrahypothalamic content of vasopressin and oxytocin in rat brain is less than was originally believed, and that there are areas of the brain such as the locus coeruleus and dorsal raphe nucleus in which the source of these peptides may be outside the hypothalamus.

Localization of vasopressin in the rat brain.

The distribution of arginine vasopressin (AVP) in the rat brain was studied using a sensitive radioimmunoassay. The highest concentration of AVP was found in the hypothalamus. Individually, the supraoptic, paraventricular and suprachiasmatic nuclei contained in the order of 10% of the total hypothalamic content. Vasopressin was also found in the thalamus, medulla, cerebellum, amygdala, substantia nigra and hippocampus. Much lower levels were detected in the pons, spinal cord, frontal and occipital lobes and caudate putamen. No AVP could be detected in any other regions of the cortex or corpus callosum. Chromatographically the vasopressin found outside the hypothalamus is of a similar nature to that of hypothalamo-hypophysial origin. This study supports previous reports of extrahypothalamic localization of vasopressin by immuno-histochemical methods. It is clear that AVP is not confined to the hypothalamo-hypophysial axis, and the possibilities that this may reflect an involvement in brain function are discussed.

EXTRAHYPOTHALAMIC VASOPRESSIN IN HUMAN-BRAIN

The distribution of arginine vasopressin immunoreactivity in post-mortem human brain was examined using a radioimmunoassay. The highest concentration was found in the hypothalamus but substantial amounts of vasopressin-like immunoreactivity were also found in the locus coeruleus, periaqueductal grey, substantia nigra compacta and reticulata and in lower concentrations in the globus pallidus. The extrahypothalamic vasopressin was immunologically and chromatographically similar to hypothalamic vasopressin. The possibility arises that the high levels of vasopressin in the locus coeruleus may relate to an effect on noradrenergic transmission.

RESPONSES OF PLASMA OXYTOCIN AND ARGININE VASOPRESSIN TO NAUSEA INDUCED BY APOMORPHINE AND IPECACUANHA

Apomorphine, a centrally‐acting emetic, was administered subcutaneously (50 /μg/kg) to nine normal subjects (four male, five female; aged 22‐36 years) and four patients with idiopathic diabetes insipidus (DI) (one male, three female; aged 24‐49 years). In the normal subjects this stimulus caused nausea (and vomiting in seven of nine) with a latency of 9‐5 ± 0‐9 min which was followed by a large increase in plasma arginine vasopressin (AVP) concentration (from 0‐9 ± 0‐2 pmol/1 to 249 ± 104 pmol/1 at 15 min after the onset of symptoms; mean ± SEM, P<001). There was a small but significant increase in plasma oxytocin (OXT) concentration (from 1‐6 ± 0‐4 pmol/1 to 6‐2 ± 3‐4 pmol/1; P<005). Mean arterial pressure (MAP) fell slightly (from 87±1‐9 mm Hg to 71±4‐4 mm Hg; P < 005) 15 min after the onset of nausea; there was no change in blood haematocrit or plasma osmolality and sodium concentration. In the DI patients apomorphine produced nausea (with vomiting in three of four) with a latency of 100±1 ‐4 min but failed to cause an increase in either plasma AVP or OXT. In the DI patients the fall in MAP did not reach statistical significance (83 ± 4 mm Hg to 71 ± 11 mm Hg); there was also no change in haematocrit, osmolality or sodium concentration. Ipecacuanha, an emetic with both peripheral and central actions, was administered orally to seven normal subjects (three male, four female; aged 22‐36 years) six of whom also underwent apomorphine tests. Nausea followed with a latency of 16‐9 ± 3‐2 min (with vomiting in five of seven). However, despite producing symptoms considered by the subjects to be as severe as those caused by apomorphine there was no increase in plasma AVP or OXT. In contrast to apomorphine, ipecacuanha produced a significant increase in MAP (from 82 ± 2 mm Hg to 11101+7 mm Hg; P<0‐05) and pulse rate (62 ± 3 min‐1 to 76 ± 4 mm‐1; P<0‐05); there was no change in haematocrit, osmolality or sodium concentration.

Differential release of vasopressin and oxytocin in response to abdominal vagal afferent stimulation or apomorphine in the ferret.

The aim of this study was to investigate whether direct afferent stimulation of the abdominal vagus could promote release of the neurohypophyseal hormones. The nucleus of the solitary tract is the major recipient of vagal afferent information, and this region of the brainstem may also be activated by stimulation of the area postrema. For this reason apomorphine, a D2 dopaminergic agonist which acts on the area postrema, and can evoke vasopressin secretion in man, was also investigated for its effect on vasopressin and oxytocin release. Our results show that vasopressin, but not oxytocin is released in vast amounts in response to electrical afferent stimulation of the abdominal vagus. Administration of apomorphine also evoked a massive vasopressin release with less marked effects on oxytocin. The possible functional implications of these results are discussed especially in the context of nausea and vomiting.

THE EFFECT OF OXYTOCIN INFUSION ON ADENOHYPOPHYSEAL FUNCTION IN MAN

The responses of the adenohypophyseal hormones adrenocorticotrophin (ACTH), growth hormone (GH), thyroid stimulating hormone (TSH), prolactin, luteinizing hormone (LH) and follicle stimulating hormone (FSH) to sub‐maximal doses of hypothalamic releasing factors were studied in six lean male volunteers (age 23‐35 years) with and without infusions of oxytocin (OXT). OXT infusion (mean plasma concentration 133.6±2.6 pmol/1) completely inhibited the plasma ACTH responses to corticotrophin releasing hormone (CRH) (saline, peak increment ACTH 1.61±0.75 pmol/l; OXT, peak increment ACTH — 0.04±0.28 pmol/l; P < 0.05). OXT infusion had no significant effect on the GH response to growth hormone releasing hormone (GHRH), the TSH and prolactin responses to thyrotrophin releasing hormone (thyroliberin, TRH) or the LH and FSH responses to gonadotrophin releasing hormone (luteoliberin, GnRH). The data support a role for OXT in the modulation of ACTH secretion in man.

Extrahypothalamic vasopressin is unchanged in Parkinson's disease and Huntington's disease

Vasopressin immunoreactivity was measured post-mortem in the locus coeruleus and substantia nigra of 16 cases of Parkinsons disease and multisystem atrophy, 10 cases of Huntingtons chorea and 28 normal controls. Amounts of vasopressin did not differ significantly (P greater than 0.05) between the 3 groups. Immunohistochemistry demonstrated vasopressin within nerve terminals. These data are consistent with an extrinsic vasopressin system in the human locus coeruleus and substantia nigra.

Comparison of the distribution of oxytocin and vasopressin in the rat brain

While immunohistochemistry has been used extensively to map both oxytocin (OT) and vasopressin (VP) pathways in the brain, little information is available concerning the quantitative distribution of these hormones--particularly oxytocin. We have isolated oxytocin from extrahypothalamic regions of the rat brain and shown it to behave identically with standard oxytocin in radioimmunoassay (RIA) and on high-performance liquid chromatography. Using sensitive RIA we have measured and compared levels of both oxytocin and vasopressin in the rat brain. Both hormones are widely distributed, with the largest amounts outside the hypothalamus being found in the locus coeruleus. Considerable quantities of both peptides (but particularly oxytocin) are found in mesencephalic, pontine and medullary nuclei. This distribution is similar to that of the catecholamines, and the possible interaction of oxytocin and vasopressin with catecholaminergic pathways in the central control of various functions is discussed.

Corticotrophin releasing hormone (CRH1–41) stimulates the secretion of adrenocorticotrophin, vasopressin and oxytocin but not adrenocorticotrophin precursors: evidence from petrosal sinus sampling in man

To examine the relationship between corticotrophin releasing hormone (CRH), arginine vasopressin (AVP) and oxytocin (OXT) we have studied the responses of adenohypophyseal and neurohypophyseal hormones to CRH in eight patients (age 26–64 years, six female) with suspected pituitary‐dependent Cushings syndrome during bilateral, simultaneous inferior petrosal sinus catheterization. Blood samples were taken from both petrosal sinuses and a peripheral vein before, and at 5‐min intervals for 15 min after, an intravenous injection of 100 μg human CRH1–41. CRH increased sinus AVP concentrations in all eight patients and OXT concentrations in four of five patients studied. Although AVP concentrations often increased in both sinuses, the side of maximal AVP rise was termed sidemax‐AVP. CRH did not affect peripheral or petrosal sinus mean concentrations of LH, FSH, GH or TSH. While there was no change in mean peripheral concentrations of AVP, OXT, ACTH, ACTH precursors or prolactin after CRH, sinus concentrations of OXT, ACTH and prolactin on sidemax‐AVP were markedly elevated over contralateral values. CRH did not increase mean sinus concentrations of ACTH precursors. In seven patients with either no radiological abnormality of the pituitary fossa or a small adenoma the mean ACTH precursor/ACTH ratio in blood sampled from all sites was 2.1 |Mp 0.16 (mean |Mp SEM, n = 50). In a patient with a large, locally invasive tumour the mean ACTH precursor/ACTH molar ratio was 32.1 |Mp 1.3 (n = 12; P > 0.001), suggesting that alterations in this molar ratio may reflect the biological properties of the tumour. The source of CRH‐stimulatable AVP and OXT remains uncertain. While it is recognized that the data were accumulated in patients with pathology of the hypothalamo—hypophyseal—adrenal axis, these observations suggest a novel relationship between AVP, OXT and CRH in the regulation of ACTH secretion in man. We suggest that the relation between plasma AVP and corticosteroids seen in clinical hypoadrenal states could be explained by chronic stimulation of AVP secretion by CRH.