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Biomedical subjects

S L Lightman

Publications and source records attributed to S L Lightman.

At least 307 records · Page 17Linked to original sources
PubMed1989

Influence of steroids on the hypothalamic corticotropin-releasing factor and preproenkephalin mRNA responses to stress.

We have used in situ hybridization histochemistry to investigate the influence of both circulating corticosteroids and the stress paradigm of i.p. hypertonic saline on the levels of mRNAs encoding corticotropin-releasing factor (CRF) and preproenkephalin in parvocellular neurons of the rat hypothalamus. Stress increased both CRF and preproenkephalin mRNAs, whereas adrenalectomy increased only CRF mRNA. After adrenalectomy, even when CRF mRNA had reached peak levels, stress still further increased CRF mRNA and caused an exaggerated rise in preproenkephalin mRNA. Dexamethasone administration in the fast or intermediate-feedback time domains had no effect on CRF or preproenkephalin mRNA responses to stress; however, when administered over a longer period of time in the slow-feedback time domain dexamethasone reduced basal CRF mRNA levels and the stress-stimulated levels of CRF and preproenkephalin mRNA. These results show that different stimuli to the parvocellular paraventricular hypothalamus differentially regulate CRF transcript levels. Furthermore, in spite of the lack of any detectable effect of changes in circulating glucocorticoid levels on basal levels of preproenkephalin mRNA, glucocorticoids markedly alter the preproenkephalin mRNA response to stress.

Adrenalectomy↗
PubMed1989

Vasopressin and oxytocin responses to hypertonic saline infusion: effect of the opioid antagonist naloxone.

Endogenous opioids inhibit the release of oxytocin (OT) when vasopressin (AVP) is secreted in response to acute pharmacological stimuli in man and to a variety of physiological and pharmacological stimuli to animals. We have investigated the effect of naloxone on the AVP and OT responses to hypertonic saline in man. In two separate studies, six male subjects were infused with hypertonic saline (675 mmol/l, 0.05 ml/kg/min for 2 h) and either naloxone (4 mg bolus and 6 mg/h) or normal saline in random order. Hypertonic saline resulted in similar significant rises of plasma osmolality and AVP in both groups and a small but significant decrease in OT. Thirst sensation was not altered by naloxone. Endogenous opioids do not play an important role in the suppression of OT release when AVP is secreted in response to an osmotic stimulus in man.

Adult↗
PubMed1989

Selective defect in gonadotrophin secretion in patients with autonomic failure.

We studied the neuroendocrine effects of a condition associated with abnormal hypothalamic amines. Hypothalamo-anterior pituitary function was assessed in five male subjects with autonomic failure (AF) and in five age and sex-matched controls. All subjects showed normal gonadotrophin and TSH responses to GnRH and TRH, respectively. In control subjects, intravenous infusion of naloxone caused a significant rise in overall LH concentrations as well as increased frequency and amplitude of LH pulses. In contrast, in AF subjects naloxone did not alter LH concentrations or increase LH pulse frequency. Naloxone also caused an increase in neurosecretory GH pulses not only in AF subjects but also in the controls. These results suggest that in man, ascending catecholamine pathways are important in the control of gonadotrophin secretion. The markedly different response of GH to an opioid antagonist in elderly subjects should be further investigated.

Aged↗
PubMed1989

Cardiovascular interactions between vasopressin, angiotensin and noradrenaline in the Brattleboro rat.

1. The cardiovascular effects of bolus intravenous injections of vasopressin, angiotensin II and noradrenaline were studied in 6-hydroxydopamine pretreated, anaesthetized Brattleboro rats with hereditary diabetes insipidus and normal rats of the parent Long Evans strain. 2. Pretreatment with 6-hydroxydopamine did not significantly affect control values for mean arterial blood pressure, cardiac output or total peripheral resistance in either Brattleboro or Long Evans rats but the pressor response to haemorrhage was reduced in both strains compared to the control animals. 3. The pressor responses of the untreated Brattleboro rats to 250 mu kg-1 vasopressin were significantly greater and more prolonged than in control rats of the Long Evans strain. 4. Pretreatment with 6-hydroxydopamine significantly enhanced the peak pressor response to vasopressin, but not to angiotensin II (1 microgram kg-1), in Brattleboro and Long Evans rats. 5. Pretreatment with 6-hydroxydopamine resulted in an enhanced pressor response to 1 microgram kg-1 noradrenaline in both Brattleboro and Long Evans rats, but the effect was significantly greater in the vasopressin-deficient animals. 6. These results indicate differences in the pressor responsiveness of Brattleboro rats to vasopressin and noradrenaline, but not to angiotensin II, compared with control Long Evans rats and provide evidence for important interactions between the sympathetic nervous system and these pressor hormones.

Angiotensin II↗
PubMed1989

Atrial natriuretic peptide response to rapid atrial pacing in cardiac-denervated dogs.

The effects of rapid atrial pacing on central hemodynamics, plasma hormones, and renal function were investigated in eight control and nine cardiac-denervated dogs under chloralose anesthesia. Pacing at approximately 250 ppm for 60 min caused similar increases in pulmonary wedge and right atrial pressures, systemic vascular resistance, and plasma atrial natriuretic peptide (ANP) in both groups. In control dogs, pacing produced a fall in both plasma vasopressin (AVP) and plasma renin activity (PRA) and a rise in urine flow rate associated with an increase in free water but not sodium clearance. In contrast, in cardiac-denervated dogs, both plasma AVP and PRA increased during pacing; urine flow rate did not change, and marked sodium retention occurred. This study supports the concept that the increase in urine flow during rapid atrial pacing is mediated by inhibition of renin and AVP secretion through intact cardiac nerves. The secretion of ANP is unaffected by cardiac denervation. The natriuretic and vasodilator actions of high plasma ANP concentrations during rapid atrial pacing can be inhibited either by neurally mediated cardiorenal effects in normal animals or by stimulation of the renin-angiotensin system after cardiac denervation.

Animals↗
PubMed1989

Dependent effect of drinking volume on vasopressin but not atrial peptide in humans.

The act of drinking causes a fall in plasma arginine vasopressin (AVP) concentration that precedes changes in plasma osmolality. To investigate the specificity of this drinking stimulus on hormone secretion, six volunteers (5 male, 1 female, aged 22-39 yr) were water deprived for 36 h and then drank 15 ml/kg water at 10-12 degrees C using 15-20 swallowing actions/min over 3.5 +/- 0.5 min (mean +/- SE). This caused a fall in plasma AVP from 4.5 +/- 0.7 to 3.2 +/- 0.5 pmol/l (P less than 0.05) and in thirst (by 5.7 +/- 0.6 on a 10-cm linear analog scale) (P less than 0.05) 5 min after drinking. No significant changes occurred in mean arterial pressure, heart rate, or plasma atrial natriuretic peptide (ANP) concentration. A second study was undertaken to determine whether the reflex inhibition of AVP secretion is activated simply by the act of swallowing regardless of the volume of liquid consumed. The six volunteers were water deprived for 36 h and then sipped and swallowed 1 ml/kg water at 10-12 degrees C using 15-20 swallowing actions/min over 3.0 +/- 0.1 min. There was no change in plasma AVP concentration, although thirst was reduced by 2.3 +/- 0.6 (P less than 0.05) at 5 min. Plasma AVP 10 min after sipping and swallowing (4.2 +/- 0.8 pmol/l) was significantly greater than at 10 min after drinking 15 ml/kg (2.8 +/- 0.5 pmol/l) (P less than 0.05) despite the fact that plasma osmolality at this stage was similar in both studies. We conclude that the drinking-mediated reflex inhibition of AVP secretion in humans is dependent on swallowing an adequate volume and is not accompanied by changes in hemodynamics or in plasma ANP concentration.

Adult↗
PubMed1989

Lactation inhibits stress-mediated secretion of corticosterone and oxytocin and hypothalamic accumulation of corticotropin-releasing factor and enkephalin messenger ribonucleic acids.

The effect of lactation on stress-induced hormone responses and changes in hypothalamic mRNA was assessed in female rats. In control animals the stimulus of ip hypertonic saline resulted in increased plasma levels of corticosterone, oxytocin, and vasopressin and hypothalamic content of CRF and enkephalin mRNA. In lactating females, however, the corticosterone response to this stress failed to reach significance, the plasma oxytocin response was markedly reduced, and the vasopressin response was unaffected. Lactation also resulted in an abolition of the CRF and enkephalin mRNA responses to stress. In contrast, the hypothalamic CRF response to adrenalectomy was unaffected by lactation status. Removal of the pups from their mothers resulted in a return of CRF and enkephalin mRNA responses to stress within 2 days. Lactation is associated with a selective inhibition of normal hypothalamic stress responses.

Animals↗
PubMed1989

Effects of thyrotropin-releasing hormone and gonadotropin-releasing hormone on inositol phospholipid turnover in endocrinologically inactive pituitary adenomas and prolactinomas.

We examined the effects of GnRH and TRH on inositol phospholipid turnover in 11 endocrinologically inactive pituitary adenomas and 5 prolactinomas. In 9 of the 11 nonsecreting adenomas, GnRH induced a significant increase in inositol phospholipid turnover; of those that responded, increased inositol phospholipid turnover in response to TRH occurred in 6. Neither of the 2 prolactinomas exposed to GnRH responded to GnRH, whereas all 5 prolactinomas responded to TRH. These findings demonstrate the presence of functional GnRH receptors on endocrinologically inactive pituitary adenomas. The phosphatidyl inositol-linked receptor status of these tumors differs from that of prolactinomas. These receptors may offer a possible target for therapeutic intervention in endocrinologically inactive adenomas.

Adenoma↗
PubMed1989

Developmental and physiological regulation of aldose reductase mRNA expression in renal medulla.

Aldose reductase (AR), an enzyme that catalyzes the conversion of glucose to sorbitol, has been implicated in the pathogenesis of many of the complications of diabetes mellitus, but its normal physiological function in various tissues remains uncertain. It has been suggested that in the kidney, sorbitol production may be an important cellular protection against medullary intersitital hypertonicity. Using in situ and Northern hybridization analyses, we found that at the time of birth, AR mRNA expression in the kidney was very low and seen only in the papilla. By 12 days of age, at about the time a corticopapillary osmotic gradient and the capacity for urinary concentration have developed, a striking increase in renal AR mRNA levels was seen. It was confined to the inner medulla and was characterized by a dramatic gradient of expression paralleling the corticopapillary osmotic gradient. Levels of expression were somewhat lower in adults, but showed the same inner medullary boundary and gradient. Under these hybridization and exposure conditions, no AR transcripts were detected in the outer medulla or cortex. Homozygous Brattleboro rats with congenital diabetes insipidus have relatively dilute corticopapillary osmotic gradients, and their level of medullary AR mRNA was significantly lower than that of controls. Conversely, normal rats made hyperosmotic and, hence, antidiuretic by salt loading showed a large increase in medullary AR mRNA. These changes in renal medullary AR gene expression in correlation with changes in medullary tonicity support the hypothesis that renal AR plays a role in cellular adaption to osmotic stress and suggest that local medullary osmolarity may regulate the level of AR gene expression.

Aging↗
PubMed1989

Developmental and physiological pattern of aldose reductase mRNA expression in lens and retina.

Aldose reductase (AR), an enzyme which converts glucose to sorbitol, has been implicated in the pathogenesis of diabetic cataracts and retinopathy. The normal physiological role of this enzyme in ocular tissue, however, remains unclear. In a developmental study in the rat using in situ and Northern hybridization analyses, we have found that there is a high level of AR mRNA expression in optic cup and lens as early as embryonic day 13. Serial sections through whole embryos at this stage showed that the eye was the only site of AR mRNA hybridization. Levels of AR mRNA declined in the retina as differentiation proceeded and were very sparse there postnatally. As lens development progressed, epithelial AR mRNA levels remained high, especially in the germinative zone, which is the source of the cells that will become lens fibers, and in the bow region, where these cells undergo a dramatic morphogenetic differentiation into lens fibers. AR mRNA was undetectable in terminally differentiated lens fibers. Since it has been suggested that AR-catalyzed sorbitol production could be an osmoprotective device of lens epithelium during systemic hyperosmolar stress, AR mRNA levels from dehydrated hyperosmolar rats were compared with euvolemic control values, and no difference was found. In summary, AR appears to be of particular importance in the development of the eye, with its retinal role receding relative to lens as differentiation is completed. A continued high level of expression in lens epithelium in adulthood may be explained by the fact that lens tissue, unlike retina, normally continues to proliferate and differentiate after birth. The temporal and spatial pattern of distribution of AR mRNA is strongly suggestive of a role for this enzyme in lens fiber morphogenesis.

Aging↗
PubMed1989

Osmotic regulation of hypothalamo-neurointermediate lobe corticotrophin-releasing factor-41 in the rat.

We have detected significant amounts of corticotrophin-releasing factor-41 (CRF-41) in the rat hypothalamo-neurointermediate lobe system using a radioimmunoassay and reversed-phase high-performance liquid chromatography. Total amounts of CRF-41 in extracts of median eminence (ME), supraoptic nucleus (SON), paraventricular nucleus (PVN) and neurointermediate lobe (NIL) from control animals were 1076 +/- 132, 196 +/- 44, 22 +/- 7 and 147 +/- 50 fmol respectively (means +/- S.E.M., n = 6). In animals given 340 mmol NaCl/l instead of tap water to drink for 12 days, no significant changes occurred in the CRF-41 content of the ME, SON or PVN, but CRF-41 content increased more than twofold in the NIL (362 +/- 58 fmol). Plasma concentrations of CRF-41 and ACTH in control animals were 23 +/- 6 and 51 +/- 8 pmol/l respectively. After saline treatment no significant change in plasma CRF-41 was detected (20 +/- 8 pmol/l) but concentrations of circulating ACTH were decreased (15 +/- 2 pmol/l). The CRF-41 content of both the ME and the NIL was significantly depleted after intracerebroventricular injection of colchicine (414 +/- 81 and 34 +/- 7 fmol respectively). These data suggest that NIL CRF-41 is of hypothalamic origin and can be regulated by an osmotic stimulus.

Adrenocorticotropic Hormone↗
PubMed1989

gamma-Aminobutyric acid regulation of neurohypophysial hormone secretion in male and female rats.

The role of gamma-aminobutyric acid (GABA) in the control of oxytocin and arginine vasopressin (AVP) release from the posterior pituitary was investigated using the GABA agonist muscimol and the GABA antagonists bicuculline and picrotoxin. Two perifusion model systems were studied using (a) intact isolated posterior pituitaries (IPP) and (b) neurosecretosomes from both male and female rats. In experiments on tissue from male rats, the stimulated release of oxytocin and AVP in both models was inhibited by muscimol, an effect which was reversed in the presence of bicuculline. Bicuculline alone increased the release of oxytocin only. Although similar responses to muscimol or bicuculline were seen in neurosecretosomes from female animals, neither agent affected oxytocin and AVP release from the intact IPP. Picrotoxin had a similar effect to bicuculline on oxytocin in isolated posterior pituitaries from male as well as female rats, although at the neurosecretosome level a paradoxical inhibition was observed. These results provide evidence for an endogenous GABA receptor mechanism at the level of the neurosecretory terminals in both male and female rats. The sexually dimorphic IPP response suggests a second more complex mechanism involving either pituicytenerve terminal interactions and/or a secondary role of other neurotransmitters in the GABA regulation of neurohypophysial hormones.

Animals↗
PubMed1989

Responses of hypothalamic and pituitary mRNA to physical and psychological stress in the rat.

In-situ hybridization histochemistry was used to measure corticotrophin-releasing factor mRNA and proenkephalin A mRNA in the paraventricular nucleus (PVN), and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary of the rat. Levels of message were determined at 1, 2, 4 and 8 h after exposure to a variety of physical and psychological stresses. Corticotrophin-releasing factor mRNA in the PVN and POMC mRNA in the anterior pituitary increased in response to i.p. hypertonic saline, restraint and swim stress but not to cold stress. Proenkephalin A mRNA was raised only in response to the physical stress of i.p. injection of hypertonic saline. These results suggest that different afferent pathways and hypothalamic neurotransmitters may be involved in mediating the hypothalamic response to different physical and psychological stresses.

Animals↗
PubMed1988

Differential effects of hypothalamic catecholamine depletion on the release of arginine vasopressin and CRF-41 into hypothalamo-hypophyseal portal blood.

The effects of 6-hydroxydopamine lesions of the ventral noradrenergic bundle (VNAB) and of intracerebroventricular 6-hydroxydopamine on hypothalamo-hypophyseal portal blood (HPB) concentrations of arginine vasopressin (AVP), corticotrophin releasing factor (CRF-41), and noradrenaline have been investigated. VNAB lesions and intracerebroventricular 6-hydroxydopamine caused a reduction of HPB CRF-41 concentration, while AVP remained unchanged. HPB noradrenaline concentration was reduced in animals treated with lateral ventricular 6-hydroxydopamine, but was unchanged in VNAB lesioned animals. Our results suggest differential effects of noradrenaline on the release of AVP and CRF-41 into HPB.

Adrenergic Fibers↗
PubMed1988

Vasopressin-stimulated turnover of phosphatidylinositol in the decentralised superior cervical ganglion of the rat.

Vasopressin (AVP) receptors have been demonstrated in the superior cervical ganglion (SCG) linked to the turnover of phosphatidylinositol (PI). We have investigated the effect of changes in autonomic function on the turnover of PI in the rat SCG in response to AVP and carbachol. Decentralisation of the SCG for 3 days causes a significant decrease in the response to AVP, while the response to carbachol is unaffected. The decrease in response to AVP is still present 21 days after decentralisation. A similar pattern of changes is present in ganglia from the homozygous Brattleboro rat. Pretreatment with reserpine has no effect on the response to AVP. The results suggest that AVP may be involved in ganglionic transmission in the autonomic nervous system, but that full expression of AVP-induced turnover of PI is dependent on an intact preganglionic input.

Animals↗
PubMed1988

Vasopressin stimulates inositol phospholipid metabolism in rat medulla oblongata in vivo.

We have investigated whether microinjections of arginine-vasopressin (AVP) into the nucleus tractus solitarii (NTS) of rats results in the stimulation of inositol phospholipid metabolism, a biochemical event related to the activation of V1-type receptors. We found that AVP, but not the related peptides oxytocin or deamino-D-AVP, increases the incorporation of [3H]myoinositol into lipids and the accumulation of labelled inositol phosphates in the dorsomedial medulla oblongata of lithium-treated rats. These effects were abolished by local pretreatment with D-(CH2)5-Tyr(Me)-AVP, a specific antagonist of V1-receptors. It is concluded that the effects of AVP in the NTS of rats are likely to be due to an action on specific receptors (V1-like) and subsequent activation of polyphosphoinositide turnover.

Animals↗