Short-loop Feedback Mechanism Research Articles

The macula densa prorenin receptor is essential in renin release and blood pressure control.

The prorenin receptor (PRR) was originally proposed to be a member of the renin-angiotensin system (RAS); however, recent work questioned their association. The present paper describes a functional link between the PRR and RAS in the renal juxtaglomerular apparatus (JGA), a classic anatomical site of the RAS. PRR expression was found in the sensory cells of the JGA, the macula densa (MD), and immunohistochemistry-localized PRR to the MD basolateral cell membrane in mouse, rat, and human kidneys. MD cell PRR activation led to MAP kinase ERK1/2 signaling and stimulation of PGE2 release, the classic pathway of MD-mediated renin release. Exogenous renin or prorenin added to the in vitro microperfused JGA-induced acute renin release, which was inhibited by removing the MD or by the administration of a PRR decoy peptide. To test the function of MD PRR in vivo, we established a new mouse model with inducible conditional knockout (cKO) of the PRR in MD cells based on neural nitric oxide synthase-driven Cre-lox recombination. Deletion of the MD PRR significantly reduced blood pressure and plasma renin. Challenging the RAS by low-salt diet + captopril treatment caused further significant reductions in blood pressure, renal renin, cyclooxygenase-2, and microsomal PGE synthase expression in cKO vs. wild-type mice. These results suggest that the MD PRR is essential in a novel JGA short-loop feedback mechanism, which is integrated within the classic MD mechanism to control renin synthesis and release and to maintain blood pressure.

Prolactin and dopamine: What is the connection? A Review Article

Dopamine (DA) holds a predominant role in the regulation of prolactin (PRL) secretion. Through a direct effect on anterior pituitary lactotrophs, DA inhibits the basally high-secretory tone of the cell. It accomplishes this by binding to D2 receptors expressed on the cell membrane of the lactotroph, activation of which results in a reduction of PRL exocytosis and gene expression by a variety of intracellular signalling mechanisms. The hypothalamic dopaminergic neurons, which provide DA to the anterior pituitary gland, are themselves regulated by feedback from PRL through a 'short-loop feedback mechanism'. A variety of other modulators of prolactin secretion act at the hypothalamic level by either disinhibition of the dopaminergic tone (e.g. serotonin, GABA, oestrogens and opioids) or by reinforcing it (e.g. substance P). All typical antipsychotic medications are associated with sustained hyperprolactinaemia due to their high affinity for the D2 receptor and their slow dissociation from the receptor once bound, but atypicals differ quite dramatically in their propensity to cause prolonged high prolactin levels. Of those atypicals that are associated with prolactin elevation, the main causative factor appears to be a higher peripheral-to-central dopamine receptor potency of either the parent drug or its active metabolite (e.g. risperidone, 9-hydroxy-risperidone and amisulpride). Antipsychotics that easily cross the blood-brain barrier and exhibit fast dissociation from the dopamine receptor once bound do not result in sustained hyperprolactinaemia.

Prolactin secretory surge during estrus coincides with increased dopamine activity in the hypothalamus and preoptic area and is not altered by ovariectomy on proestrus

Prolactin (PRL) secretory surges have been reported on the afternoons of both proestrus and estrous in cycling rats. As neuroendocrine regulation of estrous PRL surge is poorly understood, the present study aimed to investigate the involvement of hypothalamic dopamine and serotonin as well as of plasma ovarian steroids in this hormonal surge generation. For that, we determined the concentrations of dopamine, serotonin and their respective metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole-3-acetic acid (5-HIAA) in the mediobasal hypothalamus (MBH) and medial preoptic area (MPOA) throughout the day of estrus and correlated them with plasma PRL levels. In a second study, we evaluated the effect of ovariectomy on the morning of proestrus on PRL surges of both proestrus and estrus. Dopamine turnover, as determined by DOPAC/dopamine ratio, increased in both the MBH and MPOA coinciding with the afternoon PRL surge on estrus. In contrast, both the concentration and turnover (5-HIAA/serotonin) of serotonin within these areas were unaltered during estrus. In addition, ovariectomy reduced plasma estradiol and progesterone levels but did not alter the PRL surges on proestrus and estrus. Considering that dopamine is the main inhibitor of PRL release and that PRL auto-regulates its secretion through a short-loop feedback mechanism, our present results suggest that PRL may suppress its own secretion during the estrus surge through the activation of the dopaminergic neurons in the MBH and MPOA. In addition, the PRL surge on estrus seems do not depend on either the activity of hypothalamic serotonin or the increased secretion of ovarian steroids on proestrus.

Hyperprolactinaemia and the regular menstrual cycle in asymptomatic women: should it be treated during therapy for infertility?

It is known that hyperprolactinaemia can cause galactorrhoea and irregular cycles or even amenorrhoea. High serum prolactin (PRL) can disturb follicular maturation and corpus luteum function. Treatment of hyperprolactinaemia in patients with resulting bleeding anomalies is established, but the question is how to manage normal cyclic hyperprolactinaemic women? Studies have shown that in a subgroup of asymptomatic patients the serum contains mainly high molecular weight form (big big PRL), which has a low bioactivity, called macroprolactinaemia. It is evident that macroprolactin does not affect the control of pituitary PRL secretion via the short loop feedback mechanism or the secretion of gonadotrophins as does monomeric PRL. Identification of macroprolactinaemia is therefore clinically important to prevent unnecessary examinations and inappropriate treatment. Prolactinoma can be associated with macroprolactinaemia. Performance of pituitary imaging in asymptomatic patients with hyperprolactinaemia may therefore be justified, but further studies are needed to evaluate the relation of costs and benefit. An unsolved problem is the differentiation between inactive and PRL-secreting tumours. Caution should be exercised concerning medical treatment in unstimulated patients and also in patients during ovarian stimulation alone or in combination with intrauterine insemination or in-vitro fertilization. The potential clinical significance of hyperprolactinaemia/macroprolactinaemia in asymptomatic women must be further evaluated.

Effect of human chorionic gonadotropin on luteal luteinizing hormone concentrations in natural cycles

Effect of human chorionic gonadotropin on luteal luteinizing hormone concentrations in natural cycles

Does a Short Loop Feedback Mechanism for the Control of Luteinizing Hormone Secretion Exist in the Ewe?

It is not known whether a short loop feedback mechanism for the regulation of LH exists in sheep. This study on ovariectomized ewes investigated whether a bolus injection (10, 1, and 0.1 μg LH or 1μ g BSA; n = 4) or a 3-h continuous infusion of exogenous LH (100 or 1 ng/min; n = 7) into the third ventricle through a permanent indwelling cannula could influence the activity of the GnRH pulse generator, as determined by measurement of endogenous LH secretion. To assess the potential for involvement in a LH short loop feedback system and to estimate the level of LH in the hypothalamic milieu, the concentrations of LH in the peripheral circulation, portal circulation, and third ventricle were measured during an estradiol-induced preovulatory LH surge (n = 4). Neither the bolus nor continuous administration of LH into the third ventricle had any effect on the mean interpulse interval, nadir, pulse amplitude, or circulating level of systemic LH. Furthermore, despite portal LH concentrations being more than 20-fold higher than jugular LH concentrations, LH levels in third ventricular cerebrospinal fluid remained barely detectable and did not reflect dynamic secretory events in the peripheral or hypothalamo-hypophyseal portal blood. These data demonstrate that in ewes, little pituitary LH reaches the third ventricle, and the small amount that does is unable to affect peripheral gonadotropin release. Our study suggests, therefore, that a short loop feedback system for LH does not exist in the ewe.

Molecular cloning, tissue distribution, and expression of the prolactin receptor during various reproductive states in Meleagris gallopavo.

The primary sequence of the prolactin receptor (PRL-R) in turkeys was deduced from a cDNA clone isolated from a kidney cDNA library and from a polymerase chain reaction (PCR) product. The open reading frame of the turkey PRL-R (tPRL-R) predicted an 831-amino acid protein composed of a leader peptide, an extracellular domain, a single transmembrane domain, and an intracellular domain. The extracellular domain contained two homologous repeat units with 63% amino acid sequence identity to each other. Each repeat unit contained all of the conserved cysteine pairs and a WSXWS motif found in mammalian PRL-Rs. A tPRL-R transcript with a molecular size of about 3000 nucleotides was identified by Northern blot analysis. The tPRL-R transcripts were detected in all 26 tissues examined using reverse transcriptase PCR (RT-PCR). The pituitary gland, hypothalamus, crop sac, duodenum, and gizzard were found to express the highest levels of tPRL-R among the 26 tissues. The expression levels of tPRL-R in 17 tissues were compared using semi-quantitative RT-PCR in nonphotostimulated, laying, out-of-lay, incubating, and maternal hens, and male birds. In most tissues examined there was no obvious relationship between blood levels of PRL, reproductive states, and estimated concentrations of the receptor mRNA. In the pituitary gland and hypothalamus, plasma levels of PRL and levels of tPRL-R transcript were inversely correlated. In the hypothalamus, increasing blood levels of PRL were associated with decreasing levels of the receptor transcript (p < or = 0.05), whereas the opposite was observed in the pituitary gland (p < or = 0.05). These findings support the hypothesis that PRL itself may participate in the neuroendocrine control of incubation behavior through actions on both the hypothalamus via a short-loop feedback mechanism and the pituitary gland via autocrine and/or paracrine effects.

Identification of target cells for growth hormone's action in the arcuate nucleus.

Growth hormone (GH) participates in the regulation of its own secretion by acting through a short-loop feedback mechanism to regulate the synthesis and secretion of somatostatin (SS) and growth hormone-releasing hormone (GHRH). The mechanism of GH's action in certain peripheral targets involves the induction of c-fos. Similarly, we hypothesized that GH induces the expression of c-fos mRNA in SS and GHRH neurons in the hypothalamus. Using in situ hybridization, we observed a significant induction of c-fos mRNA in the arcuate nucleus of human GH-treated compared with control animals. Contrary to our hypothesis, only 11% of GHRH mRNA-containing and 5% of SS mRNA-containing neurons colabeled for c-fos mRNA. These findings indicate that GH feedback on the hypothalamus includes the induction of c-fos mRNA primarily in neurons other than GHRH and SS in the arcuate nucleus and suggest that these unidentified neurons located in the arcuate nucleus are directly involved in transducing the effects of GH in the brain.

Estrogen augments hypothalamicβ-endorphin secretion and activates an inhibitoryβ-endorphin short-loop feedback system

The role of estrogen in the regulation of hypothalamicβ-endorphin hormone secretion is studied by determiningβ-endorphin concentration in pituitary portal plasma of ovariectomized rats in the presence or absence of this steroid and/or the opioid antagonist naloxone. Twenty-six hours following s.c. injection of 10 /µg estradiol benzoate (estrogen) or oil, rats anesthetized with Saffan (alphaxolone/alphadolone) underwent pituitary stalk exposure and hypophysectomy, after which pituitary portal blood was continuously collected and stored in 15 min aliquots from 1100-1400 h. At 1100 h, animals were given an initial bolus iv injection of naloxone or saline (naloxone, 2 mg/ kg, or saline, 0.1 ml) and then infused (iv) continuously with naloxone (2 mg/kg/h) or saline (0.8 ml/h) until 1400 h. Plasma samples were extracted and assayed by radioimmunoassay forβ-endorphin. Treatment with estrogen increased the meanβ-endorphin levels twofold as compared to oil-treated controls. Naloxone potentiated estrogen action ofβ-endorphin secretion, but did not affect basalβ-endorphin secretion. These results suggest that estrogen enhancedβ-endorphin secretion from the hypothalamus. Furthermore, the hypersecretion ofβ-endorphin induced by naloxone with, but not without, estrogen supports the existence of an estrogen-activated short-loop negative feedback mechanism regulatingβ-endorphin secretion.

Evidence for short or ultrashort loop negative feedback of gonadotropin-releasing hormone secretion.

The present studies tested the hypothesis that either short or ultrashort loop negative feedback regulation of gonadotropin-releasing hormone (GnRH) secretion occurs in the ewe. As part of ongoing studies investigating the regulation of follicle-stimulating-hormone secretion, we obtained the unexpected result that a GnRH antagonist (Nal-Glu) may stimulate GnRH secretion. In that experiment, hypophyseal portal blood was collected from five short-term ovariectomized ewes at 5-min intervals for 6 h before and 6 h after intravenous injection of Nal-Glu (10 micrograms/kg body weight). An increase in GnRH pulse frequency in association with the blockade of luteinizing hormone (LH) release was evident in 3 of the 5 animals. To determine if an effect of Nal-Glu on episodic GnRH secretion would be more evident in an animal model in which low-frequency pulses of GnRH prevail, the study was repeated in six ewes in the midluteal phase of the estrous cycle and six ovariectomized ewes bearing estradiol and progesterone implants to suppress GnRH release (artificial luteal model). In luteal-phase ewes, administration of Nal-Glu was followed by an increase in GnRH pulse frequency, pulse size and the secretion of GnRH between pulses, and by a blockade of LH release. In ovariectomized ewes treated with estradiol and progesterone, Nal-Glu administration also stimulated GnRH and inhibited LH secretion. Our finding that the GnRH antagonist stimulated GnRH secretion is consistent with the hypothesis that endogenous GnRH may influence its own release via either a short or ultrashort loop feedback mechanism.

Induction of enkephalin in tuberoinfundibular dopaminergic neurons of pregnant, pseudopregnant, lactating and aged female rats.

The tuberoinfundibular dopaminergic (TIDA) neurons projecting to the external zone of the median eminence arise in the dorsomedial and ventrolateral subdivisions of the arcuate nucleus. In cycling female rats these regoins contain only scattered enkephalin-immunoreactive (ENK-i) neurons some of which coexpress dopamine, detected by immunostaining for tyrosine hydroxylase (TH). The present immunocytochemical, in situ hybridization and retrograde-labeling studies show that each TIDA neuron of pregnant, pseudopregnant, lactating, and aged female rats contains ENK-like immunoreactivity and pro-ENK mRNA and projects to the hypophysial portal circulation. Ovariectomy of lactating and aged rats did not change ENK staining within TIDA neurons, suggesting that ovarian steroids do not play a critical role in the colocalization of ENK and dopamine. Since prolactin levels are elevated in each of these experimental animals, a possible role for prolactin in the induction of the ENK gene in TIDA neurons is suggested. Prolactin stimulates dopamine and its own secretion via a short-loop feedback mechanism. The sensitivity of this regulatory mechanism is altered in these experimental animals, resulting in elevated prolactin secretion. ENK, which has prolactin-releasing activity and is colocalized with dopamine, could mediate the positive short-loop feedback regulation and sustain elevated levels of prolactin in pregnant, pseudopregnant, lactating, and aged animals.

Prolactin regulation of pro-opiomelanocortin gene expression in the arcuate nucleus of the rat hypothalamus.

It is well known that the opiate peptides, especially the pro-opiomelanocortin (POMC)-related peptide beta-endorphin, stimulate the release of prolactin (PRL) in the rat. In order to evaluate the involvement of PRL on the activity of POMC neurons in the arcuate nucleus, we have studied the effects of the injection of PRL into the third ventricle of intact and hypophysectomized rats as well as the effects of hyperprolactinemia induced by pituitary implants under the kidney capsule on POMC gene expression. The amounts of POMC mRNA in the arcuate nucleus were measured by in situ hybridization using a [35S]-labelled cDNA probe encoding for POMC. Hypophysectomy performed 2 weeks previously decreased by 24% the number of silver grains/unit of surface of labelled neurons. Intracerebroventricular injection of 3 micrograms of PRL 4 h before sacrifice induced a significant decrease in the hybridization signal of 32 and 20% in the intact and hypophysectomized rat, respectively. Hyperprolactinemia achieved by pituitary implants also led to a significant decrease in POMC mRNA levels. The present data show that hypophysectomy depresses hypothalamic POMC mRNA levels and that this effect is not related to the suppression of PRL secretion since this hormone exerts an inhibitory action on POMC gene expression. They suggest that the regulation of PRL secretion by short loop feedback mechanism might be well mediated by beta-endorphin which has already been shown to inhibit dopaminergic neuron activity in the arcuate nucleus.

Gonadotropin-Releasing Hormone (GnRH) Agonists and GnRH Antagonists Do Not Alter Endogenous GnRH Secretion in Short-Term Castrated Rams

The administration of GnRH agonists and antagonists suppresses pituitary LH secretion. However little is known about their effects on endogenous GnRH secretion. To determine if GnRH analogs act on GnRH secretion through a short or ultrashort loop feedback mechanism, experiments were performed to analyze GnRH secretion in hypophyseal portal blood of conscious short-term castrated rams under both agonist or antagonist treatment. In Study 1, six rams were castrated and surgically prepared for portal blood collection on day -7. Portal and peripheral blood were collected simultaneously every 10 min for 14-15 h on day 0. Five hours after the beginning of the portal blood collection, animals were injected im with 5 mg potent GnRH antagonist (Nal-Glu). In Study 2, six rams were treated daily from day -11 to day 0 with the GnRH agonist D-Trp6 GnRH (0.5 mg im). Castration and surgical preparation for portal blood collection were performed on day -7. On day 0 portal and peripheral blood were collected simultaneously every 10 min for 10-11 h. In both studies, to determine whether an increase in GnRH concentration in hypophyseal portal blood can overcome the inhibitory effect of the GnRH analogs, between 5 and 5.5 h after the injection of the analogs, endogenous GnRH secretion was stimulated by Naloxone administration (3 x 100 mg, iv, at 30-min intervals) followed by a bolus of exogenous GnRH (2 x 10 micrograms, iv at 30-min intervals). In Study 1, Nal-Glu administration led to a rapid cessation of pulsatile LH secretion for the duration of blood collection while GnRH pulse frequency and amplitude were not affected. GnRH and LH pulse frequency before and after Nal-Glu administration were, 6.2 +/- 0.6 vs. 5.7 +/- 0.8 (NS) and 5.3 +/- 0.3 vs. 0.3 +/- 0.2 pulses/6 h (P less than 0.001) respectively. In Study 2, peripheral LH secretion was completely suppressed while GnRH secretion (portal blood) remained pulsatile. GnRH pulses frequency and pulse amplitude were 4.3 +/- 0.3 pulses/6 h and 43.0 +/- 4.7 pg/ml, respectively. In both experiments, neither stimulation of endogenous GnRH secretion by naloxone nor administration of exogenous GnRH allowed reinitiation of LH secretion. However, additional studies in two animals of each treatment group (study-III) showed that this was clearly a dose related effect in antagonist treated but not in agonist-treated animals since higher doses of exogenous GnRH (i.e. 100 micrograms or 1000 micrograms) can increase significantly LH levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Age-Related Loss of the Responsiveness of the Tuberoinfundibular Dopaminergic Neurons to Prolactin in the Female Rat

In the old female rat the previous findings of a sustained reduction of the secretory activity of the hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons associated with a persistent hyperprolactinemia as well as the observation of a failure of the prolactin (PRL) short-loop feedback mechanism have been suggestive of an age-related loss of the responsiveness of the TIDA neurons to the stimulatory action of PRL. Yet the existence of significant impairments in the capacity of the neurons to respond to PRL could not be demonstrated in an earlier study using multiparous old rats in constant estrus compared to young nulliparous estrous rats. In the present study we have readdressed the issue using nulliparous old rats (24-26 months) compared to virgin young rats (4-5 months); two sets of old rats were studied which displayed distinct senile reproductive states, namely persistent diestrus or repetitive pseudopregnancy, and they were compared to young rats in diestrus or in repetitive pseudopregnancy, respectively. The secretory activity of the TIDA neurons was evaluated by measurement of dopamine biosynthesis in the neurons (DOPA accumulation in the median eminence after decarboxylase inhibition) and dopamine release into hypophysial portal blood, and PRL influence on the activity of the TIDA neurons was studied after repeated s.c. administrations of ovine PRL (oPRL) or the solvent vehicle. A reduced activity of the TIDA neurons was observed in both groups of nulliparous aged rats compared to their respective young control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Involvement of the somatostatin and cholinergic systems in the mechanism of growth hormone autofeedback regulation in the rat.

The involvement of the cholinergic system in GH secretion has recently acquired increasing importance. Data have been presented suggesting that in rats the effect of cholinergic modulation on GH secretion takes place through inhibition or stimulation of hypothalamic somatostatin (SRIF) release. To investigate further the significance of cholinergic-SRIF link and its role in the regulation of GH secretion, the action of cholinergic agonist and antagonist drugs in the GH short-loop feedback mechanism mediated by SRIF was investigated. Intracerebroventricular (i.c.v.) infusion of 0.2 or 2.0 micrograms GH/rat into the lateral brain ventricle of adult male rats induced a significant reduction in the GH-releasing hormone (GHRH; 2 micrograms/kg, i.v.)-induced peak GH rise, but only the 2.0 micrograms dose reduced also the GH-integrated area after administration of GHRH. This effect was absent after central administration of 20.0 micrograms GH/rat, due probably to leakage of some GH from the cerebral ventricle into the systemic circulation. Pretreatment with cysteamine (300 mg/kg, s.c.), a known depletor of hypothalamic SRIF, or with anti-SRIF serum (0.5 ml/rat) completely counteracted the lessening of the GH response to GHRH induced by 2.0 micrograms GH injected i.c.v. Similarly, pretreatment with the cholinergic agonist pilocarpine (3 mg/kg, i.v.) completely antagonized the inhibitory effect of central infusion of GH on the GHRH-induced GH response. Atropine (1.0 mg/kg, i.v.), a muscarinic cholinergic antagonist, strikingly inhibited the GHRH-induced GH rise, but when given in combination with i.c.v. infusion of GH there was no additive inhibitory effect.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of hypophysectomy and growth hormone administration on pre-prosomatostatin messenger ribonucleic acid in the periventricular nucleus of the rat hypothalamus.

Physiological evidence suggests that hypothalamic somatostatin (SS) inhibits pituitary GH release and that GH acts through a short-loop feedback mechanism to stimulate SS secretion. The feedback action of GH could be mediated by an effect on SS synthesis, secretion, or both. We hypothesized that GH acts to regulate the expression of the SS gene and that changes in the level of circulating GH would result in corresponding changes in SS mRNA in cells of the periventricular nucleus (PeN) of the hypothalamus. To test this hypothesis we measured the effect of hypophysectomy (HPX) and HPX with bovine GH (bGH) replacement on SS mRNA signal levels in cells of the PeN of the rat brain. We report that HPX male rats treated with bGH have significantly higher PeN SS mRNA signal than their vehicle-treated controls (P less than 0.05) and that bGH administration to sham-HPX rats results in elevated PeN SS mRNA signal levels compared to those in sham-HPX rats treated with vehicle (P less than 0.05). These observations suggest that GH participates in the regulation of its own secretion by influencing the expression of the SS gene and that one mechanism of short-loop pituitary feedback may involve the modulation of neuropeptide gene expression.

Inhibitory effect of adrenocorticotropin on corticotropin- releasing factor release from rat hypothalamus in vitro.

Effects of ACTH and ACTH fragments on immunoreactive corticotropin-releasing factor (I-CRF) release were examined by utilizing rat hypothalamic perifusion system and a rat CRF RIA. ACTH-(1-39) had a dose-related inhibitory effect on I-CRF release. Mean percent inhibition of I-CRF release was 52, 55, 49, 30 and less than 5 percent by ACTH-(1-39), ACTH-(1-24), alpha-MSH and ACTH-(18-39) at 2.2 nM concentrations, respectively. These results suggest the presence of a negative short-loop feedback mechanism, and also that the active core is contained within the ACTH-(1-17) structure.

Enhancement of adrenal cortisol secretion after intravenous high dose dexamethasone.

To assess the possible existence of a short loop feedback mechanism of direct glucocorticoid suppression on the adrenal glands, we performed a series of tests employing insulin hypoglycemia or ACTH infusions to obtain adrenal stimulation by ACTH levels that remained within the physiological range. Although the rapidity of glucocorticoid suppression of the pituitary thwarted efforts to use endogenous ACTH as a stimulus, we were able to mimic the stressed state by very low dose ACTH infusions (0.05 microgram/kg BW). No inhibition of cortisol secretion in response to ACTH infusions was detected in tests done after administration of dexamethasone compared to placebo [mean integrated response, 29.37 +/- 1.91 (+/- SE) vs. 29.12 +/- 1.12 microgram . h/dl, respectively]. Furthermore, when high doses of dexamethasone were administered iv, a small paradoxical increase in cortisol secretion was found (33.82 +/- 1.44 microgram . h/dl) without a difference in ACTH levels. These data do not support the concept of significant direct glucocorticoid inhibition of adrenal secretion. Non-ACTH factors that may enhance cortisol secretion in the presence of ACTH may exist.

Effect of hypophysectomy and subsequent prolactin administration on hypothalamic 5-hydroxytryptamine synthesis in ovariectomized rats.

Increased levels of PRL whether of natural or experimentally induced cause result in an increased turnover of the putative PRL-inhibiting factor dopamine (DA) within tuberoinfundibular neurons, suggesting that PRL can regulate its own release via a short loop feedback mechanism. Although it is known that activation of the hypothalamic 5-hydroxytryptamine (5HT) system stimulates PRL release, the possibility that PRL could alter metabolism or release of this amine within the hypothalamus has not been examined. In the first experiment, bilaterally ovariectomized adult Sprague-Dawley rats were divided into three groups: hypophysectomized rats (HYPOX), HYPOX rats injected sc with 0.5 mg kg-1 ovine PRL (oPRL) at 1000 h and 1800 h on the day before killing the rats (HYPOX + PRL), and rats without further surgical manipulation (controls: NON-HYPOX). Three weeks after surgical manipulation, the rats were injected iv with 100 mg kg-1 NSD-1015 and killed 15 or 30 min later. 5-Hydroxytryptophan accumulation was measured by HPLC with electrochemical detection as an index for the rate of 5HT synthesis. The rate of 5HT synthesis was increased in the median eminence (ME) and mediobasal hypothalamus (MBH) but not anterior hypothalamus of HYPOX rats in comparison to the rate of synthesis of this amine in these areas of control rats. This effect was reversed in the ME and MBH of HYPOX + PRL rats. If 5HT stimulation of PRL release were achieved by 5HT inhibition of the tuberoinfundibular DA system as has been proposed previously, then it is also conceivable that the PRL short loop feedback on hypothalamic 5HT synthesis as suggested by the results of the first experiment is mediated via this DA system. To test this hypothesis in the second experiment, adult Sprague-Dawley rats were injected at 1000 h and 1800 h on the day before their killing with 0.5 mg kg-1 oPRL; 0.5 mg kg-1 oPRL, and 10 mg kg-1 pimozide (PIM) a DA receptor antagonist; 10 mg kg-1 PIM; or, on the day of their killing, with 1 mg kg-1 apomorphine (APO), a DA receptor agonist. An additional group of ovariectomized-HYPOX as well as a group of ovariectomized-NON-HYPOX rats were also included in this experiment. On the day of the experiment the rats were injected iv with 100 mg kg-1 NSD-1015 and killed 30 min later. 5-Hydroxytryptophan accumulation was measured by HPLC with electrochemical detection as an index of the rate of 5HT synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Inhibition of captopril-induced increase in plasma renin activity by propranolol.

The inhibition of renin release by angiotensin II (AII) is well documented. However, the interaction of this short loop feedback mechanism of AII with the sympathetic nervous system is still unclear. This study was designed to investigate the possible functional relationship between AII and the beta-adrenergic receptors with respect to renin release in vivo. First, the effect of propranolol on captopril-induced renin release was examined in conscious rats. Secondly, the effect of AII on isoproterenol-induced renin release was determined. Captopril (1 mg/Kg) increased plasma renin activity (PRA) from 1.6 +/- 0.3 ng/ml/hr to 4.5 +/- 0.6 ng/ml/hr (p less than 0.01). In contrast, there was no significant change in PRA in rats which received both captopril and propranolol (before 0.9 +/- 0.2 ng/ml/hr, after 1.3 +/- 0.3 ng/ml/hr). Thus, propranolol attenuated the increase in PRA caused by captopril. Isoproterenol infusion (0.1 micrograms/Kg/min) provoked a significant increase in PRA (before 1.3 +/- 0.4 ng/ml/hr, after 6.6 +/- 1.7 ng/ml/hr, p less than 0.01). AII infusion in combination with isoproterenol also increased PRA from 1.6 +/- 0.4 ng/ml/hr to 5.2 +/- 0.3 ng/ml/hr (p less than 0.01). AII in this dose did not suppress isoproterenol-induced renin release. These results suggest that the beta-adrenergic receptor mediating renin release is functionally located distal to the AII receptor in the short loop mechanism controlling renin release.