The effects of repeated administration of a long acting TRH analogue (RX77368), on TSH, T4, T3 and prolactin in patients with motor neuron disease.
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Aged↗
Biomedical subjects
S L Lightman
Publications and source records attributed to S L Lightman.
Mechanisms of impaired excretion of a fluid load after cardiac denervation in dogs.
The influence of cardiac innervation on the renal response to volume expansion was investigated. Systemic hemodynamic, plasma hormone, and renal clearance measurements were made before, during, and after intravenous administration of 1,000 ml 0.9% saline over 10 min to six control and six cardiac-denervated, chloralose-anesthetized mongrel dogs. Volume expansion resulted in a two- to threefold rise in plasma atrial natriuretic peptide (ANP) concentrations and a 50% rise in glomerular filtration rate (GFR) in both groups. Plasma renin activity (PRA) and plasma arginine vasopressin remained higher throughout in cardiac-denervated compared with control dogs. The marked increases in urine flow rate and sodium and free water clearances seen in the controls were attenuated or abolished after cardiac denervation. These differences were due to the influence of higher PRA and vasopressin in these animals compared with the controls, rather than differences in hemodynamic responses operating via GFR or in direct humoral responses via ANP secretion.
Animals↗
Substance P stimulates arginine vasopressin and inhibits adrenocorticotropin release in vivo in the rat.
We have investigated the central effects of substance P (SP) on plasma concentrations of immunoreactive ACTH and on immunoreactive and bioactive arginine vasopressin (AVP) in the rat. The injection of SP (20 nmol) into the lateral ventricle intracerebroventricular, (i.c.v.) of ethanol-anaesthetised rats produced a prolonged antidiuresis lasting at least 30 min, associated with an increase in plasma AVP (from 7.8 +/- 0.6 to 12.5 +/- 1.9 fmol/ml, mean +/- SEM, n = 6). Concentrations of plasma ACTH were significantly decreased 30 min following SP (from 320 +/- 70 to 135 +/- 15 fmol/ml, n = 12). In rats anaesthetised with urethane, a significant decrease in plasma ACTH was observed 15 and 30 min following i.c.v. injection of SP (20 nmol); a downward trend was also observed in ACTH following a 40 nmol dose, but this was not significant. No effect of SP was observed on either basal or CRF-41-stimulated ACTH release from isolated rat anterior pituitary cells in vitro. These results demonstrate for the first time that SP exerts opposite effects upon the release of ACTH and AVP in the same animal, and suggest that these actions occur at the level of the hypothalamus.
Adrenocorticotropic Hormone↗
Altered cardiovascular and neurohumoral responses to head-up tilt after heart-lung transplantation.
Heart-lung transplantation results in afferent and efferent denervation of the transplanted organs including interruption of the central connections from the low-pressure receptors in the atria and pulmonary veins. We investigated whether the cardiovascular and neurohumoral responses to the postural stimulus of head-up tilt were affected after transplantation. Responses in eight heart-lung transplant recipients were studied and compared with those in eight normal subjects matched for age and sex during passive head-up tilt at 45 degrees for 1 hour. The transplant group had a higher initial heart rate (99 +/- 2 versus 68 +/- 2 beats/min, p less than 0.001) and diastolic blood pressure (88 +/- 5 versus 76 +/- 2 mm Hg, p less than 0.05) than did the control group. The increases in heart rate and diastolic blood pressure during head-up tilt were similar in the two groups. Systolic blood pressure remained unchanged. The decrease in cardiac output (30% versus 18%, p less than 0.05) and the increase in systemic vascular resistance (52% versus 28%, p less than 0.05) were greater in the transplant group. Baseline levels of norepinephrine, epinephrine, vasopressin, and plasma renin activity were similar in the two groups. Atrial natriuretic peptide concentrations were higher in the transplant group (26 +/- 3.8 versus 9.7 +/- 1.6 pmol/l, p less than 0.001). During head-up tilt, plasma norepinephrine levels increased to a greater extent in the transplant group than in the control group (83% versus 53%, p less than 0.01), indicating an increased sympathetic response. In contrast, plasma renin activity increased significantly in the control group but not in the transplant group.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Feedback inhibition of aldose reductase gene expression in rat renal medulla. Galactitol accumulation reduces enzyme mRNA levels and depletes cellular inositol content.
Aldose reductase (AR) is an enzyme responsible for converting glucose into sorbitol and galactose into galactitol. In the renal inner medulla, where sorbitol production plays a role in cellular osmoregulation, AR gene expression has been shown to be osmotically regulated. The present study examined the effects of the accumulation of the AR end product, galactitol, induced by galactose feeding, on AR gene expression and on the balance of other cellular osmolytes, including inositol, in the renal medulla. To differentiate between the effects of excess substrate, product, and intervening osmotic factors, rats were fed either control, galactose, galactose and sorbinil (an AR inhibitor), or control plus sorbinil diets. Renal papillae were assayed for AR mRNA, sodium, urea, galactose, galactitol, sorbitol, inositol, and other organic osmolytes. Galactose feeding resulted in a great accumulation of galactitol and reduction in AR mRNA levels in renal papillae. Associated with these changes was a significant depletion of renal papillary sorbitol, inositol, and glycerolphosphocholine. These effects were largely attenuated by sorbinil. The present findings suggest that renal cellular accumulation of the enzyme's polyol product causes downregulation of AR gene expression. Furthermore, our findings suggest that the inositol depletion associated with sorbitol or galactitol accumulation in various cell types during hyperglycemia may be a function of cellular osmoregulation.
Aldehyde Reductase↗
Vasopressin in chronic psychiatric patients with primary polydipsia.
Twelve chronic in-patients with primary polydipsia were studied, during free drinking and after fasting, by concurrent measurements of plasma AVP, serum sodium and osmolality, and urine volume, AVP, osmolality, and creatinine. A majority of the patients showed inappropriately high levels of AVP: plasma AVP estimations demonstrated that seven had Type I SIADH and two had Type II SIADH. Urinary AVP estimations confirmed inappropriately raised AVP in seven of the subjects tested, and there was a significant agreement between the plasma and urine diagnoses. Although able to concentrate their urine in response to fluid deprivation, the patients showed a decreased renal sensitivity to AVP. Despite the mitigating effect of decreased renal sensitivity to AVP, the SIADH seen in these patients appears to contribute to the development of water intoxication caused by polydipsia.
Adult↗
Naloxone inhibits oxytocin release at orgasm in man.
We examined the effect of naloxone on plasma oxytocin levels during sexual activity in men. Eight normal men took part in a double-blind, two-period, cross-over design. Mean plasma oxytocin rose to 362% of baseline values at orgasm with placebo (saline) but showed no increase with naloxone (P less than 0.01). While naloxone had no effect on heart rate or blood pressure at orgasm, a decrease in the level of subjective arousal and pleasure at orgasm was noted. We conclude that opioid receptor blockade with naloxone has an inhibitory effect on the neural pathways mediating the oxytocin response at orgasm.
Adult↗
A gonadotropin-releasing hormone (GnRH) antagonist distinguishes three populations of GnRH analog-responsive cells in human and rat pituitary in vitro and produces an acute increase in intracellular Ca2+ concentration without inducing gonadotropin secretion.
We have examined the actions of the potent GnRH antagonist [N-acetyl-D beta Na11-D-pCl-Phe2-D-Phe3-D-Arg6,Phe7,Arg8-D-Ala10]NH2GnRH++ + (GnRHa) on basal and GnRH-stimulated LH secretion, inositol phospholipid turnover, and intracellular Ca2+ levels in dispersed rat anterior pituitary tissue. As expected, GnRHa was found to be a pure antagonist of secretion, but was paradoxically equipotent with GnRH in stimulating inositol phospholipid turnover. Examination of intracellular Ca2+ changes at the single cell level using digital video-enhanced fluorescence imaging demonstrated that dispersed rat pituitary cells appeared to contain three GnRH analog-responsive cell populations: those that increased intracellular Ca2+ in response to both GnRH and GnRHa, and those that responded to either GnRH or GnRHa only. These observations were extended to studies of the relatively homogeneous gonadotroph cell populations of endocrinologically inactive pituitary adenomas. Of five adenomas examined, one increased inositol phospholipid turnover in response to GnRHa plus GnRH, but not GnRH alone, three responded to GnRH only, and one responded to both GnRH and GnRHa. Our findings, therefore, suggest that three GnRH analog-responsive cell types are also present in human pituitary and that clonal expansion of any of these cell types may be responsible for tumor formation.
Adenoma↗
Neurohypophysial secretion to insulin-induced hypoglycemia and its regulation by endogenous opioids in women.
In animals, there is sexual dimorphism of both neurohypophysial peptide secretion in response to stressful stimuli and to the inhibitory effects of opioids. In men, endogenous opioids inhibit the release of oxytocin when AVP secretion is stimulated by insulin-induced hypoglycemia. We have now investigated the role of endogenous opioids in the AVP and oxytocin response to insulin-induced hypoglycemia in women. Twelve subjects, 6 in the follicular and 6 in the luteal phase of the menstrual cycle, were infused on 2 occasions with naloxone (4 mg bolus and 6 mg/h) or saline. Soluble insulin (Human Actrapid, 0.15 mu/kg, iv) was given and serial blood samples taken. Blood sugar fell significantly (p less than 0.05) and similarly in all groups. In the follicular phase hypoglycemia led to a rise in plasma AVP from 1.3 +/- 0.2 to 1.8 +/- 0.2 pmol/l in the saline-infused subjects (NS), and from 1.0 +/- 0.1 to 2.0 +/- 0.2 pmol/l in the naloxone-infused (p less than 0.05). AVP rose similarly from 0.6 +/- 0.1 to 1.6 +/- 0.5 pmol/l (p less than 0.05) in the luteal phase controls and from 0.8 +/- 0.1 to 1.5 +/- 0.3 pmol/l (p less than 0.05) in naloxone-infused subjects in the luteal phase. There were no significant differences between any of these groups. There were no significant changes in plasma oxytocin in any group. We therefore conclude that in women, unlike men, endogenous opioids do not modulate oxytocin or vasopressin release during insulin-induced hypoglycemia.
Arginine Vasopressin↗
Stress responsiveness of hypothalamic corticotrophin-releasing factor and pituitary pro-opiomelanocortin mRNAs following high-dose glucocorticoid treatment and withdrawal in the rat.
In-situ hybridization with synthetic oligonucleotide probes was used to determine the mRNA content of corticotrophin-releasing factor (CRF) and proenkephalin A mRNA in the paraventricular nucleus, and of pro-opiomelanocortin (POMC) mRNA in the anterior pituitary gland of male rats immediately after, and during recovery from, chronic high-dose prednisolone treatment. Levels of transcripts for mRNA for both CRF and POMC were markedly reduced after the treatment, but there was a rapid return to control values for CRF mRNA within 18 h of steroid withdrawal. In untreated animals, the stressful stimulus of i.p. hypertonic saline increased CRF and proenkephalin A mRNA within 4 h with no significant difference in response seen whether the tissues were removed at 13.00 or 20.00 h. The increase in POMC mRNA did not reach statistical significance in these animals. Although prednisolone resulted in a marked reduction of basal CRF mRNA, the stress-induced increment of CRF mRNA remained comparable with that found in untreated animals. On the day following cessation of prednisolone treatment at 09.00 h, basal and stress levels of CRF mRNA were significantly higher in rats killed at 20.00 h than at 13.00 h. Proenkephalin A mRNA transcripts were below quantifiable levels of detection in control or non-stressed prednisolone-treated animals at all the time-points studied. Stress, however, resulted in the accumulation of proenkephalin A mRNA in control animals. This response was inhibited by prednisolone treatment and only returned 18 h after withdrawal. Prednisolone treatment reduced POMC mRNA below the levels detected in untreated animals, with no detectable response to stress.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Management of advanced prostatic cancer.
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Aged↗
The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis.
Diabetes insipidus is a well-recognized complication of Langerhans-cell histiocytosis (histiocytosis X), but its frequency and natural history are not well defined. Of 52 children with histiocytosis whom we studied, 12 (23 percent) had diabetes insipidus. Only two children had diabetes insipidus at presentation with histiocytosis, but the cumulative risk that it would develop during the first four years after the presentation and diagnosis of histiocytosis was found to be 42 percent. Diabetes insipidus occurred most often among children with multisystem disease and those with proptosis. To determine the natural history of diabetes insipidus in children with histiocytosis, we measured the response of urinary arginine vasopressin to water deprivation every six months in 21 children who did not have diabetes insipidus and who had had histiocytosis for less than four years. Five of the 21 children (24 percent) had subnormal responses during the initial test. One subsequently had spontaneous improvement in the functioning of the posterior pituitary, and diabetes insipidus subsequently developed in two, as it did in one of the children who initially had normal function of the posterior pituitary. Two of the children received irradiation to the pituitary within two to four weeks after diabetes insipidus developed, but they had no improvement in pituitary function. However, diabetes insipidus improved transiently during prednisolone therapy in one of these children and improved permanently after etoposide therapy in another child. We conclude that prospective study with the use of a simple water-deprivation test will allow partial defects of posterior-pituitary function to be detected in patients with histiocytosis and will permit a more appropriate evaluation of the effects of therapeutic intervention.
Adolescent↗
Relation of atrial natriuretic peptide release to atrial contraction.
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Atrial Function↗
Glucocorticoid inhibition of stress-induced changes in hypothalamic corticotrophin-releasing factor messenger RNA and proenkephalin A messenger RNA.
We have examined the effects of localised administration of the synthetic glucocorticoid dexamethasone on basal and stress-induced levels of mRNA for both corticotrophin-releasing factor (CRF) and proenkephalin A, in parvocellular neurons of the paraventricular nucleus (PVN). Unilateral implants of cholesterol directly over the PVN had no effect on either basal or stress-induced increase of CRF and proenkephalin A message. However, unilateral implants of dexamethasone significantly decreased basal CRF mRNA compared to the contralateral, unimplanted side and prevented the increase in CRF and proenkephalin A mRNA 4 hours after ip hypertonic saline stress. These findings confirm the PVN as a site for glucocorticoid feedback. Furthermore the data demonstrates a steroid-sensitive stress mediated increase in proenkephalin A mRNA which provides additional evidence for a role of the endogenous opiates in the hypothalamic neuroendocrine response to stress.
Animals↗
Somatostatin and somatostatin analogues in oncology.
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Animals↗
In vivo stimulation of phosphoinositide metabolism in the brainstem of rats following osmotic stress.
We have investigated the effects of osmotic stress on the activity of inositol phospholipid turnover in the central nervous system of rats. Intracerebroventricular injection of [3H]myo-inositol was used for metabolic labelling of brain phosphoinositides in vivo. The levels of radiolabelled inositol lipids increased in a time-dependent manner in several areas of the brain, reaching a maximum 24 h after the injection. Treatment with LiCl 20 h after the administration of tritiated myo-inositol did not modify the levels of inositol lipids, but resulted in a dose-dependent accumulation of inositol phosphates. In rats treated with 10 mEq/kg LiCl, intraperitoneal injections of hypertonic saline (1.50 M NaCl) resulted in the stimulation of phosphoinositide turnover in the brainstem, but not in any of the other regions of the brain studied. This response was not prevented by unilateral cervical vagotomy, but was significantly lower in vasopressin-deficient Brattleboro rats. Brain phosphoinositide metabolism was not stimulated by acute blood volume depletion. We conclude that osmotic stress, but not acute hypovolemia, results in vasopressin-dependent activation of brainstem neurons by stimulating inositol phospholipid metabolism. In addition, metabolic labelling in vivo followed by treatment with LiCl provides a useful approach for assessing the physiological significance of the activation of polyphosphoinositide metabolism in the central nervous system in vivo. Our study provides evidence for a functional role of this second messenger system in the brainstem.
Animals↗
Neuroendocrine control of blood tonicity and volume.
The numerous studies cited in this chapter clearly show that very complex mechanisms are involved in the cardiovascular and osmotic regulation of AVP release. Information from peripheral receptors within the cardiovascular system and from central osmoreceptors is carried by multisynaptic neural inputs to the SON and PVN. This information is co-ordinated at one or more sites within the hypothalamus, the brain stem, or even the neurohypophysis itself, to ensure release of the appropriate amount of AVP. In many cases the origin of the pathway and the nature of the neurotransmitter is known, but further studies are needed to establish their physiological role in AVP release.
Animals↗
Vasopressin secretion in diabetic subjects with and without autonomic neuropathy: responses to osmotic and postural stimulation.
1. The release of arginine vasopressin (AVP) after an osmotic stimulus and head-up tilt was assessed in diabetic subjects with and without autonomic neuropathy. 2. Six diabetic subjects with (DAN +ve) and five without (DAN -ve) evidence of autonomic neuropathy and five normal subjects were infused with 5% (w/v) NaCl at a rate of 0.05 ml min-1 kg-1 body weight for 120 min. Blood pressure, heart rate and plasma AVP were measured over this period. 3. Seven DAN +ve, six DAN -ve and six normal subjects were tilted head-up to 45 degrees for 120 min. Blood pressure, heart rate and plasma AVP were measured during the study. 4. Infusion of 5% (w/v) NaCl produced appropriate rises in plasma osmolality and plasma AVP levels which did not differ between the three groups, confirming the normal osmotic release of AVP in the diabetic subjects. 5. During head-up tilt, there were no differences in AVP responses between the three groups, despite a major hypotensive stimulus in the DAN +ve group. 6. We conclude that osmotic release of AVP is normal in diabetes, but that cardiovascular release of AVP is impaired in diabetic subjects with cardiovascular reflex evidence of autonomic neuropathy, reflecting an afferent defect.
Adult↗