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Biomedical subjects

M L Forsling

Publications and source records attributed to M L Forsling.

At least 19 recordsLinked to original sources

Randomized trial of two levels of fluid input in the perinatal period--effect on fluid balance, electrolyte and metabolic disturbances in ventilated VLBW infants.

The aim of this study was to determine whether fluid restriction does indeed significantly increase acute adverse effects. One-hundred-and-sixty-eight ventilated infants, median gestational age 27 wk (range 23-33) and birthweight 953 g (range 486-1500), entered into a randomized controlled trial of two fluid regimes. Infants on regime A were to be prescribed 60 ml/kg of fluids on day 1 which was gradually increased over the first week to 150 ml/kg, infants on fluid regime B were to be prescribed approximately 20% less fluid over the first week. Daily fluid input and output were recorded. Serum electrolytes, bilirubin, creatinine and urine osmolalities were measured daily. Arginine vasopressin levels were assessed on days 1, 3 and 5. Episodes of jaundice, hypoglycaemia and hypotension requiring treatment were noted. Infants on regime B actually received overall 11% and, in the first 4 days, 19% less fluid than those on regime A (p < 0.001). There were no statistically significant differences in the occurrence of episodes of jaundice, hypotension, hypoglycaemia, hypernatraemia or hyponatraemia between infants on the two regimes. Although the infants on regime B had significantly higher urine osmolalities and lower urine output for most of the perinatal period, their median creatinine and arginine vasopressin levels did not differ significantly from those on regime A. We conclude that fluid restriction to less than 90% of usual maintenance fluids is not associated with an excess of acute adverse effects.

Dehydration↗

Sex and oestrous cycle differences in visceromotor responses and vasopressin release in response to colonic distension in male and female rats anaesthetized with halothane.

Visceromotor responses and vasopressin release before and after colonic visceral distension were compared between male (n=5 (n=4 for vasopressin)) and female rats and between females during the oestrous cycle (proestrus n=6, oestrus n=5, metestrus n=5, diestrus n=6) at a controlled depth of anaesthesia. Pre-stimulation vasopressin and blood pressures demonstrated oestrous cycle variability. The mean (SEM) colonic balloon pressure triggering visceromotor responses was significantly higher in males (64 (4) mm Hg) than females (41 (1) mm Hg), P=0.002 and within females, proestrus rats had the lowest thresholds, (29 (1) mm Hg, P<0.01). Post-stimulation, vasopressin concentrations increased significantly in all groups (males 1.34 (0.39) to 2.24 (0.74) pmol litre(-1); females 1.54 (0.24) to 2.88 (0.58) pmol litre(-1); P=0.002). Within groups statistically significant differences were measured in proestrus 2.06 (0.56) to 3.42 (1.12) and oestrus 1.16 (0.38) to 2.76 (0.60) pmol litre(-1) (P<0.05). High vasopressin concentrations coupled with low-pressure stimulation during proestrus shows sex-hormone dependent integration of the neuroendocrine response to noxious visceral stimulation.

Analysis of Variance↗

Diurnal rhythms in neurohypophysial function.

The neurohypophysial hormones oxytocin and vasopressin show daily rhythms of secretion with elevated hormone release during the hours of sleep. This pattern can be modulated by ovarian steroids and alters with age. The pattern appears to be due in part to the nocturnal increase in melatonin secretion, which stimulates hormone release in man, while being inhibitory in the rat. Pinealectomy alters both the 24 h pattern of neurohypophysial hormone release in the rat and the firing rate of magnocellular supraoptic nucleus neurones. There is also a reduced hormone release in response to hypovolaemia and raised plasma sodium concentration compared to sham operated animals, with a smaller increase in neuronal activity, as determined by immediate-early gene expression. The normal responses can be restored by nocturnal administration of melatonin. Melatonin also influences the neurohypophysial hormone response in the human to known stimuli of release, such as raised plasma osmolality, exercise and insulin-induced hypoglycaemia. Recent studies have revealed that not only does the release of vasopressin and oxytocin vary over each 24 h, but the respective renal and pregnant uterine responses also show diurnal variations.

Animals↗

A comparison of arginine vasopressin levels and fluid balance in the perinatal period in infants who did and did not develop chronic oxygen dependency.

Arginine vasopressin (AVP) levels on days 1, 3 and 5 and fluid balance in the perinatal period were assessed in 60 infants, median gestational age 27 weeks (range 24-33). Fluid input and output, urine osmolality and episodes of hyponatraemia were recorded on a daily basis. Forty-one infants subsequently developed chronic lung disease (CLD), they were more immature, of lower birthweight and had higher AVP levels on days 3 and 5 (p < 0.05) than the rest of the cohort. Despite similar levels of fluid input, compared to the non-CLD infants, those who developed CLD had higher urine osmolalities on days 1, 5, 6 and 7 (p < 0.05), but there were not significant differences between the two groups regarding urine output or episodes of hyponatraemia. Logistic regression analysis revealed AVP levels on day 3 were significantly correlated with the duration of oxygen dependency independent of other factors. We conclude elevated AVP levels in the perinatal period are associated with CLD development, but our results suggest they have little functional significance.

Arginine Vasopressin↗

Contribution of endogenous oxytocin to sodium excretion in anaesthetized, surgically operated rats.

In order to determine the possible role of endogenous oxytocin in controlling electrolyte and water excretion in animals whose renal function is being assessed by invasive techniques, rats were anaesthetized and subjected to micropuncture surgery. Clearance measurements were made in the presence and absence of the potent oxytocin receptor antagonist d(CH(2))(5)[Tyr(Me)(2), Thr(4), Orn(8), Tyr(NH(2))(9)]-vasotocin. In rats infused with vehicle alone, glomerular filtration rate (GFR), sodium excretion and urine flow rate remained stable. In contrast, in antagonist-treated rats GFR was modestly reduced (P<0.05), and there were large falls in both absolute and fractional sodium excretion (P<0.01 in each case) and absolute and fractional water excretion (P<0.05 in each case), indicating effects on both filtered load and fractional tubular reabsorption. The antinatriuresis was not accompanied by a change in the fractional excretion of lithium, suggesting that proximal tubular function is unaffected by oxytocin receptor antagonism; nor was it accompanied by a change in the fractional excretion of potassium, suggesting that the tubular effect is located beyond the potassium secretory site, i.e. downstream of the cortical collecting tubule. We conclude that circulating plasma concentrations of oxytocin during anaesthesia and moderate surgery are sufficient to enhance GFR and reduce fractional tubular sodium and water reabsorption. This has important implications for the interpretation of invasive studies such as micropuncture.

Animals↗

The effect of opioid antagonism and environmental restriction on plasma oxytocin and vasopressin concentrations in parturient gilts.

Oxytocin plays an important role at parturition due to its involvement in uterine contractions, foetal expulsion and the onset of maternal behaviour. The role of the related neurohypophysial hormone, vasopressin, is less clear; however, there is some evidence that it is also involved in maternal behaviour and its role in osmotic regulation is well established. The aim of this study was to investigate the inhibitory effects of endogenous opioids on these hormones during the expulsive phase of parturition in the pig, and to examine how opioid restraint interacts with environmental restriction. The subjects of this study were 31 Large Whitex Landrace primiparous sows (gilts). An indwelling jugular catheter was implanted under general anaesthesia at 12 days before the expected parturition day (EPD). From 5 days before the EPD 15 of the gilts were individually housed in a restrictive parturition crate without straw and 16 were individually housed in a straw-bedded pen. Blood samples were taken with increasing frequency towards and during parturition through a catheter extension to reduce disturbance. At 7.5 min after the birth of the first piglet half of the gilts in each environment received a dose of the opioid receptor antagonist naloxone (1 mg/kg, i.v.) with the remaining gilts receiving saline as a control. Overall, there was no effect of environment on either circulating oxytocin or vasopressin. However, both oxytocin and vasopressin were inhibited by endogenous opioids during the expulsive phase. The inhibitory effects of opioids on these hormones did not appear to have any adverse effects on the progress of parturition as judged by cumulative piglet birth intervals. The regulation of the opioid inhibition of oxytocin and vasopressin during parturition is discussed in relation to other neurotransmitters and whether opioid inhibition of these neurohypophysial hormones is part of the 'normal' physiological response to parturition or whether it is stress-induced.

Analysis of Variance↗

Effect of reproductive status on plasma oxytocin concentrations and the renal response to oxytocin in the conscious rat.

The magnitude of diuresis and natriuretis produced by oxytocin in the female rat has been shown to be dependent on the stage of the oestrous cycle. A study has been performed to determine the role of ovarian steroids in modulating the renal response to oxytocin infused at a rate of 100 fmol min-1 in hypotonic saline. Observations were performed on ovariectomised rats with and without steroid treatment and rats with suppressed oestrous cycles following treatment with the long-acting gonadotrophin-releasing hormone analogue Zoladex, given as a 100 mg S.C. depot, or the antioestrogen tamoxifen, given as three daily injections of 1 mg. Steroid treatment comprised a single dose of 10 microgram oestradiol benzoate or 2.0 mg progesterone, or a combination of the two hormones given 30 h apart. Ovariectomy had no significant effect on plasma oxytocin concentrations, although progesterone treatment produced an increase. The natriuresis in ovariectomised animals of 27% was smaller (P < 0.05) than that seen on the day of pro-oestrus and closer to that seen in the intact rat at oestrus. The responses in animals with suppressed oestrous cycles following treatment with tamoxifen were not significantly different from those observed following ovariectomy, neither was the diuresis following Zoladex. The renal responses were greater following treatment with oestradiol than in the ovariectomised group. Thus ovarian steroids do influence the renal responsiveness to oxytocin with oestradiol augmenting the response.

Animals↗

Gonadotrophin-releasing hormone and oxytocin secretion from the hypothalamus in vitro during pro-oestrus: the effects of time of day and melatonin.

An accurately timed surge of luteinizing hormone (LH), during the second half of the day of pro-oestrus in rats, is a crucial part of the endocrine signal that leads to expulsion of an ovum from an ovarian follicle. LH release is partly controlled by a number of peptides, including gonadotrophin-releasing hormone (GnRH) and oxytocin, which travel from the hypothalamus to the pituitary. The profile of secretion of these peptides is poorly understood. Therefore, the amounts of GnRH and oxytocin that were secreted from hypothalamic explants were determined at several time points during the day of pro-oestrus. Basal secretion of oxytocin from hypothalami taken later in pro-oestrus was greater than from hypothalami taken earlier in the day (p < 0.02). On the other hand, basal secretion of GnRH decreased during the day of pro-oestrus (p < 0.03). The different trends of GnRH and oxytocin secretion reveal that their secretion is regulated by distinct mechanisms. GnRH secretion was higher at midpro-oestrus than late in the day (o < 0.05) consistent with a peak of GnRH having been observed by others in portal blood in the second half of the day of pro-oestrus. Responsiveness of oxytocin to stimulation by K+ of the hypothalami declined from the early light hours to the evening dark hours (p < 0.02). Thus, oxytocin modulation might be achieved partly by modification of intracellular processes. Melatonin, secreted during hours of darkness, is frequently involved in modulating time-dependent events in mammals, but its contribution to peptide regulation during the ovulatory cycle is unclear. Melatonin was observed to inhibit basal oxytocin secretion from hypothalami collected during light hours (p < 0.05). The investigation has, therefore, revealed the potential for melatonin to modulate peptide secretion from the hypothalamus during the day of pro-oestrus. We also observed that secretion from the hypothalamus of the two LH-regulating peptides, GnRH and oxytocin, are differently regulated during the day of pro-oestrus.

Animals↗

The effect of melatonin administration on pituitary hormone secretion in man.

OBJECTIVE: Evidence is accumulating that the nocturnal increase in melatonin may influence pituitary hormone secretion. The aim of this study was to determine the effect of exogenous melatonin, in concencetrations spanning the physiological range, on the release of pituitary hormones in man during daylight hours. DESIGN: A double blind, randomized, crossover study. SUBJECTS: Eight healthy male volunteers with a mean age of 21 +/- 0.5 years were studied on four occasions, observations being made after the adminstration of melatonin in doses of 0.05, 0.5 or 5.0 mg or placebo. They refrained from taking heavy exercise, alcohol and from smoking for 24 h prior to the study. MEASUREMENTS: Serum cortisol, growth hormone, prolactin and plasma oxytocin, vasopressin, sodium, osmolality and packed cell volume were measured in samples taken at 30 minutes intervals for 150 minutes after the administration of melatonin. RESULTS: Melatonin produced dose-dependent changes in circulating concentrations of oxytocin and vasopressin, the 0.5 mg dose being stimulatory, while 5.0 mg was inhibitory. These two doses stimulated growth hormone release, while there was no significant effect on prolactin or cortisol release. CONCLUSIONS: These results confirm that the nocturnal increase in melatonin could contribute to the patterns of oxytocin, vasopressin and growth hormone release seen over 24 h.

Adult↗

The effect of growth hormone secretagogues and neuropeptide Y on hypothalamic hormone release from acute rat hypothalamic explants.

Growth hormone (GH) secretagogues (GH-releasing peptides and their non-peptide analogues) stimulate growth hormone release via specific G-protein coupled receptors both directly from the pituitary gland and through stimulation of the hypothalamus. The exact mechanism of action in the hypothalamus is not known. The presence of endogenous GH releasing hormone (GHRH) seems to be necessary for the in-vivo actions of growth hormone secretagogues (GHSs), but data suggest that further factors must be involved as well. The effect of GHSs is not entirely specific for the GH axis; they release prolactin and stimulate the hypothalamo-pituitary-adrenal axis causing elevations in circulating ACTH and cortisol levels in both animal and human studies. Recently, it has also been suggested that GHSs stimulate hypothalamic neuropeptide Y (NPY) neurones. In the present study, we have therefore investigated the direct effect of several GHSs (GHRP-6, hexarelin and the non-peptide analogues L-692, 429 and L-692, 585) on GHRH, somatostatin (SS), corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) release in vitro in an acute rat hypothalamic incubation system. We also assessed the effect of NPY on GHRH, SS and AVP release. Freshly removed hypothalami were incubated in control media for 20 min and then in 1-4 consecutive 20-min periods in each of the test substances at different concentrations. There was no significant change in either the basal or potassium-stimulated release of GHRH or SS at low concentrations of any of the secretagogues; however, at millimolar doses a paradoxical inhibition of GHRH was observed with GHRP-6, hexarelin and L-692 585 (data are expressed as the ratio of treated to preceding basal release; at 20 min control group: 0.97+/-0.02, GHRP-6: 0.55+/-0.04, P<0.001 compared to control group; hexarelin: 0. 56+/-0.06, P<0.001, L-692,585: 0.70+/-0.03, P<0.001), while SS was stimulated after 60 or 80 min (at 80 min control: 0.80+/-0.03, hexarelin: 1.23+/-0.07, P<0.05 and L-692,585: 1.37+/-0.11, P<0.05). GHSs stimulated hypothalamic AVP release (at 20 min control: 0. 99+/-0.06 ratio to basal release, 10-4 M concentration of GHRP-6: 6. 31+/-1, P<0.001, hexarelin: 1.88+/-0.4, P<0.01, L-692,429: 1.90+/-0. 5, P<0.05 and L-692,585: 2.34+/-0.96, P<0.01), while no stimulatory effect was found on CRH release. NPY significantly stimulated SS and inhibited basal and potassium-stimulated GHRH release, while potentiating potassium-evoked AVP secretion. The Y1 receptor antagonist BIBP 3226 did not inhibit the effects of NPY on SS, GHRH or AVP release. We therefore conclude that, in this in-vitro rat hypothalamic incubation model, growth hormone secretagogues stimulate the release of AVP but have no effect on either GHRH, SS or CRH at low doses; at high doses paradoxically they inhibit the hypothalamic GH axis similar to in-vivo data in the rat. We speculate that these effects might be mediated by NPY.

Animals↗

Stress-induced suppression of pulsatile Luteinising hormone release in the female rat: role of vasopressin.

Insulin-induced hypoglycaemic (IIH) stress evokes the release of arginine vasopressin (AVP) and suppresses luteinising hormone (LH) pulses in a number of species, a phenomenon augmented by the presence of oestradiol (E2). The aim of this study was to test the hypothesis that AVP not only disrupts pulsatile LH secretion in the female rat, but specifically mediates the effect of IIH stress on suppressing LH release. The role of E2 in augmenting the disruptive effect of AVP on LH secretion was also addressed. Rats were ovariectomized (OVX) and fitted with intracerebroventricular (i.c.v. ) and intravenous (i.v.) cannulae. For experiments requiring comparisons of neuroendocrine responses in the presence and absence of E2, animals were implanted subcutaneously with E2 or oil-filled capsules respectively. AVP (5 microg) administered via the i.c.v. cannula suppressed LH secretion by decreasing LH pulse amplitude without affecting LH pulse frequency, an effect that was blocked by central administration of an AVP antagonist (25 microg). This inhibitory response was evident only in E2-replaced OVX rats, thus suggesting a sensitizing influence of the gonadal steroid. In the AVP-deficient Brattleboro rats, IIH stress did not interrupt pulsatile LH secretion as demonstrated in Long Evans and Wistar controls. While these data might suggest a pivotal role for AVP in stress-induced suppression of LH release, central administration of an AVP antagonist did not prevent the interruption of LH pulses in response to IIH stress. Furthermore, it would appear that AVP is not primarily involved in hypoglycaemic stress-induced suppression of pulsatile LH secretion since central administration of very high doses of AVP resulted in a suppression of LH pulse amplitude and not frequency, while hypoglycaemic stress caused an interruption of LH pulses.

Animals↗

The effect of combined oestrogen and progesterone replacement on the renal responses to oxytocin and vasopressin in ovariectomized rats.

OBJECTIVE: Renal responsiveness to the neurohypophyseal hormones, oxytocin and vasopressin, has been shown in the rat to vary during pregnancy and lactation. A study was performed to determine whether ovarian steroids could contribute to the observed changes. DESIGN: Using a previously validated method, fluid excretion during infusion of oxytocin or vasopressin was monitored in ovariectomized animals with and without chronic administration of oestrogen and progesterone. METHODS: After 14 days treatment with vehicle or 12.5 mg hydroxyprogesterone caproate and 0.25 mg oestradiol valerate injected every 3 days, rats were infused with 0.077 mol/l NaCl for an equilibration period of approximately 2.5h. Timed urine collections for the determination of volume and electrolytes were then made during a control period of at least 45 min and for 60 min while the infusate was supplemented with vasopressin (40 fmol/min) or oxytocin (50 fmol/min). Further observations were made for a final 90 min of hypotonic saline infusion. In control infusions saline alone was given. RESULTS: Treatment with ovarian steroids did not affect the volume of urine excreted during hormone infusion. Electrolyte excretion, however, was affected with lower concentrations of sodium and chloride on oxytocin infusion being seen in the steroid-treated animals. During vasopressin infusion, peak electrolyte concentrations were also achieved later in this group of animals. CONCLUSION: The increased circulating concentrations of oestrogen and progesterone seen during pregnancy could contribute to variations in the natriuretic response to neurohypophyseal hormones observed in the rat.

Animals↗

Effect of 5-hydroxytryptamine and pineal metabolites on the secretion of neurohypophysial hormones.

It has been shown that 5-hydroxytryptamine and melatonin, an indoleamine for which 5-hydroxytryptamine is a precursor, influence the release of vasopressin and oxytocin from the rat hypothalamus both in vivo and in vitro. The oral administration of melatonin has been shown to decrease oxytocin release and modulate the nocturnal vasopressin release in humans. 5-hydroxytryptamine and its metabolites, 5-hydroxytryptophol, 5-methoxytryptamine and 5-methoxytryptophol, are detected within the pineal, and there is evidence that 5-methoxytryptamine and 5-methoxytryptophol may have some physiological role. The aim of this study was to evaluate the effects of 5-hydroxytryptamine, 5-hydroxytryptophol, 5-methoxytryptamine and 5-methoxytryptophol on neurohypophysial hormone release from the rat hypothalamus in vitro. It was found that 5-hydroxytryptamine and 5-hydroxytryptophol increased neurohypophysial hormone release, 5-methoxytryptamine decreased the release of vasopressin and oxytocin and 5-methoxytryptophol was found to have no effect, thus providing further evidence for a role of indole compounds in the control of neurohypophysial hormone secretion.

5-Methoxytryptamine↗

Endotoxin stimulates an endogenous pathway regulating corticotropin-releasing hormone and vasopressin release involving the generation of nitric oxide and carbon monoxide.

Although the administration of endotoxin in vivo activates the neuroendocrine stress axis in the process of crosstalk between the immune and endocrine axes, the direct application of endotoxin to the hypothalamus in vitro does not stimulate the release of the hypothalamic peptides controlling the hypothalamo-pituitary-adrenal (HPA) axis, corticotropin-releasing hormone (CRH) and vasopressin. The hypothesis has therefore been tested that endotoxin may also activate inhibitory pathways, specifically those involving the generation of nitric oxide (NO) and carbon monoxide (CO). Studies were performed on the isolated rat hypothalamus using endotoxin in the presence or absence of inhibitors of heme oxygenase (which generates CO) and nitric oxide synthase, and ferrous hemoglobin. Endotoxin alone decreased both CRH and vasopressin secretion from the hypothalamus. However, when applied together with a nitric oxide synthase inhibitor, the inhibitory effect on CRH was lost. Conversely, co-administration with heme oxygenase inhibitors transformed the inhibition of vasopressin to stimulation, while having no effect on the inhibition of CRH. Ferrous hemoglobin reversed the inhibition of vasopressin, but did not lead to stimulation. It is therefore concluded that endotoxin may stimulate endogenous pathways that lead to the generation of NO, which in turn inhibits CRH. In addition, it generates CO, which modulates the release of vasopressin. These gases are thus potential counter-regulatory controls to the activation of the HPA.

Animals↗

Acute and subacute effects of endotoxin on hypothalamic gaseous neuromodulators.

Although two-way communication between the hypothalamus and the immune system in now well established, particularly for the hypothalamo-pituitary-adrenal axis, the role of the gaseous neurotransmitters nitric oxide (NO) and carbon monoxide (CO) is much less well understood in terms of hypothalamic function. These agents are an important part of the peripheral inflammatory response; and their synthetic enzymes, NO synthase (NOS) and heme oxygenase (HO), respectively, have been localized to the hypothalamic PVN and SON. The induced generation of both NO and CO leads to the suppression of CRH and vasopressin, the major stimulators of the HPA. Thus, the addition of hemin to hypothalamic explants is maximally active at 1 microM in attenuating the release of CRH and vasopressin, and this dose is also most effective in generating biliverdin and associated CO. CO generation is also able to stimulate cyclooxygenase to produce prostaglandin E2, an established intermediary in the cytokine-stimulated activation of the HPA. Finally, inducible NOS mRNA is specifically induced in the hypothalalmus in response to endotoxin, in parallel to interleukin-1. These data provide increasing evidence in favor of NO and CO as counterregulatory agents in the HPA response to immune activation.

Animals↗

Mechanisms of melatonin inhibition of neurohypophysial hormone release from the rat hypothalamus in vitro.

Although melatonin has been reported to influence neurohypophysial hormone release, no binding has been demonstrated in the neurohypophysial system, suggesting melatonin could affect afferent inputs. The effect of neurotransmitter receptor antagonists on the inhibitory effect of melatonin on neurohypophysial hormone release from the rat hypothalamus in vitro was therefore determined. The agents employed were atropine, a muscarinic cholinergic antagonist; mecamylamine, a nicotinic cholinergic antagonist; atenolol, a beta-adrenergic antagonist; phentolamine, a nonselective alpha-adrenergic antagonist; prazosin, a selective alpha-adrenergic antagonist; haloperidol, a dopaminergic antagonist; naloxone, an opioid antagonist; and ibuprofen, a cyclooxygenase inhibitor. Rat hypothalami were incubated in either medium alone or medium containing melatonin or melatonin and antagonist, and hormone release determined. Melatonin (43 nM) significantly inhibited (p < 0.05) vasopressin and oxytocin release. Inhibition was still observed in the presence of atenolol, phentolamine, and naloxone, suggesting that neither adrenergic nor opioid pathways contribute to the response. The inhibitory effect of melatonin on vasopressin and oxytocin release was abolished (p < 0.05) in the presence of atropine (10[-8] M), mecylamine (10[-6] and 10[-4] M), ibuprofen (10[-4] M) and haloperidol (10[-6] and 10[-5] M). The melatonin-induced inhibition of oxytocin release was also attenuated in the presence of prazosin (10[-8] and 10[-6] M). This study suggests that melatonin may influence neurohypophysial hormone release through modulation of afferent pathways mediated by acetylcholine, dopamine, and/or prostaglandin.

Animals↗