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Biomedical subjects

S L Lightman

Publications and source records attributed to S L Lightman.

At least 253 records · Page 14Linked to original sources
PubMed1991

Regulation of ANP secretion in insulin-dependent diabetes mellitus and the influence of autonomic neuropathy.

In order to determine the effect of diabetic autonomic neuropathy (DAN) on the atrial natriuretic peptide (ANP) response to dynamic stimuli, we studied the ANP response to 60 degrees head-up and 60 degrees leg-up tilt in diabetic subjects with (DAN + ve, n = 8) and without (DAN - ve, n = 8) evidence of autonomic neuropathy and seven matched non-diabetic controls. Mean baseline plasma ANP concentrations were similar in all three groups. Head-up tilt was associated with a fall in plasma ANP in all seven healthy controls (21.8 (16.8-30.7) to 16.8 (7.1-29.1), P = 0.06, mean (range)), seven of the eight DAN - ve (16.9 (6.5-33.7) to 8.5 (3.0-21.1), P = 0.015) and all eight DAN + ve subjects (27.3 (8.5-101.5) to 15.4 (1.0-67.6), P = 0.044). Leg-up tilt caused a rise in plasma ANP in six of the seven healthy controls (17.6 (7.5-27.9) to 22.4 (15.2-48.1), P = 0.041), six of the eight DAN - ve (12.5 (7.8-27.8) to 15.5 (7.3-31.3), P = 0.054) and seven of the eight DAN + ve subjects (18.2 (2.8-55.1) to 25.1 (4.5-92.8), P = 0.013). There was no significant difference in the fall in plasma ANP during head-up tilt or in the rise in plasma ANP during leg-up tilt between the three groups. We conclude that the regulation of ANP secretion is normal in diabetes mellitus, and is unaffected by the presence of autonomic neuropathy.

Adult↗
PubMed1991

Role of catecholamines in mediating messenger RNA and hormonal responses to stress.

The role of catecholamines in regulating the neuroendocrine stress response is controversial. We have investigated the effects of unilateral ventral noradrenergic bundle (VNAB) lesions on corticotrophin-releasing factor (CRF) and proenkephalin A mRNA responses in the parvocellular paraventricular nucleus (pPVN) to both physical and psychological stresses. We have also determined the effects of direct bilateral PVN lesions on CRF mRNA, plasma ACTH and corticosterone responses to psychological stress. 6-OHDA lesions whether to the VNAB or direct to the PVN did not result in any change in basal levels of CRF mRNA. Depletion of endogenous noradrenaline following unilateral lesions of the VNAB did not affect the CRF mRNA or the proenkephalin A mRNA response to stress. These data suggest that noradrenergic pathways are not involved in maintaining basal levels of CRF mRNA and that the noradrenergic input through the VNAB does not mediate the accumulation of CRF and proenkephalin A mRNAs in response to these stressors. Direct bilateral lesions to the PVN prevented the accumulation of CRF mRNA but not the ACTH and corticosterone responses to restraint stress. This suggests that monoamines are involved in the regulation of CRF mRNA through a mechanism independent of CRF-41 secretion.

Adrenocorticotropic Hormone↗
PubMed1991

Intracerebroventricular vasopressin reduces CSF absorption rate in the conscious goat.

Cerebrospinal fluid (CSF) levels of vasopressin (AVP) are elevated in some disorders associated with raised intracranial pressure. We have previously demonstrated that intracerebroventricular infusion of AVP in the conscious goat leads to elevation of intracranial pressure by a mechanism independent of changes in arterial blood pressure or circulating neurohypophysial peptide concentrations. We have now examined the effect of increasing CSF AVP levels on CSF dynamics using the technique of ventriculo-cisternal perfusion in the conscious goat. Intracerebroventricular perfusion with 5 pmol/min AVP in artificial CSF did not alter CSF formation rate but significantly reduced CSF absorption rate (24% decrease; p less than 0.01), when compared with perfusion using artificial CSF alone. This AVP-mediated reduction in CSF absorption rate may represent increased resistance to resorption of CSF or may reflect the effect of raised intracranial pressure.

Analysis of Variance↗
PubMed1991

Neuropeptide Y and tyrosine hydroxylase mRNA levels in the locus coeruleus show similar increases after reserpine treatment.

In situ hybridisation histochemistry was used to study the effect of intra-peritoneal reserpine administration on messenger RNA (mRNA) levels in the locus coeruleus (LC) of the rat. 48h after injection, levels of mRNA encoding tyrosine hydroxylase (TH) and neuropeptide Y (NPY) in the LC increased to approximately 250% of control values (p less than 0.05). The level of beta-tubulin mRNA was unaffected by reserpine administration. The similar and selective increase in TH and NPY mRNA in the LC following reserpine administration suggests that NPY may play a role in the neurotransmitter function of this catecholaminergic nucleus.

Animals↗
PubMed1991

Substance P and substance K in the rat hypothalamus following monosodium glutamate lesions of the arcuate nucleus.

Adult rats treated neonatally with monosodium glutamate (MSG) exhibit lesions in the arcuate nucleus of the hypothalamus. Following MSG lesioning, dopamine content in median eminence/arcuate nucleus (ME/AN) tissue extracts declined by 60-70%. Substance P (SP) content as determined by radioimmunoassay was significantly decreased in the paraventricular nucleus (PVN) (531 +/- 30 pg, mean +/- SEM) compared to controls (871 +/- 110 pg) but was unchanged in ME/AN extracts. Substance K (SK) content decreased to 257 +/- 20 pg in the PVN of lesioned animals compared to controls (367 +/- 31 pg) and the ME/AN content of SK was also significantly decreased (236 +/- 36 pg compared to control levels of 619 +/- 65 pg). The CRF-41 content of the PVN and ME/AN was unchanged by MSG lesioning, indicating that these areas are not affected by MSG. The partial depletion of SP and SK in the PVN following MSG treatment provides evidence that at least some of the neurokinin content of the PVN may originate in cell bodies of the arcuate nucleus. However, the lack of response of ME/AN SP to MSG treatment may suggest that the arcuate nucleus is not the major source of SP in the median eminence.

Animals↗
PubMed1991

Rapid changes in the content of proenkephalin A and corticotrophin releasing hormone mRNAs in the paraventricular nucleus during morphine withdrawal in urethane-anaesthetized rats.

Quantitative in situ hybridization was used to measure corticotrophin-releasing hormone (CRH) and proenkephalin A mRNA in the medial parvocellular paraventricular nucleus (PVN) 4 h after test procedures. Urethane anaesthesia alone resulted in a significant increase in both CRH and proenkephalin transcripts. The additional stimulus of i.p. hypertonic saline, however, resulted in a further significant increase in both mRNA species. Female rats were given intracerebroventricular (i.c.v.) infusion for 5 days of either morphine sulphate to induce tolerance and dependence, or vehicle, via a subcutaneous osmotic minipump implanted under ether anaesthesia. The rats were then anaesthetized with urethane, fitted with an intravenous cannula for injections and 65 min later either naloxone (5 mg/kg) or vehicle was injected. Naloxone alone in the i.c.v. vehicle rats had no effect on CRH or proenkephalin A mRNA. In i.c.v. morphine-infused rats proenkephalin a mRNA in the PVN was significantly less than in controls. Naloxone given to i.c.v. morphine-infused rats resulted in a doubling of hybridization to proenkephalin mRNA in the PVN which was significantly greater than that seen in the i.c.v. vehicle group. CRH mRNA in the PVN was not altered either by naloxone in control rats, or by chronic i.c.v. morphine infusion. By contrast, naloxone did increase CRH mRNA by ca. 40% in morphine-infused rats. The results show that stress-induced increases in CRH and enkephalin mRNAs in the PVN do not require conscious appreciation of the stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, General↗
PubMed1991

Neuroendocrine and behavioural responses to hyperosmolality in rats with lesions of the lateral hypothalamus made by N-methyl-D-aspartate.

Excitotoxic lesions of rat lateral hypothalamus produce impairments in eating and drinking, but not motor deficits. However, it has not been established what causes these eating and drinking impairments. In the present experiments, drinking, plasma osmolality and arginine-vasopressin concentration were measured in lateral hypothalamic-lesioned and control rats following systemic injection of hypertonic saline. In response to hyperosmolality, N-methyl-D-aspartate-lesioned rats drank significantly less than controls but showed normal increases in plasma osmolality and arginine-vasopressin concentration. This dissociation of neuroendocrine and behavioural responses suggests that the impairment of rats with excitotoxic lesions of the lateral hypothalamus is unrelated to physiological (as opposed to behavioural) mechanisms of homeostasis.

Animals↗
PubMed1991

Characteristics and kinetics of proopiomelanocortin mRNA expression by human leucocytes.

Northern blot analysis of total and poly(A)+ RNA demonstrated that human leucocytes contain several proopiomelanocortin (POMC) mRNA species, including 0.8-, 1.2-, 1.5-, and 9.5-kb transcripts. Peripheral blood lymphocytes (PBL) were found to express all four species. The other cell types had either the 0.8-kb species alone or both 0.8- and 9.5-kb species. Neutrophils were the only cells to express the 9.5-kb transcript alone. In T cell clones, both interleukin (IL)-2 alone or the antigen for which the clone was specific induced POMC accumulation within 18-24 h. Cytoplasmic dot blot analysis of PBL RNA demonstrated that POMC expression could be induced by corticotrophin releasing factor, rIL-1, and phorbol ester, but not by calcium ionophore (A23187). In PBL activated in a mixed lymphocyte culture there was increased expression, particularly of the smaller species (0.8, 1.2, and 1.5 kb), within 1-3 days of activation. The intensity of the bands began to decline thereafter. The 9.5-kb POMC transcript essentially disappeared by Day 3.

Blotting, Northern↗
PubMed1991

Effect of a long-acting somatostatin analogue (BIM23014) on proliferative diabetic retinopathy: a pilot study.

A pilot study on the use of a continuous infusion of somatostatin, by subcutaneous pumps in the management of proliferative diabetic retinopathy is reported. Two patients out of eight with proliferative retinopathy demonstrated improvement. One patient demonstrated regression of disc new vessels and the other a reduced area of retinal capillary non-perfusion, both demonstrated by fluorescein angiography. Control patients showed worsening of fluorescein leakage over the observation period of four to six weeks whereas the other six patients given the somatostatin infusion did not demonstrate any deterioration. The mechanism of action of somatostatin in this study is unknown but it is thought to have direct anti-angiogenic properties as well as inhibiting growth hormone secretion.

Adult↗
PubMed1991

Plasma atrial natriuretic peptide concentration and platelet atrial natriuretic peptide binding site density in ageing and hypertension.

1. Ageing and hypertension are associated with changes in the way in which the body handles sodium. This may involve changes in plasma atrial natriuretic peptide concentration, since atrial natriuretic peptide is a regulator of sodium handling by the kidney and the plasma atrial natriuretic peptide concentration is increased in both ageing and hypertension. An increase in the plasma atrial natriuretic peptide concentration could also be associated with a change in atrial natriuretic peptide receptor density, possibly involving down-regulation. 2. To investigate these possibilities plasma atrial natriuretic peptide concentration and platelet atrial natriuretic peptide binding site density were measured in 18 young, 11 middle-aged and 12 elderly healthy subjects and in 23 patients with mild to moderate essential hypertension. 3. In normotensive subjects, the plasma atrial natriuretic peptide concentration increased with age (r = 0.49, P less than 0.01) and was significantly higher in elderly than young subjects (mean +/- SEM, 31.9 +/- 4.5 versus 18.3 +/- 2.0 pmol/l, P less than 0.05). The plasma atrial natriuretic peptide concentration increased with the mean arterial pressure in normotensive subjects (r = 0.47, P less than 0.01). Multiple regression analysis did not show independent relationships between the plasma atrial natriuretic peptide concentration and either age or mean arterial pressure in normotensive subjects alone. However, when normotensive subjects and hypertensive patients were considered together, multiple regression revealed both age and mean arterial pressure as independent predictors of the plasma atrial natriuretic peptide concentration (P less than 0.05, P less than 0.01, respectively). In normotensive subjects, the platelet atrial natriuretic peptide binding site density did not change with age (r = 0.19, P = 0.27).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Permeability of blood-brain and blood-nerve barriers in experimental diabetes mellitus in the anaesthetized rat.

Diabetes was induced with streptozotocin in rats weighing about 160 g. These were maintained with age-matched controls for up to 14 months, blood glucose being periodically monitored. Half the diabetic and control rats received the aldose reductase inhibitor, Ponalrestat, in their diet. At 3 weeks, 6-7 months and 13-14 months, the vascular permeability in regions of brain, and in optic and sciatic nerves, were measured by maintaining radiotracers in the bloodstream--125I-albumin (100 min), [14C]sucrose (60 min) and 131I-albumin (5 min)--followed by tissue sampling and counting at termination. 131I-albumin estimated residual intravascular plasma. Diabetes of up to 13-14 weeks caused no measurable increase in the sucrose permeability of microvessels in eight different brain regions, in optic or in sciatic nerve. At 3 weeks of diabetes, sucrose permeability in all brain regions and in optic nerve was reduced relative to that in controls. Extravascular albumin entry into different regions of brain and optic nerve was insignificant and insensitive to diabetes, except in the hypothalamus and optic nerves where it was raised with increasing duration of diabetes. In sciatic nerve, extravascular albumin distribution was markedly increased by diabetes, but sucrose permeability was not demonstrably affected. At the level used in the diet, Ponalrestat reduced the sorbitol content of diabetic sciatic nerve but did not protect again the increased permeability to albumin.

Aldehyde Reductase↗
PubMed1991

Albumin escape from microvessels in kidney, heart and skeletal muscle in experimental diabetes mellitus in the anaesthetized rat.

Diabetes was induced with streptozotocin in rats weighing about 160 g. These were maintained with age-matched controls for up to 14 months, blood glucose being periodically monitored. Half the diabetic and control rats received the aldose reductase inhibitor, Ponalrestat, in their diet. Distribution of volumes of 131I-albumin (5 min) and 125I-albumin (100 min) were estimated in various tissues at 3 weeks, 6-7 months and 13-14 months of diabetes. The former space was assumed to represent the intravascular plasma space, while the latter was taken to include both the extravascular and intravascular albumin volumes in the kidney. In heart and skeletal muscle, equilibration between the specific activities of extravascular albumin and of plasma albumin was not assumed to be complete at 100 min. In the cortex and medulla of kidney, the extravascular albumin pool increased significantly at 13-14 months of diabetes (for both, P less than 0.01). Significantly increased entry of albumin into the interstitium occurred at 6 months (P less than 0.05) and at 13-14 months (P less than 0.01) in skeletal muscle, and at 13-14 months (P less than 0.05) in heart. The intravascular plasma volumes were not influenced by diabetes and the aldose reductase inhibitor had no effect at any time in either diabetic or control rats. These findings indicate increased movement of plasma albumin into the interstitium in the late phase of diabetes in the heart, skeletal muscle and in the kidney. Enlargement of the interstitial albumin pool is likely to affect the fluid balance between capillary and interstitium and may contribute to the effect of diabetes on the function of these organs.

Albumins↗
PubMed1991

Use of orbital floor steroids in the management of patients with uniocular non-necrotising scleritis.

Most cases of non-necrotising scleritis can be successfully treated with non-steroidal anti-inflammatory drugs. If these are ineffective, then high-dose systemic corticosteroids, with all their attendant side-effects, are usually required. We have used orbital floor injections of depot steroid in the management of nine patients with non-necrotising scleritis in an attempt to avoid the use of systemic steroids, or to allow the dose of steroids to be reduced while maintaining disease control. A temporary reduction in inflammation was achieved in all cases, which allowed the use of systemic steroids to be avoided altogether in two patients and delayed in the others. Non-steroidal anti-inflammatory drugs and systemic corticosteroids remain the mainstay of treatment for non-necrotising scleritis, but orbital floor injections may be a useful adjunct in certain cases.

Adult↗
PubMed1991

Use of cyclosporin in the management of steroid dependent non-necrotising scleritis.

Many patients with non-necrotising scleritis can be treated adequately with non-steroidal anti-inflammatory drugs or steroids. But, as many of them are young, treatment may present problems if they require high doses of steroids to control the scleral inflammation and then relapse when the dosage is reduced. Five such patients were treated with a combination of steroids and low-dose cyclosporin therapy, and in all cases the scleritis remained under control on a much lower dose of steroids than when steroids were used alone. Cyclosporin is therefore a useful drug in the management of younger patients dependent on high-dose steroids to control their scleral inflammation.

Adult↗
PubMed1991

'Low sodium' diuresis and ileal loss in patients with ileostomies: effect of desmopressin.

Patients with ileostomies show an early diuresis when sodium restricted; this, together with an obligatory ileal sodium loss, predisposes them to severe salt and water depletion. The role of arginine vasopressin in this circumstance and whether it is natriuretic, or antinatriuretic, is unclear. There is also controversy over its likely effect on small bowel fluid reabsorption. We have examined the effect of the non-pressor (V2) synthetic vasopressin analogue 1-deamino-8-D-arginine (desmopressin) on renal and ileal sodium and water excretion in ileostomy patients during acute adaptation to a low sodium diet. Patients were studied on two separate occasions (nonrandomised) with and without the administration of desmopressin (0.75 micrograms intramuscular, three times a day). In eight subjects without desmopressin there was pronounced diuresis on the first low sodium day, associated with a fall in renal sodium excretion and no change in ileal output or composition. In five (of the original) subjects with desmopressin there was pronounced antidiuresis, no change in renal sodium excretion, and no change in ileal output or composition. In both studies rises in plasma renin activity and salivary aldosterone concentration lagged behind the early decline in renal sodium excretion. We have confirmed the phenomenon of 'low sodium' diuresis after sodium restriction in ileostomy patients and shown that it can be prevented by desmopressin. Desmopressin has no direct or indirect effect on renal sodium excretion or ileal fluid and electrolyte loss in humans.

Aged↗
PubMed1991

Dopamine modulation of prolactin and vasopressin but not behavior on satiation of sheep.

We have investigated the rapid changes in plasma prolactin and arginine vasopressin (AVP) associated with water satiation in ruminants. Sheep deprived of water for 72 h were allowed voluntary access to ad libitum water. Each sheep drank approximately 5 liters in a single draft. This was performed in a head-down position, which was maintained for approximately 2-3 min and ceased rapidly with an abrupt movement to the upright position. During dehydration, plasma sodium, osmolality, and AVP all increased significantly, but prolactin was unaffected. On rehydration, AVP fell to basal levels within 5 min, but prolactin increased as a short pulse, after which it rapidly fell again. Plasma sodium and osmolality returned to predehydration levels within 6 h of satiation. A possible role of dopaminergic mechanisms in these responses was investigated by the administration of the dopamine agonist bromocriptine or the antagonist metoclopramide. Neither of these agents had any observable effects on the drinking behavior of the sheep during water satiation. During metoclopramide treatment, dehydration was associated with a marked fall in prolactin, and on rehydration there was a prompt and very marked increase in prolactin level. There was also an exaggerated increase of AVP during dehydration and a decrease on rehydration. Bromocriptine had relatively little effect on prolactin responses but prevented the drinking-associated inhibition of AVP, demonstrating an unexpected dissociation between AVP secretion and the stereotyped drinking response.

Animals↗
PubMed1991

Altered adrenocorticotropin, corticosterone and oxytocin responses to stress during chronic salt load.

We have investigated the effects of stress on the plasma levels of adrenocorticotropin (ACTH), corticosterone and oxytocin (OT) in rats given 2% saline to drink for 12 days. Plasma ACTH levels were markedly decreased from 972 +/- 165 pg/ml in the control animals on water to 349 +/- 114 pg/ml in animals given 2% saline to drink. Stress-induced release of ACTH observed in animals on water (controls = 972 +/- 165 pg/ml and stressed animals = 1,439 +/- 105 pg/ml) was completely abolished following 2% saline treatment for 12 days (controls = 349 +/- 114 pg/ml and stressed animals = 205 +/- 27 pg/ml). After 2% saline, plasma corticosterone levels were unaltered in control and stressed animals as compared to control animals on water in which stress increased plasma corticosterone from 28.8 +/- 7.9 to 99.5 +/- 8 ng/ml. In contrast to ACTH, the OT response to stress was intact in animals on 2% saline despite raised plasma OT in the control group due to the osmotic stimulus. Removal of the source of circulating glucocorticoids by adrenalectomy partially restored both basal levels of ACTH and the response to stress in animals on 2% saline. Our results demonstrate that 2% saline treatment activates an inhibitory mechanism over the release of ACTH.

Adrenalectomy↗