[Regulation of the glomerular filtration rate].
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Glomerular Filtration Rate↗
Biomedical subjects
S H Shin
Publications and source records attributed to S H Shin.
Extensive ultrastructural changes in rat mammotrophs following administration of the dopamine agonist ergocristine-reflecting inhibition of prolactin release.
We have demonstrated an extensive reorganization of organelles in mammotrophs immediately following administration of ergocristine (a dopamine agonist) to estradiol-primed male rats. Our ultrastructural findings are consistent with our previous results that ergocristine can block prolactin release without any noticeable latent period. Following three-week priming of male rats with estradiol implants, ergocristine was administered by a bolus injection through an indwelling cannula. Within two min of its administration, ergocristine induced dramatic changes in the ultrastructure of mammotrophs, i.e., (1) increased numbers of secretory granules, (2) peripheral relocation of rough endoplasmic reticulum which tends to sequester secretory granules, (3) change in location of nucleus and (4) increased numbers of intracellular bodies associated with secretory granules. We suggest that the extensive ultrastructural changes that occurred in such a short period following ergocristine administration may be indications of specific factors associated with blockage of hormone release.
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Ultrastructural changes rapidly induced by somatostatin may inhibit prolactin release in estrogen-primed rat adenohypophysis.
Apart from the known hypothalamic controls, which have been well documented, a myriad of compounds both endogenous and exogenous have proved effective in influencing secretion of prolactin (PRL). Recent studies have shown that somatostatin (SRIF), when injected intra-atrially as a bolus, is able to inhibit PRL secretion in vivo. However, the inhibitory effect of SRIF occurs only in adenohypophyses previously primed with estradiol. This research was undertaken to examine the ultrastructural effects of that inhibition using male Sprague-Dawley rats primed for three weeks with subcutaneous implants of estradiol. Within 2 min of injection of SRIF (1 mg/kg), the adenohypophyses were removed and processed for electron microscopy. We found dramatic changes in the estradiol-primed mammotrophs, including 1) an apparent rearrangement of rough endoplasmic reticulum (RER) into concentric cisternae, and 2) the appearance of intracellular bodies closely associated with granules. These changes were not observed in non-estradiol-primed male rats injected with SRIF which is consistent with the fact that in the normal male rats, SRIF failed to inhibit PRL secretion. These findings suggest that SRIF causes reorganization of cellular organelles so that PRL granules are sequestered thereby inhibiting secretion of PRL.
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Prolactin increases the activity of tuberoinfundibular and nigroneostriatal dopamine neurons: prolactin antiserum inhibits the haloperidol-induced increases in dopamine synthesis rates in median eminence and striatum of rats.
The role of PRL in mediating the haloperidol-induced increase in tuberoinfundibular dopamine synthesis rate was assessed by studying the effects of administration of PRL antiserum. Antiserum to PRL generated in rabbits and not cross-reacting with other anterior pituitary hormones was administered IV to adult, male rats which received haloperidol 2.5 mg/kg or tartaric acid vehicle SC 22 hr and 12 hr before measurement of dopamine turnover. Comparable groups of haloperidol or vehicle-treated animals received normal rabbit serum as control. Dopamine synthesis or turnover rate was estimated by measurement of accumulation of L-dihydroxyphenylalanine following inhibition of L-aromatic amino acid decarboxylase with m-hydroxybenzylhydrazine. Haloperidol increased median eminence dopamine synthesis rate, and PRL antiserum completely prevented this effect, supporting the thesis that the haloperidol-induced increase in tuberoinfundibular dopamine turnover is mediated by PRL. PRL antiserum did not alter basal median eminence dopamine synthesis rate in male rats. In addition to its effect in median eminence, PRL antiserum blunted the haloperidol-induced increase in striatal dopamine synthesis rate, suggesting that the haloperidol-induced increase in nigroneostriatal dopamine turnover is mediated in part by PRL. Neither haloperidol nor PRL antiserum altered serotonin synthesis rate in mediobasal hypothalamus or striatum. The data provide further support for a mechanism by which PRL can regulate its own secretion. They also suggest that prolactin alters the activity not only of tuberoinfundibular but also of nigroneostriatal neurons.
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Dopamine creates a physical barrier to inhibit prolactin release in mammotrophs of estradiol-primed male rats.
After finding that ergocristine and somatostatin can cause extensive changes in mammotroph ultrastructure within 2 min of administration, we chose dopamine, the putative physiological prolactin-inhibiting factor, to correlate ultrastructural changes to inhibition of prolactin release. In order to choose a dose of dopamine for this study we tested the effects of 2 doses of dopamine (10 and 1,000 micrograms/kg) on inhibition of prolactin release. The higher dose of dopamine (1,000 micrograms/kg) completely inhibited prolactin release immediately (in less than 2 min) and maintained complete blockage for a period of 14 min. For the ultrastructural study we injected dopamine (1,000 micrograms/kg) in the right atrium of conscious free-moving rats through indwelling cannulae, and killed the rats by decapitation 2 min after dopamine administration. The following changes in mammotrophs were observed after the dopamine treatment: (1) increased numbers of secretory granules, (2) peripheral relocation of rough endoplasmic reticulum, and (3) increased numbers of 'intracellular bodies' (putative prolactin granule disposal system) associated with secretory granules. Because these rapid ultrastructural changes have been observed after treatment with three different compounds (dopamine, somatostatin and ergocristine), we do not believe that they are the unique effect of any one compound but the common denominator of the three compounds, i.e., inhibition of prolactin secretion being closely linked to the ultrastructural changes. We thus propose that the extensive ultrastructural changes that occurred in such a short period of time following dopamine administration are the mechanism of inhibition of prolactin release.
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Serotonin stimulates prolactin secretion in the hypophysectomized adenohypophyseal grafted rat.
Normal male, oestrogen (F2) primed male and hypophysectomized adenohypophyseal grafted male rats (HAG rats) were used in the experiments. Serotonin creatinine sulphate was injected as a bolus via an indwelling atrial cannula in the conscious free moving rat. Serotonin caused a dose-dependent increase in plasma prolactin (Prl) in normal (1, 3 and 10 mg/kg serotonin) and E2 primed (1 and 3 mg/kg serotonin) male rats that began immediately after injection and reached a peak within 12-15 min of injection. Oestrogen priming significantly increased the magnitude of the response to serotonin. To analyze the site of action of serotonin in the rat, serotonin (1 mg/kg) was injected into HAG rats. Serotonin increased plasma Prl in this rat preparation, indicating that serotonin acts directly on the ectopic pituitary.
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Detailed examination of episodic bursts of rGH secretion by high frequency blood sampling in normal male rats.
Episodic bursts of rat growth hormone (rGH) secretion were examined in detail by monitoring circulating rGH concentration every 2 min (70 ul blood samples were taken). Conscious free moving normal male rats implanted with indwelling cannulae were used. Between 11:00-13:00 h and between 14:00-15:20 h, basal levels of rGH were found to be 30-50 ng/ml. Bursts of rGH secretion had many different shapes, including a "single spike", "compound peak" and "plateau" but not regularity or periodicity of changes of rGH concentration was observed. Therefore we could not apply basic statistical treatments such as the standard deviation or standard error of means which are based on the assumption of normal distributions. When the downward slopes of each major spikes comprised more than 3 sequential samples, the decay slope was analyzed. Of 16 slopes, 10 were parallel with a theoretical curve of a 7 min half-life (rGH half-life is 5-7 min) indicating that no more rGH was secreted during the period of the downward slope. The slopes with significantly slower disappearance rates can be interpreted as indicating that a significant amount of rGH is secreted during the period of the downward slopes. Our experimental design revealed a more complex pattern or rGH secretory bursts than had hitherto been described. Our technique revealed more physiological characteristics of rGH secretion by more frequent sampling of very small volumes of blood. This technique eliminated unnecessarily excessive bleeding and avoided the necessity of returning red blood cells.
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Normal prolactin content of rat pituitary may be maintained by Nebenkern formations.
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Animals↗
Vasopressin has a direct effect on prolactin release in male rats.
Prolactin-releasing (PRF) activity was found in Pitressin (a commercial extract from posterior pituitary for vasopressin). Injection of Pitressin into conscious free-moving rats implanted with a permanent atrial indwelling cannula, produced a transient increase in prolactin concentration in the circulation. In order to find out whether the PRF activity was due to vasopressin or to an unidentified component in the Pitressin, we tested synthetic lysine vasopressin and demonstrated that vasopressin (1 U/kg) elevated plasma prolactin concentration about threefold. In contrast, oxytocin (1 U/kg) did not alter the prolactin concentration. In order to find out whether the effect of vasopressin is a direct or indirect action, we tested the vasopressin effect on hypophysectomized rats which had previously been implanted with 2 adenohypophyses under the kidney capsule. Again this dose (2 U/kg) of vasopressin elevated circulating plasma prolactin. These experiments indicate that vasopressin can elevate circulating prolactin concentration in nonestrogen-primed normal male rats and that vasopressin also stimulates prolactin secretion from transplanted glands dissociated from direct hypothalamic control.
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Desmosomes between mammotrophs suggest the existence of a functional syncytium.
Lactotrophs in the adenohypophysis have the apparent inherent capability to produce simultaneous secretion of prolactin from individual cells. There are two possibilities to account for this synchronized, discrete pulsatile secretion: (1) humoral communication, or (2) cell-to-cell syncytial communication. As a first step in examining the second possibility, we searched for ultrastructural evidence of intercellular contacts. The presence of desmosomes, the conventional junctions that serve to anchor adjacent cells, would be the first step in proving contact between homologous cells. In order to increase the observation of desmosomes, the population of lactotrophs in the adenohypophysis was increased by implantation of capsules containing estradiol in male Sprague-Dawley rats. The adenohypophyses were then examined by electron microscopy for indications of these intercellular bridges. Desmosomes were discovered between lactotrophs, indicating that cell-to-cell contact does exist, and suggesting that the desmosome may help the formation of a syncytium among lactotrophs, either directly or indirectly. Since an ectopic pituitary without direct help from the hypothalamus can secrete prolactin in a pulsatile fashion and since there are desmosomes between lactotrophs, it is possible that the synchronized prolactin release occurs through a direct cell-to-cell communication system which is linked by the desmosomes.
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Newly synthesized prolactin is preferentially secreted by the adenohypophysis in a primary cell culture system.
A relationship between prolactinin synthesis and release was studied using a dispersed adenohypophysial cell primary-culture system. Newly synthesized prolactin was identified by the amount of prolactin-associated tritium activity. No new prolactin was synthesized during a 1-h incubation with 3H-Leu. After 4 h a significant amount of newly synthesized prolact was released into the medium but no labelled prolactin was detected in the cells. Radioimmunoassayable prolactin, however, was equally divided between the cells and the medium indicating that the newly synthesized prolactin was preferentially secreted. In contrast, approx. 2 times more newly labelled GH was found in the cell extract than in the medium while by GH-radioimmunoassay, the cells contained twice as much GH as the medium in the control group. During the 1-h incubation, estradiol (1.0 ng/ml) increased prolactin content in the medium, although no newly synthesized prolactin appeared in the medium or the cells. During the 4-h incubation period significantly more labelled prolactin was released into the medium in the presence of estradiol (1.0 ng/ml) than in the control. These results indicate that (1) estradiol has a stimulatory effect on prolactin secretion, (2) estradiol activates a prolactin-synthesis mechanism, (3) newly synthesized prolactin is preferentially released, and (4) the rate of release of newly synthesized prolactin and GH having different mechanisms of hypothalamic control, an inhibiting factor for the prolactin and a releasing factor for GH.
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Somatostatin inhibits prolactin secretion in the estradiol primed male rat.
Somatostatin inhibits not only growth hormone secretion, but also the secretion of several other hormones. The role of somatostatin in prolactin (PRL) secretion has not been clearly demonstrated. The present study was undertaken to examine the effects of somatostatin on rat PRL secretion in several different circumstances where the circulating PRL level is elevated: (1) the estradiol primed intact male rat, (2) normal and (3) estradiol primed rats pretreated with pimozide, (4) normal and (5) estradiol primed hypophysectomized male rats with adenohypophyses grafted under the kidney capsule (HAG rat). Blood samples (70 microL) were taken every 2 min via an indwelling atrial cannula from conscious, unrestrained animals. In the estradiol primed intact rats, a bolus injection of somatostatin (10, 100, and 1000 micrograms/kg) lowered PRL levels in a dose-dependent manner. When the PRL concentration was elevated by the administration of pimozide (3 mg/kg), a dopaminergic receptor blocking agent, somatostatin was ineffective in decreasing plasma PRL concentration but the PRL concentration was lowered by somatostatin when the rat had been primed with estradiol. Somatostatin had no effect on the normal HAG rats, but lowered the plasma PRL concentration in the estradiol primed HAG rats. Since somatostatin inhibits PRL secretion only in the estradiol primed rats, it is suggested that estradiol priming creates a new environment, presumably via new or altered receptors, which can be inhibited by somatostatin.
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Adenohypophysis has an inherent property for pulsatile prolactin secretion.
Hypophysectomized male rats with adenohypophyses grafted under the kidney capsule (HG rat) for 3 weeks with or without estradiol implantation, were used to examine prolactin (PRL) secretion independent of hypothalamic influence. Changes in the circulating PRL concentration were monitored by taking blood samples every 2 min via an indwelling atrial cannula. The circulating PRL concentration did not remain at a constant level but fluctuated with time. When estradiol (100 microgram/kg) was administered to HG rats through the indwelling cannula the size of the PRL pulses was magnified. The ability of the grafted adenohypophyses to generate pulsatile changes in the plasma PRL indicates that the adenohypophysis possesses an inherent interlactotroph communication system to permit synchronized PRL secretion without the direct involvement of hypothalamic PRL-releasing factors or inhibiting factors.
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Temporal and other effects of catechol estrogens on prolactin secretion in the rat.
Temporal alterations in plasma prolactin levels caused by the administration of 2-hydroxyestradiol and 2-hydroxyestrone (100 microgram/kg) into the right atrium of freely-moving conscious male rats were examined. The catechol estrogens were given in a single bolus via an indwelling cannula and plasma prolactin concentration was monitored by taking blood samples every 2 min. A pulsatile elevation of plasma prolactin occurred approximately 4 h after the injection of 2-hydroxyestradiol and a small increase was also observed when it was administered to rats bearing a Silastic capsule containing estradiol. 2-Hydroxyestrone had no effect in untreated male rats but produced a 5- to 6-fold elevation in plasma prolactin level 4 h after its administration to rats implanted with estradiol. It is proposed that 2-hydroxyestrone suppresses the action of estradiol on prolactin secretion from the pituitary and that the accumulated hormone is released when the concentration of this catechol estrogen falls below a critical level. A longer latent period was required to produce an elevation in plasma prolactin levels by 2-hydroxyestradiol than by estradiol.
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beta-Endorphin-induced prolactin secretion is mediated by suppression of release of newly synthesized hypothalamic dopamine.
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Animals↗
Comparative studies of prolactin secretion in estradiol-primed and normal male rats induced by ether stress, pimozide and TRH.
The differences in plasma prolactin concentration between normal and estradiol-implanted male rats were compared after treatment with 3 different stimulating agents of prolactin secretion [ether anesthesia, pimozide (a "specific' dopaminergic receptor blocking agent) and TRH] using conscious, free-moving rats implanted with permanent intra-atrial cannulae. It has recently been shown that ether stress raises the circulating prolactin concentration by stimulating PRF secretion. The ether stress elevated prolactin concentration from 100 to 400 ng/ml in the estradiol-implanted rat and from 10 to 40 ng/ml in the normal male. Thus, the ether stress elevated the prolactin concentration 4 times over the basal level in both normal male and estradiol-implanted male rats, implying that the physiological role of the PRF is not changed by the estradiol implantation. A bolus injection of pimozide (1 mg/kg) elevated the plasma prolactin concentration in both the normal and estradiol-implanted male with an initial surge followed by descent to a maintained plateau level. This plateau level in the estradiol-primed rat was 600 ng/ml and in the nonprimed male rat, 50 ng/ml. The ratio of the plateau concentration over the basal level was 4 times for both groups, suggesting that the physiological role of the PIF in the estradiol-implanted rat is not different from that in the normal male rat. It is known that TRH not only stimulates TSH secretion but will stimulate prolactin secretion as well. A very large dose (0.6 mg/kg) of TRH elevated prolactin concentration 6-fold in the estradiol-implanted rat but stimulate little prolactin secretion in the normal male rat. Since ether exposure appears to stimulate prolactin secretion in both estradiol-primed and non-primed male rats through PRF secretion, while TRH was not able to stimulate a significant amount of prolactin secretion in the normal male rat, we concluded that TRH acts to stimulate prolactin secretion in estradiol-primed rats but through a different mechanism than that operating for PRF.
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Physiological evidence for the existence of prolactin releasing factor: stress-induced prolactin secretion is not linked to dopaminergic receptors.
Experiments were undertaken to demonstrate the existence of a physiological role of prolactin releasing factor (PRF). Hypothalamic control of prolactin secretion is achieved by secretion of prolactin inhibiting factor (PIF) and/or PRF. Since the putative PIF is dopamine, complete blockage of the dopaminergic PIF receptors should permit demonstration of PRF activity. The changes in prolactin concentration were monitored by taking a blood sample every 2 min through an indwelling atrial cannula. An excessive amount of pimozide (3 mg/kg) was used to block dopaminergic receptors and prolactin concentration was elevated as a result. This higher concentration of circulating prolactin was maintained for more than 30 h after a bolus injection of pimozide. In this situation, lacking functional dopaminergic PIF receptors, there were fluctuations in the circulating prolactin concentration throughout the experiment. If, after pimozide administration, rats were exposed to an acute (ether) stress, the stress consistently elevated the circulating prolactin concentration. Since there are no functional dopaminergic PIF receptors available under these conditions, a dopaminergic PIF cannot be involved in producing the prolactin surge induced by the acute stress. Therefore, these results suggest that a physiological PRF is involved in the generation of this prolactin surge, through the evidence is not direct.
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Dopaminergic mediation of beta-endorphin-induced prolactin secretion.
Intracisternal administration of synthetic human beta-endorphin increases plasma praolactin concentration, and this effect is blocked by naloxone. Drugs which stimulate dopamine receptors (apomorphine or bromocriptine) or increase availability of dopamine (pargyline) inhibited the effect of beta-endorphin on plasma prolactin. Drugs which antagonize dopamine receptors (haloperidol) or decrease availability of dopamine (alpha-methyltyrosine) potentiated the effect of beta-endorphin on plasma prolactin. Some of these drugs act only in neurons and not in anterior pituitary, supporting a brain site of action for these drug interactions with beta-endorphin which altered prolactin secretion. These pharmacological studies provide support for a concept of dopaminergic mediation of beta-endorphin-induced prolactin secretion.
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