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G Fink

Publications and source records attributed to G Fink.

At least 145 records · Page 8Linked to original sources
PubMed1989

The effects of knife cuts in the sub-paraventricular zone of the female rat hypothalamus on oestrogen-induced diurnal surges of plasma prolactin and LH, and circadian wheel-running activity.

To investigate the role of suprachiasmatic efferent connections in the expression of diurnal hormone rhythms, the efferent pathway from the suprachiasmatic nucleus (the putative circadian generator in the rat) to the subparaventricular zone (the main terminal area of suprachiasmatic efferents) was disrupted using bilateral horizontal knife cuts in ovariectomized oestrogen-treated rats. The position of the knife cut was assessed by observing its effect on vasoactive intestinal polypeptide immunoreactivity (a marker for suprachiasmatic efferents into the sub-paraventricular zone). The size of both the diurnal plasma LH and prolactin surges was markedly and consistently reduced over the 3-week period following the lesion in animals with a total deafferentation of the subparaventricular zone, compared with sham-operated animals or lesioned animals with an intact subparaventricular zone. When lesioned animals were grouped according to the presence or absence of damage to the preoptic area, no significant differences were found in the sizes of the plasma hormone surges. When similar knife cuts were given to animals whose activity cycles were observed, no significant effects were noted in the ability of the animals to synchronize to a light/dark regime or to free-run in constant light conditions. These results suggest that the suprachiasmatic nucleus influences the diurnal surges of plasma LH and prolactin in oestrogen-treated ovariectomized rats, initially by an interaction with the subparaventricular zone and not by a direct influence on gonadotrophin-releasing hormone neurones or other more rostral structures.

Animals↗
PubMed1988

Pseudoketogenesis in the perfused rat heart.

Ketogenesis is usually measured in vivo by dilution of tracers of (3R)-hydroxybutyrate or acetoacetate. We show that, in perfused working rat hearts, the specific activities of (3R)-hydroxybutyrate and acetoacetate are diluted by isotopic exchanges in the absence of net ketogenesis. We call this process pseudoketogenesis. When hearts are perfused with buffer containing 2.3 mM of [4-3H]- plus [3-14C]acetoacetate, the specific activities of [4-3H] and [3-14C]acetoacetate decrease while C-1 of acetoacetate becomes progressively labeled with 14C. This is explained by the reversibility of reactions catalyzed by mitochondrial 3-oxoacid-CoA transferase and acetoacetyl-CoA thiolase. After activation of labeled acetoacetate, the specific activity of acetoacetyl-CoA is diluted by unlabeled acetoacetyl-CoA derived from endogenous fatty acids or glucose. Acetoacetyl-CoA thiolase partially exchanges 14C between C-1 and C-3 of acetoacetyl-CoA. Finally, 3-oxoacid-CoA transferase liberates weakly labeled acetoacetate which dilutes the specific activity of extracellular acetoacetate. An isotopic exchange in the reverse direction is observed when hearts are perfused with unlabeled acetoacetate plus [1-14C]-, [13-14C]-, or [15-14C]palmitate; here also, acetoacetate becomes labeled on C-1 and C-3. Computations of specific activities of (3R)-hydroxybutyrate, acetoacetate, and acetyl-CoA yield minimal rates of pseudoketogenesis ranging from 19 to 32% of the net uptake of (3R)-hydroxybutyrate plus acetoacetate by the heart.

3-Hydroxybutyric Acid↗
PubMed1988

Oestrogen and progesterone interactions in the control of gonadotrophin and prolactin secretion.

Oestrogen and progesterone have marked effects on the secretion of the gonadotrophins and prolactin. During most of the oestrous or menstrual cycle the secretion of gonadotrophin is maintained at a relatively low level by the negative feedback of oestrogen and progesterone on the hypothalamic-pituitary system. The spontaneous ovulatory surge of gonadotrophin is produced by a positive feedback cascade. The cascade is initiated by an increase in the plasma concentration of oestradiol-17 beta which triggers a surge of luteinizing hormone releasing hormone (LHRH) and an increase in pituitary responsiveness to LHRH. The facilitatory action of oestrogen on pituitary responsiveness is reinforced by progesterone and the priming effect of LHRH. How oestrogen and progesterone exert their effects is not clear but the facilitatory effects of oestrogen take about 24 h, and the stimulation of LHRH release is produced by an indirect effect of oestradiol on neurons which are possibly opioid, dopaminergic or noradrenergic and which modulate the activity of LHRH neurons. In the rat, a spontaneous prolactin surge occurs at the same time as the spontaneous ovulatory gonadotrophin surge. The prolactin surge also appears to involve a positive feedback between the brain-pituitary system and the ovary. However, the mechanism of the prolactin surge is poorly understood mainly because the neural control of prolactin release appears to be mediated by prolactin inhibiting as well as releasing factors, and the precise role of these factors has not been established. The control of prolactin release is further complicated by the fact that oestradiol stimulates prolactin synthesis and release by a direct action on the prolactotrophes. Prolactin and gonadotrophin surges also occur simultaneously in several experimental steroid models. A theoretical model is proposed which could explain how oestrogen and progesterone trigger the simultaneous surge of LH and prolactin.

Animals↗
PubMed1988

Gonadal steroids influence neurophysin II distribution in the forebrain of normal and mutant mice.

The distribution of arginine vasopressin-associated neurophysin (neurophysin II) immunoreactivity was investigated in normal and mutant house mice during development and after various gonadal steroid manipulations. During postnatal development of normal mice dense networks of neurophysin II immunoreactivity in the lateral septal nucleus and lateral habenular nucleus appeared earlier in male than in female mice, with an adult pattern of immunoreactivity being attained by 8 weeks and 12 weeks of age, respectively. The neurophysin II immunoreactivity in the male was denser than that in female mice. After gonadectomy of adult normal mice there was a gradual loss of neurophysin II immunoreactivity in the lateral septum and lateral habenula over a period of 15 weeks. In hypogonadal mice, a mutant in which gonadal development is arrested postnatally due to a deficiency in hypothalamic gonadotrophin releasing hormone, no immunoreactive neurophysin II could be detected in the lateral septum or lateral habenula. A pattern of neurophysin II immunoreactivity similar to that in normal control mice was observed in hypogonadal mice which had been implanted for 4 weeks with silicone elastomer capsules containing testosterone or oestradiol-17 beta, but not 5 alpha-dihydrotestosterone or progesterone. Stimulation of gonadal development and endogenous steroid production in hypogonadal mice by third ventricular grafts of preoptic area tissue from normal neonatal animals also produced a normal pattern of neurophysin II immunoreactivity in the lateral septum and lateral habenula. In the androgen-insensitive testicular feminized mouse immunoreactive neurophysin II was undetectable in the lateral septum and lateral habenula. Treatment of testicular feminized mice with oestradiol-17 beta, but not progesterone, produced a normal pattern of neurophysin II immunoreactivity. The main immunohistological findings were confirmed by radioimmunoassay of tissue extracts which showed that the concentration of arginine vasopressin in lateral septum was far greater in normal males than females and was undetectable in hypogonadal mice; no oxytocin could be detected in the septum of normal or hypogonadal mice. These results show that the expression of neurophysin II immunoreactivity in the lateral septum and lateral habenula of the mouse brain is dependent on the presence of aromatizeable androgens or oestrogens.

Aging↗
PubMed1988

The patterns of [14C]2-deoxyglucose uptake in female rat brain produced by electrical stimulation of hypothalamic and limbic brain areas.

The aim of this study was to investigate the pattern of [14C]2-deoxyglucose uptake in anaesthetized rat brain produced by electrical stimulation of brain areas implicated, by previous electrical stimulation studies, in the neural control of pituitary hormone and especially gonadotrophin secretion. Stimulation of the median eminence led to a significant increase in the relative metabolic activities of the arcuate, ventromedial hypothalamic, supraoptic and paraventricular nuclei and the preoptic area. Stimulation of the suprachiasmatic or paraventricular nuclei or the medial preoptic area, anterior hypothalamic area, the dorsal or ventral hippocampus or amygdala led to an increase in the relative metabolic activity of many brain regions known to have direct connections with these areas, but in addition produced increases in the relative metabolic activity of areas which have secondary connections. Hippocampal stimulation confirmed previous neuroanatomical findings of major intrinsic functional connections between different fields of the ipsilateral and contralateral hippocampus. Stimulation of the amygdala, unexpectedly, did not change the relative metabolic activity of the arcuate nucleus and medial preoptic area which have neuroanatomical connections with the amygdala. Similarly, stimulation of the medial preoptic area did not change significantly the relative metabolic activity of the mamillary body and dorsomedial thalamic area. The effect of preoptic area stimulation on the relative metabolic activity of several brain regions was changed by ovariectomy and by injection of oestradiol benzoate. Stimulation of the preoptic area and suprachiasmatic nuclei, but not the anterior hypothalamic area or other brain regions, increased significantly the plasma concentrations of luteinizing hormone. These results show that (i) electrical stimulation of brain areas concerned with the control of gonadotrophin and other pituitary hormone secretion changes the metabolic activity of nuclei and neural pathways extrinsic as well as intrinsic to the hypothalamic-pituitary system, (ii) the [14C]2-deoxyglucose method can detect changes in antidromic as well as orthodromic activity and in multi-synaptic pathways, (iii) neuroanatomical pathways are not always activated metabolically by electrical stimulation, and (iv) the preoptic-suprachiasmatic nucleus gonadotrophin control system is discrete and is little affected by increased metabolic activity of the hypothalamus produced by stimulation of the anterior hypothalamic area or other brain areas.

Animals↗
PubMed1988

The connections between the suprachiasmatic, ventrolateral geniculate and raphe nuclei studied by uptake of [14C]2-deoxyglucose.

The [14C]2-deoxyglucose method was used to investigate the role of the ventrolateral geniculate and raphe nuclei in the control of the metabolism of the suprachiasmatic nuclei in adult female Wistar rats anaesthetized with alphaxalone. Three to seven days before the [14C]2-deoxyglucose studies a stimulating electrode was implanted or a lesion was made in the ventrolateral geniculate nucleus, or the ascending projection from the raphe nuclei was severed. Stimulation of the ventrolateral geniculate nucleus (biphasic rectangular pulses, 30 s on and 30 s off, 50 Hz, 500 microA pulse amplitude and 1 ms pulse duration) led to a significant increase in the relative metabolic activity of the ipsilateral suprachiasmatic nucleus and a smaller increase in the relative metabolic activity of the contralateral suprachiasmatic nucleus. The stimulus also increased significantly the relative metabolic activities of mainly the ipsilateral hypothalamus, midbrain central gray and reticular formation, all of which are too remote from the ventrolateral geniculate nucleus to be affected by current spread. In animals in which the ventrolateral geniculate nucleus had been lesioned, the relative metabolic activity of the suprachiasmatic nuclei was not significantly different from normal. In animals in which the ascending projection from the raphe nuclei had been severed, there was a slight, though significant increase in the relative metabolic activity of the suprachiasmatic nucleus of one side. These results, together with the effects of stimulating the suprachiasmatic nuclei [R. C. Maxwell and G. Fink, Neuroscience 23, 241-263 (1987)], show that the connections between the ventrolateral geniculate, raphe nuclei and suprachiasmatic nuclei are "metabolically functional", but that the integrity of the ventrolateral geniculate nucleus is not essential for maintaining the relative metabolic activity of the suprachiasmatic nuclei. The raphe nuclei may reduce the relative metabolic activity of the suprachiasmatic nucleus.

Animals↗
PubMed1988

Bioavailability of beta-carotene in humans.

Normal healthy volunteers were studied after they ingested various beta-carotene doses. Daily administration of 15 or 45 mg beta-carotene resulted in significant increase in plasma beta-carotene levels. The extent of increase and the pattern of plasma beta-carotene levels showed substantial interindividual variation. Absorption of beta-carotene was affected by dietary fat concentration. Individuals placed on a high-fat diet showed significant increases in plasma beta-carotene as compared with those placed on a low-fat diet. Pharmacological doses of beta-carotene (45 and 90 mg) were used in intermittent schedules (5-6 d intervals) without altering the steady state of beta-carotene plasma levels. Yellowing of the skin occasionally occurred during daily dosing with 45 mg beta-carotene without evidence of toxicity. The observed individual variation in bioavailability of beta-carotene raises questions regarding clinical use of this micronutrient. It appears that determination of target plasma beta-carotene concentrations is essential for effective use of this compound in prevention or treatment.

Adult↗
PubMed1988

Effects of adrenalectomy and glucocorticoids on the peptides CRF-41, AVP and oxytocin in rat hypophysial portal blood.

1. The effects of adrenalectomy (3 weeks) and dexamethasone (3 h) treatment on the release of corticotrophin-releasing factor-41 (CRF-41), arginine vasopressin (AVP), oxytocin (OT), adrenocorticotrophin (ACTH) and corticosterone were studied in adult female Wistar rats. 2. The animals were anaesthetized with sodium pentobarbitone which, as assessed by the effects on the circadian rhythm of plasma ACTH and corticosterone, appeared to be a better anaesthetic than either urethane or alphaxalone for studies on the hypothalamic-pituitary-adrenal system. 3. Adrenalectomy increased the concentrations of ACTH in peripheral plasma and the output of CRF-41 and AVP into hypophysial portal plasma. 4. Dexamethasone administered to adrenalectomized rats significantly reduced the concentration of ACTH in peripheral plasma and the amount of AVP released into portal plasma. However, dexamethasone did not affect the output of CRF-41 into portal blood. 5. The output of OT into portal plasma was unaffected by either adrenalectomy or dexamethasone treatment. 6. Dexamethasone administered to adrenalectomized rats reduced significantly the ACTH response to CRF-41. 7. These results show that the feed-back action of glucocorticoids is mediated by two mechanisms. The increased release of ACTH which follows adrenolectomy [corrected] is produced predominantly by an increased release of both CRF-41 and AVP into hypophysial portal blood. The intermediate negative feed-back of glucocorticoids is produced by a reduction in the output of AVP but not CRF-41 into portal blood and, as well, by a significant reduction in the responsiveness of the anterior pituitary gland to CRF-41.

Adrenalectomy↗
PubMed1988

Preoptic-hypothalamic pathways controlling nocturnal prolactin surges, pseudopregnancy, and estrous cyclicity in the rat.

Frontal, dorsal, or sham deafferentations were placed at various locations within the hypothalamus in order to study the neural pathways involved in pseudopregnancy (PSP), estrous cyclicity, and prolactin (PRL) secretion in the rat. Dorsal or sham transections did not interfere with PSP or estrous cyclicity. Frontal cuts placed on day 3-4 of PSP between the posterior border of the optic chiasm and the anterior tip of the mediobasal hypothalamus (MBH) led to interruption of diestrus within 3-5 days. With frontal cuts placed more caudally in the MBH, and with frontal cuts placed rostrally at the anterochiasmatic area, the duration of PSP was within normal range. Irrespective of their effects on PSP, anterochiasmatic and retrochiasmatic cuts were associated with onset of persistent estrus, and MBH transections resulted in either persistent estrus in some rats or regular estrous cycles in the others. In deafferentated rats that showed persistent estrus, the basal plasma concentrations of PRL measured 3-4 weeks after ovariectomy were 2- to 3-fold higher than in deafferentated and sham-deafferentated animals that were cyclic before ovariectomy. Electrical vaginocervical stimulation induced secretion of nocturnal PRL surges in long-term ovariectomized rats with dorsal or sham transections, but not in those bearing frontal cuts, regardless of the neuroanatomical location of the frontal cut. These results suggest that (1) impulses generated at the uterine cervix must reach the medial preoptic area, a putative 'anti-surge center', and proceed from there to the MBH, in order to allow initiation of nocturnal PRL release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Metabolic mapping of functional activity in the olfactory system of normal and hypogonadal (hpg) mice.

The hypogonadal mouse, which lacks gonadotropin-releasing hormone, has been suggested as an animal model of Kallmann's syndrome, one symptom of which is hyposmia. We have determined the metabolic activity of the olfactory system, in normal and hypogonadal mice, using [14C]-2-deoxyglucose quantitative autoradiography. In the olfactory lobes, deoxyglucose uptake was greatest in the glomerular and granule cell layers and low in the olfactory nerve layer and bulb core. The pattern of uptake was similar in both hypogonadal and normal mice breathing filtered air. Exposure of normal mice to ethyl acetoacetate significantly increased deoxyglucose uptake in the olfactory nerve layer and glomerular layer, but not in the granule cell layer. Several foci of intense metabolic activity were produced, apparently corresponding to small groups of activated glomeruli. There were no changes in the secondary or tertiary projections of the olfactory system. In hypogonadal mice, ethyl acetoacetate failed to increase the number of foci and the density of labelling in the olfactory nerve layer and glomerular layer. These data show that the functional activity of the olfactory system in hypogonadal mice breathing air is apparently normal. However, the olfactory response to ethyl acetoacetate is significantly less in hypogonadal mice. Whether this is due to their lack of gonadotropin-releasing hormone requires further experimentation.

Acetoacetates↗
PubMed1988

Changes in local cerebral glucose utilization associated with the spontaneous ovulatory surge of luteinizing hormone in the rat.

Brain activity during the spontaneous ovulatory surge of luteinizing hormone (LH) has been studied by measuring local cerebral glucose utilization (LCGU) by the [14C]-2-deoxyglucose method. The LCGU was determined in 37 brain areas and the pituitary gland in conscious, freely moving female rats in the morning and the late afternoon of proestrus. No increases in LCGU were detected, but, unexpectedly, there was a significant decrease in the LCGU measured in the afternoon compared with the morning of proestrus in the medial preoptic and anterior hypothalamic areas, the arcuate nucleus, median eminence and amygdala. Significant reductions in LCGU also occurred in the midbrain central grey and reticular formation. These results suggest that the LH and/or the prolactin surge is associated with a significant reduction in the activity of brain areas known to be essential components of the central control of gonadotropin and prolactin secretion. In the case of the arcuate nucleus and median eminence, for example, the results could be explained by a decreased activity of the opioid and dopaminergic neurons which are known to inhibit the release of luteinizing hormone releasing hormone (LHRH). Disinhibition of LHRH neurons would result in the increased release of LHRH into the hypophysial portal vessels. Reduction in the activity of the arcuate dopamine neurons could also play a major role in the prolactin surge. The decreased LCGU of the midbrain central grey may be related to the onset of lordosis behavior which appears to be time-locked to the LH surge.

Animals↗
PubMed1988

Neurohypophysial peptides in guinea pig hypophysial portal blood: equimolar release of the carboxyl terminal glycopeptide with arginine vasopressin.

A method has been devised for collecting hypophysial portal blood from the anaesthetised guinea pig in order to measure the release in vivo of the neurohypophysial peptides, oxytocin (OT), vasopressin (AVP), neurophysin (NP), and the glycopeptide (GP) found at the carboxyl terminus of the AVP precursor. These peptides were measured in samples of portal and peripheral venous plasma by specific radioimmunoassays. The concentration of OT and AVP was 50- to 100-fold higher in hypophysial portal blood than in peripheral blood, with more OT than AVP usually present. There were correspondingly large amounts of NP and GP also present in portal blood. In particular, GP levels paralleled AVP levels over a wide range of concentrations and in virtually equimolar proportions. These results provide the first in vivo evidence which shows that, as for the magnocellular neurohypophysial system, GP is synthesised, processed and released in equal amounts with AVP from their common precursor in the subpopulation of parvocellular AVP neurons which project from the paraventricular nucleus to the median eminence.

Animals↗
PubMed1988

Comparison of adrenocorticotropin control in Brattleboro, Long-Evans, and Wistar rats. Measurement of corticotropin-releasing factor, arginine vasopressin, and oxytocin in hypophysial portal blood.

The purpose of this study was to compare the control of adrenocorticotropin (ACTH) and corticosterone secretion in homozygous Brattleboro rats with their syngeneic controls, Long-Evans rats, and with rats of the Wistar strain. Plasma concentrations of ACTH and corticosterone were measured by radioimmunoassay in trunk blood, and corticotropin-releasing factor 41 (CRF-41), arginine vasopressin (AVP), and oxytocin were assayed in hypophysial portal vessel blood. Portal plasma was extracted with methanol for CRF-41 determination, and four different antisera and several different high-performance liquid chromatography (HPLC) systems were used to investigate AVP release. The peripheral plasma concentrations of ACTH and corticosterone were significantly higher in Long-Evans and homozygous Brattleboro than in Wistar rats. This difference was due, at least in part, to an approximately twofold greater release of CRF-41 into hypophysial portal blood of the Long-Evans and Brattleboro compared with Wistar rats. There was no significant difference between the strains in the output of oxytocin into portal blood. While no AVP could be detected in the neural lobe of homozygous Brattleboro rats, a small amount of AVP-like immunoreactivity was detected in unextracted hypophysial portal blood from homozygous Brattleboro rats. However, this AVP-like immunoreactivity was clearly distinct from authentic AVP in several HPLC systems, had no antidiuretic activity, and on gel filtration had a relative molecular mass greater than 5 kD. In contrast, the AVP-like immunoreactivity in hypophysial portal blood from Long-Evans rats co-eluted with authentic AVP in all HPLC systems tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1988

Regulation of pituitary alpha-subunit, beta-luteinizing hormone and prolactin messenger ribonucleic acid by gonadotropin-releasing hormone and estradiol in hypogonadal mice.

We have investigated the effects of three different GnRH injection regimens and the effects of estradiol benzoate (EB) on expression of the common alpha-subunit, beta-LH, and PRL genes in male and female hpg mice. GnRH was injected once daily (100 ng), every 2 h (100 ng) or every 30 min (25 ng), and EB (10 micrograms) was injected once daily. The effects of continuous exposure to the superactive agonist D-Trp6-GnRH released from microcapsules were also studied. Northern blot analysis showed that administration of GnRH increased alpha-subunit mRNA levels 2- to 10-fold in male and female hpg but not normal mice and had no significant effect on beta-LH or beta-TSH mRNA levels. The greatest increase in alpha-mRNA occurred when 100 ng GnRH were injected every 2 h and could be detected within 6 h of the first GnRH injection. More frequent injections (25 ng every 30 min) were less effective in increasing alpha-mRNA, as was prolonged exposure to the D-Trp6-GnRH superagonist. The increase in alpha-mRNA was associated with an increase in pituitary FSH content of similar magnitude. Continuous exposure of the pituitary gland to D-Trp6-GnRH (approximately 1500 ng/day) resulted in a smaller (2-fold) increase in alpha-mRNA and pituitary FSH content, suggesting that desensitization had occurred. EB had little effect on beta-LH mRNA and did not alter alpha-mRNA levels or affect the increase in alpha-mRNA caused by GnRH. Injection of GnRH every 2 h increased pituitary PRL mRNA levels in female but not male hpg mice, probably due to an indirect effect resulting from increased estrogen secretion. We conclude that GnRH administration to hpg mice significantly increases alpha-subunit but not beta-LH mRNA levels and that maximal effects occur with 100 ng GnRH injections every 2 h. Although EB does have direct effects upon pituitary gonadotropin content in hpg mice, the absence of significant changes in alpha- and beta-LH mRNA suggests that these effects may be largely posttranscriptional.

Animals↗
PubMed1988

The role of protein kinase C in LHRH-induced LH and FSH release and LHRH self-priming in rat anterior pituitary glands in vitro.

We have investigated the role of protein kinase C (PKC) in LHRH-induced LH and FSH secretion and LHRH priming. Hemipituitary glands from prooestrous rats were incubated with agents known to affect PKC and with or without LHRH, during which time the secretion of gonadotrophins was measured. Phorbol esters and phospholipase C, activators of PKC, released LH and FSH in a concentration-dependent manner and potentiated the LHRH-induced secretion of gonadotrophins in parallel with their ability to release these hormones alone. Inhibitors of PKC had either no effect on LH release (1-(5-isoquinolinesulphonyl)-2-methylpiperazine hydrochloride) or they augmented LHRH-induced gonadotrophin release (polymyxin B and 8-(N,N-diethylamino) octyl-3,4,5-trimethoxybenzoate). Neither the activators nor the inhibitors of PKC, when present with LHRH, caused any change in LHRH priming, even though the activators alone produced a release of gonadotrophins that showed a temporal pattern similar to that produced by LHRH priming. The profiles of effects on LH and FSH secretion were always qualitatively similar. These results show that PKC may be involved in general regulation of gonadotrophin release but that it is not important in acute responses to LHRH nor in LHRH self-priming.

Animals↗
PubMed1988

Facilitated calcium mobilization and inositol phosphate production in the priming effect of LH-releasing hormone in the rat.

The ability of LHRH to induce Ca2+ mobilization and production of inositol phosphates in rat anterior pituitary tissue in vitro was investigated in relation to the self-priming effect of LHRH. Prior exposure to LHRH (which caused a characteristic potentiation of subsequent secretory responses) specifically enhanced LHRH-induced inositol phosphate production and mobilization of intracellular Ca2+ stores. LHRH-induced influx of Ca2+ through dihydropyridine-sensitive Ca2+ channels was unaltered, as was ligand binding to LHRH receptors. These data suggest that a novel facilitation of signalling may occur in the phospho-inositide-Ca2+ mobilization response mechanism during LHRH priming, and that this may represent an important means of regulating cellular responsiveness in gonadotrophs.

Animals↗
PubMed1988

Pharmacological survey of recombinant hirudin.

The pharmacological properties of a genetically engineered recombinant hirudin (r-hirudin) were studied in animal experiments. r-Hirudin proved to be a well tolerated substance. I.v. injection of up to 200 mg/kg did not lead to perceptible functional or morphological changes. There were no treatment-related effects on the cardiovascular system of dogs and rats after administration of up to 10 mg/kg. After long-term treatment (4 weeks, 1.0 mg/kg daily), no r-hirudin-related histopathological, haematological or biochemical changes could be found. Formation of antibodies was not detectable. Absorption, distribution, and elimination of r-hirudin were studied in dogs and rats. Pharmacokinetics could be best described by an open two-compartment model with first-order kinetics. After i.v. injection in dogs, r-hirudin is distributed into the extracellular space and eliminated through the kidneys in active form by glomerular filtration. After i.v. administration, a half-life of about 1 h was estimated; s.c. administration prolonged the apparent half-life. Pulmonary absorption was shown. Enteral absorption, placental transfer as well as transfer through the fetal integument were very low. r-Hirudin did not pass the blood-brain barrier. The efficacy of r-hirudin in preventing both venous and arterial thrombosis, vascular shunt occlusion or disseminated intravascular coagulation was demonstrated in rats. Depending on the dose, r-hirudin was able to prevent or reduce stasis-induced venous thrombosis, prolong the patency of an extracorporeal arteriovenous shunt, reduce the incidence of arterial thrombosis caused by vascular wall lesions as well as of microthrombosis induced by thrombin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗