The privileges of a Nobel laureate.
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Gonadotropin-Releasing Hormone↗
Biomedical subjects
S M McCann
Publications and source records attributed to S M McCann.
Participation of the ascending serotonergic system in the stimulation of atrial natriuretic peptide release.
Results obtained in our laboratories have provided evidence for the participation of the hypothalamic atrial natriuretic peptide (ANP) neuronal system in the regulation of water and electrolyte homeostasis. The anterior ventral third ventricular (AV3V) region, a site of the perikarya of the ANP neurons, receives important afferent input from ascending serotoninergic axons. We hypothesized that the ascending serotoninergic tract might be involved in control of the liberation of ANP. Therefore, electrolytic lesions were produced in the mesencephalic dorsal raphé nucleus (DRN), the site of perikarya of serotonin (5-HT) neurons whose axons project to the AV3V region. Rats with sham lesions constituted the control group. In a second group of animals, the serotoninergic system was depleted of 5-HT by lateral ventricular administration of p-chlorophenylalanine (PCPA), an amino acid that causes depletion of 5-HT from the serotoninergic neurons. Control animals were injected with an equal amount of isotonic saline. The DRN lesions induced an increase of water intake and urine output beginning on the first day that lasted for 1 week after lesions were produced. There was a concomitant sodium retention that lasted for the same period of time. When water-loaded, DRN-lesioned and PCPA-injected animals showed diminished excretion of sodium, accompanied by a decrease in basal plasma ANP concentrations, and blockade of the increase in plasma ANP, which followed blood volume expansion by intraatrial injection of hypertonic saline. The results are interpreted to mean that ascending stimulatory serotoninergic input into the ANP neuronal system in the AV3V region produces a tonic stimulation of ANP release, which augments sodium excretion and inhibits water intake. Therefore, in the absence of this serotoninergic input following destruction of the serotoninergic neurons by DRN lesions or intraventricular injection of PCPA, an antinatriuretic effect is obtained that is associated with increased drinking, either because of sodium retention per se or removal of ANP-induced inhibition of release of the dipsogenic peptide, angiotensin II. The serotoninergic afferents also play an essential, stimulatory role in volume expansion-induced release of ANP and the ensuing natriuresis.
Animals↗
Role of cytokines in the endocrine system.
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Animals↗
Nitric oxide mediates sexual behavior in female rats.
Nitric oxide (NO), an active free radical formed during the conversion of arginine to citrulline by the enzyme NO synthase (NOS), mediates vasorelaxation, cytotoxicity, and neurotransmission. Neurons containing NOS (NOergic) are located in the hypothalamus. These NOergic neurons control the release of several hypothalamic peptides. Release of NO from these NOergic neurons stimulates pulsatile release of luteinizing hormone-releasing hormone (LHRH) in vivo and LHRH release in vitro. LHRH not only induces LH release, which induces ovulation, but also facilitates female sexual behavior. Sexual behavior can be induced reliably in estrogen-primed ovariectomized female rats by progesterone (P). This behavior consists of proceptive behavior to attract the male and the assumption of a clear characteristic posture, lordosis, when mounted by the male. To ascertain the role of NO in the control of sexual behavior in female rats, an inhibitor of NOS, NG-monomethyl-L-arginine was microinjected into the third cerebral ventricle (3V) of conscious, ovariectomized, estrogen-primed rats with indwelling cannulae. NG-Monomethyl-L-arginine (10-1000 micrograms) prevented P-facilitated lordosis when administered intracerebroventricularly into the 3V, 20 min prior to the 3V injection of P. NG-Monomethyl-D-arginine, which does not inhibit NOS, did not inhibit lordosis under the same experimental conditions. Microinjection into the 3V of sodium nitroprusside (SNP), which spontaneously releases NO, facilitated lordosis in estrogen-primed rats in the absence of P. The facilitation of lordosis induced by either P or SNP was prevented by intracerebroventricular injection of hemoglobin, which binds NO. Lordosis facilitated by P or SNP was blocked by injection of LHRH antiserum into the 3V. The results are interpreted to mean that the P-facilitated lordosis response is mediated by LHRH release. Furthermore, since NO release from SNP also facilitates lordosis in the absence of P and this response could be blocked by LHRH antiserum, we conclude that P brings about the release of NO, which stimulates LHRH release that facilitates lordosis. Thus, the results indicate that NO induces LHRH release and that LHRH then plays a crucial role in mediation of sexual behavior in the female rats.
Amino Acid Oxidoreductases↗
Role of nitric oxide in eicosanoid synthesis and uterine motility in estrogen-treated rat uteri.
Cholinergic stimulation of vascular endothelin activates NO synthase (NOS), leading to generation of NO from arginine. This NO diffuses to the overlying vascular smooth muscle and causes vasodilatation. NOS has also been found in the central and peripheral nervous systems and it is clear now that NO plays an important role as a neurotransmitter. Here we investigate the role of NO in controlling contraction of uterine smooth muscle. Our previous work showed that NO activates the cyclooxygenase enzyme in the hypothalamus, leading to production of prostaglandin E2 (PGE2). We began by determining whether NO was involved in production of arachidonic acid metabolites in the uterus. Uteri were removed from female rats that had been treated with estrogen (17 beta-estradiol). Control animals were similarly injected with diluent. Tissues were incubated in vitro in the presence of [14C]arachidonic acid for 60 min. Synthesis of PGs and thromboxane B2 (TXB2) was markedly stimulated by sodium nitroprusside (NP), the releaser of NO. The effect was greatest on TXB2; there were no significant differences in increases of different PGs. The response to NP was completely prevented by Hb, a scavenger of NO. The inhibitor of NOS, NG-monomethyl-L-arginine (NMMA), significantly decreased synthesis of PGE2 but not the other prostanoids (6-keto-PGF1 alpha and PGF2 alpha). Addition of Hb to scavenge the spontaneously released NO inhibited synthesis of 6-keto-PGF1 alpha, PGE2, and PGF2 alpha, but not TXB2. There was a much lesser effect on products of lipoxygenase, such that only 5-hydroxy-5,8,11,14-eicosatetraenoic acid (5-HETE) synthesis was increased by NP, an effect that was blocked by Hb; there was no effect of NMMA or Hb on basal production of 5-HETE. Thus, NO stimulates release of the various prostanoids and 5-HETE; blockade of NOS blocked only PGE2 release, whereas Hb to scavenge the NO released also blocked synthesis of 6-keto-PFG1 alpha, PGE2, and PGF2 alpha, indicating that basal NO release is involved in synthesis of all these PGs, especially PGE2. Presumably, NMMA did not block NOS completely, whereas Hb completely removed released NO. This may explain the different responses of the various prostanoids to NMMA and Hb. To determine the role of these prostanoids and NO in control of spontaneous in vitro uterine contractility in the estrogen-treated uterus, the effect of blocking NOS with NMMA and of scavenging NO produced by Hb on the time course of spontaneous uterine contractility was studied. Surprisingly, blockade of NOS or removal of NO by Hb prevented the spontaneous decline in uterine motility that occurs over 40 min of incubation. We interpret this to mean that NO was released in the preparation and activated guanylate cyclase in the smooth muscle, resulting in production of cGMP, which reduces motility and induces relaxation. When the motility had declined to minimal levels, the effect of increased NO provided by NP was evaluated; apparently by stimulating the release of prostanoids, a rapid increase in motility that persisted for 10 min was produced. This effect was completely blocked by Hb. The action of NO was also blocked by indomethacin, indicating that it was acting via release of PGs. Apparently, when motility is low, activation of PG synthesis by NO to activate the cyclooxygenase enzyme causes a rapid induction of contraction, whereas, when motility is declining, NO acts primarily via guanylate cyclase to activate cGMP release; the action of the prostanoids released at this time is in some manner blocked.
Animals↗
Role of laminin on prolactin and gonadotrophin release from anterior pituitaries of male rats.
The effect of rat laminin on the release of prolactin (PRL), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from anterior pituitaries of adult male rats was studied in vitro. Laminin had a bidirectional effect on basal release of PRL, being stimulatory at 10(-12)M and inhibitory at 10(-9) and 10(-8)M. LH release was only stimulated by the 10(-12)M concentration and no changes in FSH release were observed. Laminin did not modify the stimulatory action of thyrotropin-releasing hormone (TRH) nor luteinizing hormone releasing hormone (LHRH), but the response of FSH to LHRH was inhibited with a maximal effect at 10(-10)M. To assess its physiological role, the effect of a rabbit antibody to laminin on the release of PRL, LH and FSH was also studied. IgG anti-laminin at 2 x 10(-7)M had a highly significant stimulatory effect on PRL release after 3 and 5 hr of incubation, as compared to IgG from normal rabbit serum and medium alone used as controls. No changes on the release of LH and FSH were detected. These results suggest that laminin plays a physiologically significant inhibitory role on PRL release at the pituitary level in vitro.
Animals↗
Effects of alpha-inhibin-92 fragments and alpha-inhibin-92 antiserum on the control of follicle-stimulating hormone release in male rats.
Alpha-inhibin-92 (alpha-IB-92) has been characterized from human seminal plasma and found to be active in suppressing FSH release in vitro and in vivo. In order to determine if smaller fragments of this 92 amino acid peptide would still be active to suppress FSH release, we have evaluated 5 of these fragments for their effects on FSH and LH release in the present study. Five alpha-IB-92 fragments (1-34, 1-46, 35-65, 35-92 and 66-92) were synthesized and injected intravenously (iv) into castrated adult rats (2 days post operation). Only fragments alpha-IB-92-(35-65) and alpha-IB-92-(66-92) significantly lowered plasma FSH, but not LH, at doses of 10 micrograms. These fragments exerted a preferential FSH-suppressing effect, but their activities were less than that of alpha-IB-92. In view of the rapid action of these peptides and the preferential FSH suppressing effect, they could be useful clinically to suppress FSH release. To determine the possible physiologic significance of alpha-IB-92, we injected antiserum raised against alpha-IB-92 into immature male rats and evaluated its effects on FSH and LH release. Normal rabbit serum (NRS) or anti-alpha-IB-92 serum was injected iv through indwelling jugular catheters into conscious, unrestrained 18 day-old male rats. Blood samples (0.2 ml) were collected at various intervals. Intravenous injection of alpha-IB-92 antiserum (0.1 ml/rat) selectively elevated plasma levels of FSH but not LH from 2-8 h post-injection in 18 day-old male rats (P < 0.01). Since immunoneutralization of alpha-IB-92 significantly elevated FSH release in immature rats, alpha-IB-92 has a physiological inhibiting role in control of FSH but not LH release at this stage of development.
Animals↗
Determination of the structural requirements for the inhibitory action of gastrin-releasing peptide on growth hormone release.
We have previously determined that gastrin-releasing peptide (GRP) suppresses plasma growth hormone (GH) levels and blocks the response to growth hormone releasing factor (GRF) following its injection into the third ventricle (3V) of conscious male rats. To determine the portion of the peptide required for this action, fragments of the peptide were injected at various doses to determine their effect on plasma growth hormone and the response to a test dose of GRF (1 microgram/kg IV). The GRP 1-16 lowered plasma GH and blocked the response to GRF following an intraventricular injection of 2 micrograms but not 0.2 microgram of the peptide. Carboxy-terminal fragments were more effective. AcGRP20-27 was partially effective at a 100 times lower dose of 2.0 ng, a result similar to that obtained with the related peptide, bombesin. Even the C-terminal heptapeptide AcGRP-27 was effective at a dose of 2 ng. The results indicate that the C-terminal heptapeptide is the minimal requirement for intraventricularly injected GRP to suppress plasma GH levels and block the response to GRF.
Amino Acid Sequence↗
Nitric oxide mediates the stimulation of luteinizing-hormone releasing hormone release induced by glutamic acid in vitro.
Previous experiments from our laboratory have indicated that LHRH release is controlled in vivo and in vitro by NO. Since glutamic acid, the major excitatory transmitter in the brain, has been shown to release LHRH, we wished to determine whether or not this LHRH release was mediated by NO. Consequently, arcuate-median eminence explants from normal male rats were incubated in vitro in Krebs-Ringer bicarbonate glucose (KRBG) media in a Dubnoff metabolic shaker for a preincubation period of 30 min. Fresh media were added containing the substances to be tested and incubation was continued for 30 min. Sodium nitroprusside (NP, 500 microM), which releases NO spontaneously, stimulated the release of LHRH, which indicates that NO can release LHRH. Glutamic acid (10 mM) also produced a robust release of LHRH, and this release was blocked by the inhibitor of NO synthase, NG-monomethyl-L-arginine (NMMA). Furthermore, the release of LHRH induced by glutamic acid was prevented by the addition of hemoglobin (20 micrograms/ml), a scavenger of NO, which would remove the NO released by the action of glutamic acid. The results indicate that glutamic acid stimulated LHRH release is induced by NO.
Amino Acid Oxidoreductases↗
Induction by cytokines of the pattern of pituitary hormone secretion in infection.
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Animals↗
Cyclosporin A inhibits interleukin-2-induced release of corticotropin-releasing hormone.
Cyclosporin A (CSA), a potent immunosuppressive drug, has recently been shown to bind with high affinity to the immunophilin, cyclophilin. Calcineurin, the calcium-dependent protein phosphatase, binds the cyclophilin/CSA complex, rendering it inactive and blocking dephosphorylation of phosphoproteins. Very high concentrations of cyclophilin have been reported in the brain with a localization identical to that of calcineurin. We have reported that interleukin-2 (IL-2) releases corticotropin-releasing hormone (CRH) by generation of nitric oxide (NO). Nitric oxide synthase (NOS), the enzyme in nitric oxidergic neurons that converts arginine into citrulline plus NO, is inactive in the phosphorylated state. We hypothesized that cyclosporin might therefore inhibit IL-2-induced acute CRH release by blocking the dephosphorylation of NOS by calcineurin. Consequently, we examined the effect of CSA on the release of CRH from mediobasal hypothalami (MBH) in vitro in 'basal' conditions and in the presence of IL-2, which we had previously shown to stimulate CRH release acutely in this preparation. Incubation of MBH for 30 min with IL-2 (10(-13) M), the concentration that was most effective in previous experiments, evoked a significant release of CRH. CSA at 10(-6) or 10(-8) M did not alter basal release of CRH; however, addition of either concentration completely blocked the IL-2-induced release of CRH. This acute action of CSA within the brain is probably mediated by blockade of the dephosphorylation of NOS by calcineurin.
Animals↗
Blockade by interleukin-1-alpha of nitricoxidergic control of luteinizing hormone-releasing hormone release in vivo and in vitro.
Nitric oxide (NO) synthase (NOS), the enzyme that converts arginine into citrulline plus NO, the latter a highly active free radical, occurs in a large number of neurons in the brain, including certain neurons in the hypothalamus. Our previous experiments have shown that norepinephrine (NE)-induced prostaglandin E2 (PGE2) release from medial basal hypothalamic explants (MBH) is mediated by NO. Because release of luteinizing hormone (LH)-releasing hormone (LHRH) is also driven by NE and PGE2, we hypothesized that NO controls pulsatile release of LHRH in vivo, which in turn induces pulsatile LH release. Indeed, in vivo and in vitro experiments using an inhibitor of NOS (NG-monomethyl-L-arginine; NMMA) demonstrated that pulsatile LH release is mediated by NO; LHRH release in vitro is also mediated by this free radical. Cytokines that are released from cells of the immune system during infection also inhibit LHRH release. We compared the action of one such cytokine, interleukin-1 alpha (IL-1 alpha), on LHRH release with that of substances which inhibit or induce NO release. Microinjection of IL-1 alpha (0.06 pmol in 2 microliters) into the third cerebral ventricle (3V) of conscious, castrated male rats had an action similar to that of 3V microinjection of NMMA (1 mg in 5 microliters): it blocked pulsatile LH, but not follicle-stimulating hormone (FSH) release. The only difference between the responses to NMMA and IL-1 alpha was that the latency to onset was greater with IL-1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Physiological significance of neurotensin in pituitary glycoprotein hormone release as revealed by in vivo and in vitro studies with neurotensin antiserum.
The neuropeptide, neurotensin, is localized to neurons within the hypothalamus which project to the median eminence. It is released from the terminals in the median eminence into the hypophyseal portal vessels and is carried to the gland. The content in the pituitary gland cells may be partly related to the delivery of the peptide via the portal vessels, but it also appears to be produced directly in pituitary cells. The peptide has actions on the release of glycoprotein hormones from the pituitary and in the present experiments, we attempted to determine whether these actions of the peptide were physiologically significant by microinjecting purified antiserum directed against neurotensin into the third cerebral ventricle or intravenously into conscious freely moving rats. Blood samples were withdrawn from an indwelling intra-right atrial catheter. In ovariectomized rats with high levels of plasma gonadotropins because of removal of ovarian steroid negative feedback, the intraventricular injection of the higher (3 microliters) dose of neurotensin antiserum (NT-AS) induced a more than 2-fold increase in plasma LH within 2 h which was maintained until 3 h after the injection and returned to basal values in the 4th and 5th hour. The lower 1-microliter dose was ineffective and there was no response to the control normal rabbit serum (NRS) injections into the third ventricle in this and the other experiments.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Hypothalamic control of water and salt intake and excretion.
This article provides a personal and historical review of research concerning the hypothalamic control of water and salt intake and excretion. The following major points will be considered: 1. Electrical, osmotic, cholinergic, alpha-adrenergic and peptidergic stimulation of the hypothalamus. 2. Determination of the pathways involved in these neuroendocrine responses. 3. The participation of ANP in the control of thirst and salt excretion. 4. The participation of the brain ANPergic neuronal system in ANP release. 5. The role of hypothalamic ANPergic neurons and of sinoaortic and renal baroreceptors in the regulation of volume expansion-induced release of ANP. 6. Effects of the brain ANP system on other hormones.
Angiotensin II↗
Role of nitric oxide in the control of luteinizing hormone-releasing hormone release in vivo and in vitro.
Nitric oxide (NO) synthase, the enzyme which converts arginine into citrulline plus NO, a highly active free radical, has been found in many neurons in the brain, including neurons in the hypothalamus. Our previous experiments showed that norepinephrine-induced prostaglandin E2 release from hypothalamic explants incubated in vitro is mediated by NO. Since the release of luteinizing hormone-releasing hormone (LHRH) is also driven by norepinephrine and prostaglandin E2, we hypothesized that NO might also control pulsatile release of LHRH in vivo, resulting in turn in pulsatile release of luteinizing hormone (LH). To ascertain the role of NO in control of pulsatile LH release in vivo, an inhibitor of NO synthase, NG-monomethyl-L-arginine (NMMA), was microinjected into the third cerebral ventricle (1 mg/5 microliters) of conscious castrate male rats at time 0 and 60 min later; blood samples were taken every 10 min during this period. NMMA blocked pulsatile LH release within 20 min, and plasma LH concentration declined further without pulses after the injection at 60 min. Pulsatile release of LH was not altered in diluent-injected controls. NMMA did not alter pulsatile release of follicle-stimulating hormone, which suggests that its release does not require NO. Incubation of medial basal hypothalami with norepinephrine (10 microM) induced an increase in LHRH release that was inhibited by NMMA (300 microM). NMMA alone did not alter basal LHRH release, whereas it was augmented by sodium nitroprusside (100 microM), which releases NO spontaneously. This augmentation was prevented by hemoglobin (2 micrograms/ml), which binds the NO released by nitroprusside. Our previous experiments showed that norepinephrine-induced release of prostaglandin E2 is mediated by NO. Nitric oxidergic neurons were visualized in the median eminence adjacent to the LHRH terminals. The combined in vivo and in vitro results indicate that the pulsatile release of LHRH induced by norepinephrine is brought about by alpha 1-adrenergic activation of NO synthase. NO then induces prostaglandin E2 release that activates exocytosis of LHRH secretory granules into the portal vessels to induce pulsatile LH release.
Amino Acid Oxidoreductases↗
Essential role of hypothalamic muscarinic and alpha-adrenergic receptors in atrial natriuretic peptide release induced by blood volume expansion.
Expansion of the blood volume induces natriuresis, which tends to return the blood volume to normal. This response is mediated at least in part by the release of atrial natriuretic peptide (ANP) into the circulation. Previous experiments have shown the participation of the anterior ventral third ventricular (AV3V) region of the hypothalamus in the ANP release that follows volume expansion. When injected into the AV3V region, the cholinergic drug carbachol induces natriuresis and the release of ANP. In the present experiments, microinjection of norepinephrine into the AV3V region induced natriuresis and an increase in plasma ANP. To determine whether cholinergic and alpha-adrenergic pathways are crucial to the volume expansion-induced release of ANP, certain receptor-blocking drugs were injected into the AV3V region of conscious rats. Thirty minutes later blood volume was expanded by intravenous injection of 2.0 ml/100 g of body weight of hypertonic saline (0.3 M NaCl). Microinjection of isotonic saline (2 microliters) into AV3V region of control animals 30 min prior to volume expansion had no effect on the 3-fold increase in plasma ANP concentrations measured 5 min after volume expansion. In contrast, although the receptor-blocking drugs did not alter the initial concentrations of plasma ANP 30 min later, just prior to volume expansion, blockade of muscarinic cholinergic receptors by intraventricular injection of 5 nmol (2 microliters) of atropine sulfate or methylatropine markedly reduced the response to volume expansion but did not obliterate it. Microinjection of the alpha receptor blocker phentolamine (5 nmol) into the AV3V 30 min prior to volume expansion also markedly suppressed the ANP response. Intraperitoneal (i.p.) injection of methylatropine (0.01 mmol/100 g of body weight), which does not cross the blood-brain barrier, also did not affect the basal levels of ANP 30 min after i.p. injection. But, in striking contrast with the blockade of the response to volume expansion induced by intraventricular injection of methylatropine, the response to volume expansion was markedly enhanced by i.p. injection of methylatropine. The results therefore indicate that hypothalamic muscarinic and alpha-adrenergic synapses are essential to release of ANP in response to volume expansion. These results are consistent with a hypothetical pathway for physiological control of ANP release which involves distension of baroreceptors within the right atria, carotid and aortic sinuses, and kidney which alters afferent input to brain stem noradrenergic neurons with axons projecting to the AV3V region. There they activate cholinergic interneurons by an alpha 1-adrenergic synapse. The cholinergic neurons in turn stimulate ANP neurons in this brain region via muscarinic receptors. The stimulation of these neurons activates efferent pathways which induce the release of ANP.
Animals↗
Insulin-like growth factor I modulates hypothalamic somatostatin through a growth hormone releasing factor increased somatostatin release and messenger ribonucleic acid levels.
Insulin-like growth factor I (IGF-I) has been shown to participate in feedback inhibition of growth hormone (GH) secretion at the level of both the pituitary and hypothalamus. Therefore, we tested the possible involvement of IGF-I on somatostatin (SRIF) and GH-releasing factor (GRF) release in median eminence (ME) fragments and periventricular nucleus (PeN) of male rats. The levels of SRIF messenger ribonucleic acid (mRNA) were also determined in PeN incubated in vitro with IGF-I. The ME's were incubated in Krebs-Ringer bicarbonate glucose buffer in the presence of various concentrations of IGF-I (10(-7) to 10(-11) M) for 30 min. SRIF and GRF released into the medium were quantitated by RIA. The release of SRIF and GRF from the ME's was stimulated significantly (P < 0.025 and P < 0.05, respectively) by 10(-9) M IGF-I. To determine whether the effect of IGF-I on SRIF release is mediated by GRF release in the ME, a specific GRF antibody (ab) (1:500) was used concomitantly with IGF-I (10(-9) M). The release of SRIF induced by IGF-I was blocked by the GRF ab (P < 0.001), but not by normal rabbit serum used at the same dilution. To determine the effect of IGF-I on the regulation of SRIF mRNA levels, SRIF mRNA was determined in PeN explants incubated in the presence of IGF-I (10(-8) to 10(-10) M) for 2 to 6 h. Levels of SRIF mRNA were determined by a S1 nuclease protection assay using a 32P-labelled rat SRIF riboprobe.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Growth hormone increases somatostatin release and messenger ribonucleic acid levels in the rat hypothalamus.
Growth hormone (GH) suppresses its own secretion by stimulating somatostatin (SRIF) release. Thus, the possible regulation of GH-releasing factor (GRF) and SRIF release and SRIF messenger ribonucleic acid (mRNA) by GH was studied in the hypothalamus of male rats in vitro. The median eminences (ME's) were incubated in buffer containing 10(-7)-10(-11) M GH for 30 min. SRIF and GRF released into the medium were quantitated by RIA. The release of SRIF from ME fragments was significantly increased (P < 0.001) by 10(-9) M GH; however, 10(-9) M GH also inhibited (P < 0.01) GRF release from the ME. To determine the effect of GH on SRIF mRNA levels, periventricular nucleus (PeN) explants were cultured during 6 h in medium with 10(-7)-10(-11) M GH. Levels of SRIF mRNA (determined by an S1 nuclease protection assay) were significantly elevated in the presence of 10(-10)-10(-7) M GH. Likewise, 10(-9) M GH significantly stimulated SRIF release from PeN explants at 30 min and at 6 h. Surprisingly, 10(-9) M GH also significantly increased GRF release from the PeN explants at these times as well. This GRF was not responsible for the increased SRIF release or SRIF mRNA induced by GH since GRF antibody did not modify the GH-induced increases in SRIF release and mRNA levels. These results demonstrate a negative short-loop feedback of GH mediated at the ME by suppression of GRF and stimulation of SRIF release, whereas in the PeN GH increased both SRIF release and SRIF mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗