Biomedical subjects

S M McCann

Publications and source records attributed to S M McCann.

At least 55 records · Page 3Linked to original sources

PubMed2000

Control of salivary secretion by nitric oxide and its role in neuroimmunomodulation.

In many in vivo systems exposure to endotoxins (LPS) leads to the co-induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), which is important to the regulation of the function of different systems during infection. In submandibular glands (SMG) neural (n)NOS is localized in neural terminals and in striated, granular convoluted and excretory ducts, endothelial (e)NOS in vascular endothelium and ducts, and iNOS in macrophages and in tubules and ducts. In normal adult male rats, injection of an inhibitor of NOS decreased the stimulated salivary secretion and a donor of NO potentiated it, indicating that NO exerts a stimulatory role. A single high dose of LPS (5 mg/kg, i.p.) induced an increase in NOS activity measured by the 14C-citrulline method, increased PGE content almost 100% as measured by RIA, and blocked stimulated salivary secretion. The administration of a specific iNOS inhibitor, aminoguanidine (AG), with LPS not only decreased NOS activity but significantly decreased PGE content, indicating that NO triggered the activation of COX-2. LPS increased conversion of labeled arachidonate to prostaglandins (PGs) showing that COX was induced. Since a PGE1 analogue blocked stimulated salivation, the LPS-induced inhibition of salivation is probably due to release of PGs. Therefore, the use of inhibitors of iNOS and COX-2 could be very useful to increase salivation during infection since saliva has antimicrobial actions.

Animals↗

PubMed2000

Methylene blue inhibits the increase of inducible nitric oxide synthase activity induced by stress and lipopolysaccharide in the medial basal hypothalamus of rats.

In infection bacterial products such as lipopolysaccharides (LPS) induce inducible nitric oxide synthase (iNOS) that produces large quantities of NO toxic to the invading organisms, but also often has toxic effects on host cells. Therefore, inhibition of iNOS activity might be beneficial in combatting these adverse effects. To determine if methylene blue (MB), an oxidizing agent that inactivates iNOS, would reduce the iNOS levels in the medial basal hypothalami (MBH) of conscious male rats, LPS (5 mg/kg) was injected intravenously (i.v.), and after 3 h they were injected i.v. with either MB (3 mg/kg) or saline and the effects on iNOS in the MBH determined. iNOS was measured by conversion of labeled arginine into citrulline by incubating MBH in the absence of calcium (Ca(2+)) since iNOS does not require Ca(2+) for activation. The results indicate that iNOS was induced by the injection of saline, but the induction by LPS was much greater, an increase of 10-fold above that of control sham-operated animals. Both the induction of iNOS from the stress of saline injections and LPS were completely eliminated by MB indicating that MB might be beneficial in preventing injury to brain tissue following LPS injection. There was no effect of either LPS or MB on the Ca(2+)-dependent constitutive NOS activity.

Animals↗

PubMed2000

Oxytocin is a cardiovascular hormone.

Oxytocin (OT), a nonapeptide, was the first hormone to have its biological activities established and chemical structure determined. It was believed that OT is released from hypothalamic nerve terminals of the posterior hypophysis into the circulation where it stimulates uterine contractions during parturition, and milk ejection during lactation. However, equivalent concentrations of OT were found in the male hypophysis, and similar stimuli of OT release were determined for both sexes, suggesting other physiological functions. Indeed, recent studies indicate that OT is involved in cognition, tolerance, adaptation and complex sexual and maternal behaviour, as well as in the regulation of cardiovascular functions. It has long been known that OT induces natriuresis and causes a fall in mean arterial pressure, both after acute and chronic treatment, but the mechanism was not clear. The discovery of the natriuretic family shed new light on this matter. Atrial natriuretic peptide (ANP), a potent natriuretic and vasorelaxant hormone, originally isolated from rat atria, has been found at other sites, including the brain. Blood volume expansion causes ANP release that is believed to be important in the induction of natriuresis and diuresis, which in turn act to reduce the increase in blood volume. Neurohypophysectomy totally abolishes the ANP response to volume expansion. This indicates that one of the major hypophyseal peptides is responsible for ANP release. The role of ANP in OT-induced natriuresis was evaluated, and we hypothesized that the cardio-renal effects of OT are mediated by the release of ANP from the heart. To support this hypothesis, we have demonstrated the presence and synthesis of OT receptors in all heart compartments and the vasculature. The functionality of these receptors has been established by the ability of OT to induce ANP release from perfused heart or atrial slices. Furthermore, we have shown that the heart and large vessels like the aorta and vena cava are sites of OT synthesis. Therefore, locally produced OT may have important regulatory functions within the heart and vascular beds. Such functions may include slowing down of the heart or the regulation of local vascular tone.

Animals↗

PubMed2000

Role of the hypothalamic pituitary adrenal axis in the control of the response to stress and infection.

The release of adrenocorticotropin (ACTH) from the corticotrophs is controlled principally by vasopressin and corticotropin-releasing hormone (CRH). Oxytocin may augment the release of ACTH under certain conditions, whereas atrial natriuretic peptide acts as a corticotropin release-inhibiting factor to inhibit ACTH release by direct action on the pituitary. Glucocorticoids act on their receptors within the hypothalamus and anterior pituitary gland to suppress the release of vasopressin and CRH and the release of ACTH in response to these neuropeptides. CRH neurons in the paraventricular nucleus also project to the cerebral cortex and subcortical regions and to the locus ceruleus (LC) in the brain stem. Cortical influences via the limbic system and possibly the LC augment CRH release during emotional stress, whereas peripheral input by pain and other sensory impulses to the LC causes stimulation of the noradrenergic neurons located there that project their axons to the CRH neurons stimulating them by alpha-adrenergic receptors. A muscarinic cholinergic receptor is interposed between the alpha-receptors and nitric oxidergic interneurons which release nitric oxide that activates CRH release by activation of cyclic guanosine monophosphate, cyclooxygenase, lipoxygenase and epoxygenase. Vasopressin release during stress may be similarly mediated. Vasopressin augments the release of CRH from the hypothalamus and also augments the action of CRH on the pituitary. CRH exerts a positive ultrashort loop feedback to stimulate its own release during stress, possibly by stimulating the LC noradrenergic neurons whose axons project to the paraventricular nucleus to augment the release of CRH.

Adrenocorticotropic Hormone↗

PubMed1999

Locus ceruleus lesions block pulsatile LH release in ovariectomized rats.

Luteinizing hormone (LH) secretion during the reproductive cycle and in ovariectomized (OVX) rats is pulsatile and this pattern of secretion is determined by intermittent discharges of LH-releasing hormone (LHRH) into the hypophysial portal vessels. LHRH secretion is probably controlled by prior pulsatile norepinephrine (NE) release. The locus ceruleus (LC) is an important source of NE to the LHRH neurons. We have shown previously that LC lesions block the preovulatory LH surge and ovulation and also cause a decrease in plasma LH concentrations in OVX rats. The possible role of the LC in regulating pulsatile LH release has not been explored. Therefore, the aim of this work was to investigate, in OVX rats, the effects of LC lesions on pulsatile LH secretion. LC lesions were produced in adult female rats three weeks after OVX. On the next morning, the jugular vein was catheterized and, on the afternoon of the same day, blood samples (0.3 ml) were withdrawn every 5 min, during 90 min, from conscious freely moving rats. Plasma LH was measured by radioimmunoassay. LC lesions greatly suppressed pulsatile LH secretion by decreasing both LH pulse frequency and amplitude. The basal as well as total secretion of LH were also decreased. This inhibitory effect of the lesions was observed only when at least 50% of the nucleus was destroyed. Data from sham-operated animals as well as those with less than 50% destruction of the LC did not differ from those of the control rats without brain lesions. Since LC lesions induce a decrease in NE content in the preoptic area and median eminence, the inhibition of pulsatile LH release in ovariectomized rats with LC lesions occurs presumably as result of decreased pulsatile NE release into these areas of the brain that decreases both the frequency and the amount of LHRH released per pulse.

Animals↗

PubMed1999

beta-Endorphin blocks luteinizing hormone-releasing hormone release by inhibiting the nitricoxidergic pathway controlling its release.

beta-Endorphin blocks release of luteinizing hormone (LH)-releasing hormone (LHRH) into the hypophyseal portal vessels by stimulating mu-opiate receptors, thereby inhibiting secretion of LH. LHRH release is controlled by release of nitric oxide from nitricoxidergic (NOergic) neurons in the basal tuberal hypothalamus. To determine whether beta-endorphin exerts its inhibitory action on this NOergic pathway, medial basal hypothalami (MBH) from male rats were incubated with beta-endorphin (10(-8) M). beta-Endorphin decreased basal secretion of LHRH, and significantly inhibited the release of prostaglandin E2 (PGE2), a known stimulant of LHRH release. Incubation of MBH with beta-endorphin at various concentrations (10(-9)-10(-6) M) in vitro decreased the activity of NO synthase (NOS) (measured by the conversion of [14C]arginine to labeled citrulline). Conversely, the activity of NOS was increased by the mu-receptor antagonist, naltrexone (10(-8) M). Not only was the inhibitory action of beta-endorphin on LHRH and PGE2 release blocked by naltrexone (10(-8) M), but it increased NOS activity and LHRH and PGE2 release. beta-Endorphin also stimulated gamma-aminobutyric acid (GABA) release. Because GABA inhibits both nitroprusside (NP-induced PGE2 and LHRH release by blocking the activation of cyclooxygenase by NO, this is another mechanism by which beta-endorphin inhibits NP-induced PGE2 and LHRH release. The results indicate that beta-endorphin stimulates mu-opioid receptors on NOergic neurons to inhibit the activation and consequent synthesis of NOS in the MBH. beta-Endorphin also blocks the action of NO on PGE2 release and, consequently, on LHRH release, by stimulating GABAergic inhibitory input to LHRH terminals that blocks NO-induced activation of cyclooxygenase and consequent PGE2 secretion.

Animals↗

PubMed1999

Atrial natriuretic peptide and oxytocin induce natriuresis by release of cGMP.

Our hypothesis is that oxytocin (OT) causes natriuresis by activation of renal NO synthase that releases NO followed by cGMP that mediates the natriuresis. To test this hypothesis, an inhibitor of NO synthase, L-nitroarginine methyl ester (NAME), was injected into male rats. Blockade of NO release by NAME had no effect on natriuresis induced by atrial natriuretic peptide (ANP). This natriuresis presumably is caused by cGMP because ANP also activates guanylyl cyclase, which synthesizes cGMP from GTP. The 18-fold increase in sodium (Na+) excretion induced by OT (1 microgram) was accompanied by an increase in urinary cGMP and preceded by 20 min a 20-fold increase in NO3- excretion. NAME almost completely inhibited OT-induced natriuresis and increased NO3- excretion; however, when the dose of OT was increased 10-fold, a dose that markedly increases plasma ANP concentrations, NAME only partly inhibited the natriuresis. We conclude that the natriuretic action of OT is caused by a dual action: generation of NO leading to increased cGMP and at higher doses release of ANP that also releases cGMP. OT-induced natriuresis is caused mainly by decreased tubular Na+ reabsorption mediated by cGMP. In contrast to ANP that releases cGMP in the renal vessels and the tubules, OT acts on its receptors on NOergic cells demonstrated in the macula densa and proximal tubules to release cGMP that closes Na+ channels. Both ANP- and OT-induced kaliuresis also appear to be mediated by cGMP. We conclude that cGMP mediates natriuresis and kaliuresis induced by both ANP and OT.

Animals↗

PubMed1999

Localization of immunoreactive lamprey gonadotropin-releasing hormone in the rat brain.

A highly specific antiserum against lamprey gonadotropin-releasing hormone (GnRH) was used to localize 1-GnRH in areas of the rat brain associated with reproductive function. Immunoreactive 1-GnRH-like neurons were observed in the ventromedial preoptic area (POA), the region of the diagonal band of Broca and the organum vasculosum lamina terminalis, with fiber projections to the rostral wall of the third ventricle and the organum vasculosum lamina terminalis. Another population of 1-GnRH-like neurons was localized in the dorsomedial and lateral POA, with nerve fibers projecting caudally and ventrally to terminate in the external layer of the median eminence. Other fibers apparently projected caudally and circumventrically to terminate around the cerebral aqueduct in the mid-brain central gray. By using a highly specific antiserum directed against mammalian luteinizing hormone-releasing hormone (m-LHRH), the localization of the LHRH neuronal system was compared to that of the 1-GnRH system. There were no LHRH neurons in the dorsomedial or the lateral region of the POA that contained the 1-GnRH neurons. As expected, there was a large population of LHRH neurons in the ventromedial POA associated with the diagonal band of Broca and organum vasculosum lamina terminalis. In both of these regions, there were many more LHRH neurons than 1-GnRH neurons and the LHRH neurons extended more dorsally and laterally than the 1-GnRH neurons. The LHRH neurons seemed to project to the median eminence in the same areas as those that were innervated by the 1-GnRH neurons. Absorption studies indicated that 1-GnRH cell bodies were eliminated by adding 1 microg of either 1-GnRH-I or 1-GnRH-III, but not m-LHRH to the antiserum before use. Fibers were largely eliminated by the addition of 1 microg 1-GnRH-III to the antiserum. No chicken GnRH-II neurons or nerve fibers could be visualized by immunostaining. Because the antiserum recognized GnRH-I and GnRH-III equally, we have visualized an 1-GnRH system in rat brain. The results are consistent with the presence of either one or both of these peptides within the rat hypothalamus. Because 1-GnRH-I has only weak nonselective gonadotropin-releasing activity, whereas 1-GnRH-III is a highly selective releaser of follicle-stimulating hormone, and because 1-GnRH neurons are located in areas known to control follicle-stimulating hormone release selectively, our results support the hypothesis that 1-GnRH-III, or a closely related peptide, may be mammalian follicle-stimulating hormone-releasing factor.

Animals↗

PubMed1999

Brain iNOS: current understanding and clinical implications.

Nitric oxide (NO) is a unique informational substance first identified as the endothelium-derived relaxing factor. It is generated by NO synthases and plays a prominent role in controlling a variety of organ functions in the cardiovascular, immune, reproductive and nervous systems. Inducible nitric oxide synthase (iNOS) is not normally present in the brain in youth but it can be detected in the brain after inflammatory, infectious or ischemic damage, as well as in the normal, aging brain. Brain iNOS seems to contribute to the pathophysiology of many diseases that involve the central nervous system, but the role of iNOS appears to go beyond tissue damage. Brain iNOS might be required for adequate repair following injury or damage. The effects of brain iNOS on the balance between damage and repair make this enzyme a promising therapeutic target in human disease.

Animals↗

PubMed1999

Estrogen and leptin have differential effects on FSH and LH release in female rats.

Prior experiments have shown that the adipocyte hormone leptin can advance puberty in mice. We hypothesized that it would also stimulate gonadotrophin secretion in adults. Since the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) is drastically affected by estrogen, we hypothesized that leptin might have different actions dependent on the dose of estrogen. Consequently in these experiments, we tested the effect of injection of leptin into the third cerebral ventricle of ovariectomized animals injected with either the oil diluent, 10 microg or 50 microg of estradiol benzoate 72 hr prior to the experiment. The animals were ovariectomized 3-4 weeks prior to implantation of a cannula into the third ventricle 1 week before the experiments. The day after implantation of an external jugular catheter, blood samples (0. 3 ml) were collected just before and every 10 min for 2 hr after 3V injection of 5 microl of diluent or 10 microg of leptin. Both doses of estradiol benzoate equally decreased plasma LH concentrations and pulse amplitude, but there was a graded decrease in pulse frequency. In contrast, only the 50-microg dose of estradiol benzoate significantly decreased mean plasma FSH concentrations without significantly changing other parameters of FSH release. The number of LH pulses alone and pulses of both hormones together decreased as the dose of estrogen was increased, whereas the number of pulses of FSH alone significantly increased with the higher dose of estradiol benzoate, demonstrating differential control of LH and FSH secretion by estrogen, consistent with alterations in release of luteinizing hormone releasing hormone (LHRH) and the putative FSH-releasing factor (FSHRF), respectively. The effects of intraventricularly injected leptin were drastically altered by increasing doses of estradiol benzoate. There was no significant effect of intraventricular injection of leptin (10 microg) on the various parameters of either FSH or LH secretion in ovariectomized, oil-injected rats, whereas in those injected with 10 microg of estradiol benzoate there was an increase in the first hr in mean plasma concentration, area under the curve, pulse amplitude, and maximum increase of LH above the starting value (Deltamax) on comparison with the results in the diluent-injected animals in which there was no alteration of these parameters during the 2 hr following injection. The pattern of FSH release was opposite to that of LH and had a different time-course. In the diluent-injected animals, probably because of the stress of injection and frequent blood sampling, there was an initial significant decline in plasma FSH at 20 min after injection, followed by a progressive increase with a significant elevation above the control values at 110 and 120 min. In the leptin-injected animals, mean plasma FSH was nearly constant during the entire experiment, coupled with a significant decrease below values in diluent-injected rats, beginning at 30 min after injection and progressing to a maximal difference at 120 min. Area under the curve, pulse amplitude, and Deltamax of FSH was also decreased in the second hour compared to values in diluent-injected rats. In contrast to the stimulatory effects of intraventricular injection of leptin on pulsatile LH release manifest during the first hour after injection, there was a diametrically opposite, delayed significant decrease in pulsatile FSH release. This differential effect of leptin on FSH and LH release was consistent with differential effects of leptin on LHRH and FSHRF release. Finally, the higher dose of E2 (50 microg) suppressed release of both FSH and LH, but there was little effect of leptin under these conditions, the only effect being a slight (P < 0.04) increase in pulse amplitude of LH in this group of rats. The results indicate that the central effects of leptin on gonadotropin release are strongly dependent on plasma estradiol levels. These effects are consistent w

Activity Cycles↗

PubMed1999

Median eminence lesions reveal separate hypothalamic control of pulsatile follicle-stimulating hormone and luteinizing hormone release.

The effects of hypothalamic lesions designed to destroy either the anterior median eminence (ME) or the posterior and mid-ME on pulsatile release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were determined in castrated male rats. In sham-operated animals, mean plasma FSH concentrations rose to peak at 10 min after the onset of sampling, whereas LH declined to a nadir during this time. In the final sample at 120 min, the mean FSH concentrations peaked as LH decreased to its minimal value. In rats with anterior ME lesions, there was suppression of LH pulses with continuing FSH pulses in 12 of 21 rats. On the other hand, in animals with posterior to mid-ME lesions, 3 out of 21 rats had elimination of FSH pulses, whereas LH pulses were maintained. Fifteen of 42 operated rats had complete ME lesions, and pulses of both hormones were abolished. The remaining 12 rats had partial ME lesions that produced a partial block of the release of both hormones. The results support the concept of separate hypothalamic control of FSH and LH release with the axons of the putative FSH-releasing factor (FSHRF) neuronal system terminating primarily in the mid- to caudal ME, whereas those of the LHRH neuronal system terminate in the anterior and mid-median eminence. We hypothesize that pulses of FSH alone are mediated by release of the FSHRF into the hypophyseal portal vessels, whereas those of LH alone are mediated by LHRH. Pulses of both gonadotropins simultaneously may be mediated by pulses of both releasing hormones simultaneously. Alternatively, relatively large pulses of LHRH alone may account for simultaneous pulses of both gonadotropins since LHRH has intrinsic FSH-releasing activity.

Animals↗

PubMed1999

Possible involvement of A1 receptors in the inhibition of gonadotropin secretion induced by adenosine in rat hemipituitaries in vitro.

We investigated the participation of A1 or A2 receptors in the gonadotrope and their role in the regulation of LH and FSH secretion in adult rat hemipituitary preparations, using adenosine analogues. A dose-dependent inhibition of LH and FSH secretion was observed after the administration of graded doses of the R-isomer of phenylisopropyladenosine (R-PIA; 1 nM, 10 nM, 100 nM, 1 microM and 10 microM). The effect of R-PIA (10 nM) was blocked by the addition of 8-cyclopentyltheophylline (CPT), a selective A1 adenosine receptor antagonist, at the dose of 1 microM. The addition of an A2 receptor-specific agonist, 5-N-methylcarboxamidoadenosine (MECA), at the doses of 1 nM to 1 microM had no significant effect on LH or FSH secretion, suggesting the absence of this receptor subtype in the gonadotrope. However, a sharp inhibition of the basal secretion of these gonadotropins was observed after the administration of 10 microM MECA. This effect mimicked the inhibition induced by R-PIA, supporting the hypothesis of the presence of A1 receptors in the gonadotrope. R-PIA (1 nM to 1 microM) also inhibited the secretion of LH and FSH induced by phospholipase C (0.5 IU/ml) in a dose-dependent manner. These results suggest the presence of A1 receptors and the absence of A2 receptors in the gonadotrope. It is possible that the inhibition of LH and FSH secretion resulting from the activation of A1 receptors may have occurred independently of the increase in membrane phosphoinositide synthesis.

Adenosine↗

PubMed1999

The role of nitric oxide in reproduction.

Nitric oxide (NO) plays a crucial role in reproduction at every level in the organism. In the brain, it activates the release of luteinizing hormone-releasing hormone (LHRH). The axons of the LHRH neurons project to the mating centers in the brain stem and by afferent pathways evoke the lordosis reflex in female rats. In males, there is activation of NOergic terminals that release NO in the corpora cavernosa penis to induce erection by generation of cyclic guanosine monophosphate (cGMP). NO also activates the release of LHRH which reaches the pituitary and activates the release of gonadotropins by activating neural NO synthase (nNOS) in the pituitary gland. In the gonad, NO plays an important role in inducing ovulation and in causing luteolysis, whereas in the reproductive tract, it relaxes uterine muscle via cGMP and constricts it via prostaglandins (PG).

Animals↗

PubMed1998

Rat heart: a site of oxytocin production and action.

We report here that the rat heart is a site of oxytocin (OT) synthesis and release. Oxytocin was detected in all four chambers of the heart. The highest OT concentration was in the right atrium (2128 +/- 114 pg/mg protein), which was 19-fold higher than in rat uterus but 3.3-fold lower than in the hypothalamus. OT concentrations were significantly greater in the right and left atria than in the corresponding ventricles. Furthermore, OT was released into the effluent of isolated, perfused rat heart (34.5 +/- 4.7 pg/min) and into the medium of cultured atrial myocytes. Reverse-phase HPLC purification of the heart extracts and heart perfusates revealed a main peak identical with the retention time of synthetic OT. Southern blots of reverse transcription-PCR products from rat heart revealed gene expression of specific OT mRNA. OT immunostaining likewise was found in atrial myocytes and fibroblasts, and the intensity of positive stains from OT receptors paralleled the atrial natriuretic peptide stores. Our findings suggest that heart OT is structurally identical, and therefore derived from, the same gene as the OT that is primarily found in the hypothalamus. Thus, the heart synthesizes and processes a biologically active form of OT. The presence of OT and OT receptor in all of the heart's chambers suggests an autocrine and/or paracrine role for the peptide. Our finding of abundant OT receptor in atrial myocytes supports our hypothesis that OT, directly and/or via atrial natriuretic peptide release, can regulate the force of cardiac contraction.

Animals↗

PubMed1998

Adenosine acts by A1 receptors to stimulate release of prolactin from anterior-pituitaries in vitro.

Adenosine has been identified in the anterior pituitary gland and is secreted from cultured folliculostellate (FS) cells. To determine whether adenosine controls the secretion of anterior pituitary hormones in vitro, adenosine was incubated with anterior pituitaries. It stimulated prolactin (PRL) release at the lowest concentration used (10(-10) M); the stimulation peaked at 10(-8) M with a threefold increase in release and declined to minimal stimulation at 10(-4) and 10(-3) M. Follicle-stimulating hormone release was maximally inhibited at 10(-8) M, whereas luteinizing hormone release was not significantly inhibited. Two selective A1 adenosine receptor antagonists (10(-7) or 10(-5) M) had no effect on basal PRL release, but either antagonist completely blocked the response to the most effective concentration of adenosine (10(-8) M). In contrast, a highly specific A2 receptor antagonist (10(-7) or 10(-5) M) had no effect on basal PRL release or the stimulation of PRL release induced by adenosine (10(-8) M). We conclude that adenosine acts to stimulate PRL release in vitro by activating A1 receptors. Since the A1 receptors decrease intracellular-free calcium, this would decrease the activation of nitric oxide synthase in the FS cells, resulting in decreased release of nitric oxide (NO). NO inhibits PRL release by activating guanylate cyclase that synthesizes cGMP from GTP; cGMP concentrations increase in the lactotrophs leading to inhibition of PRL release. In the case of adenosine, NO release from the FS cells decreases, resulting in decreased concentrations of NO in the lactotrophs, consequent decreased cGMP formation, and resultant increased PRL release.

Adenosine↗

PubMed1998

Role of nitric oxide in the neuroendocrine responses to cytokines.

During infection, bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause the release of cytokines from immune cells. These cytokines can reach the brain by several routes. Furthermore, cytokines, such as interleukin-1 (IL-1), are induced in neurons within the brain by systemic injection of LPS. These cytokines determine the pattern of hypothalamic-pituitary secretion which characterizes infection. IL-2, by stimulation of cholinergic neurons, activates neural nitric oxide synthase (nNOS). The nitric oxide (NO) released diffuses into corticotropin-releasing hormone (CRH)-secreting neurons and releases CRH. IL-2 also acts in the pituitary to stimulate adrenocorticotropic hormone (ACTH) secretion. On the other hand, IL-1 alpha blocks the NO-induced release of luteinizing hormone-releasing hormone (LHRH) from LHRH neurons, thereby blocking pulsatile LH but not follicle-stimulating hormone (FSH) release and also inhibiting sex behavior that is induced by LHRH. IL-1 alpha and granulocyte macrophage colony-stimulating factor (GMCSF) block the response of the LHRH terminals to NO. The mechanism of action of GMCSF to inhibit LHRH release is as follows. It acts on its receptors on gamma-aminobutyric acid (GABA)ergic neurons to stimulate GABA release. GABA acts on GABAa receptors on the LHRH neuronal terminal to block NOergic stimulation of LHRH release. This concept is supported by blockade of GMCSF-induced suppression of LHRH release from medial basal hypothalamic explants by the GABAa receptor blocker, bicuculline. IL-1 alpha inhibits growth hormone (GH) release by inhibiting GH-releasing hormone (GHRH) release, which is mediated by NO, and stimulating somatostatin release, also mediated by NO. IL-1 alpha-induced stimulation of prolactin release is also mediated by intrahypothalamic action of NO, which inhibits release of the prolactin-inhibiting hormone dopamine. The actions of NO are brought about by its combined activation of guanylate cyclase-liberating cyclic guanosine monophosphate (cGMP) and activation of cyclooxygenase and lipoxygenase with liberation of prostaglandin E2 and leukotrienes, respectively. Thus, NO plays a key role in inducing the changes in release of hypothalamic peptides induced in infection by cytokines. Cytokines, such as IL-1 beta, also act in the anterior pituitary gland, at least in part via induction of inducible NOS. The NO produced inhibits release of anterior pituitary hormones.

Animals↗

PubMed1998

Role of nitric oxide and alcohol on gonadotropin release in vitro and in vivo.

Alcohol suppresses reproduction in humans, monkeys, and small rodents by suppressing release of luteinizing hormone (LH). The major action is on the hypothalamus to decrease release of LH-releasing hormone (LHRH). The release of LHRH is controlled by nitric oxide (NO) as determined by in vivo and in vitro experiments. The hypothesized pathway is via norepinephrine (NE)-induced release of NO from NOergic neurons, which activates LHRH release. We have evaluated details of this process in male rats by incubating medial basal hypothalamic (MBH) explants in vitro and examining the release of NO and metabolites generated by NO that control LHRH release. NE increased release of NO as measured by determining the content of the enzyme at the end of the experiment (30 min) by adding [14C]arginine to the homogenate and measuring its conversion to [14C]citrulline since this is formed in equimolar quantities with NO by NO synthase (NOS). Because this increase in content, presumably caused by activation of the enzyme by NE, was blocked by the alpha 1 receptor blocker prazosin, it appears that alpha 1 receptors activate NOS by increasing intracellular free calcium in the NOergic neurons, which combines with calmodulin to activate NOS. The release of LHRH induced by nitroprusside (NP), a donor of NO, is accompanied by an increase in cyclic guanosine monophosphate (cGMP) in the medium supporting the activation of guanylate cyclase by NO. This activation is important in releasing LHRH since addition of 8-monobutyryl cGMP also released the peptide. Ethanol had no effect on the content of NOS or on the increase in content induced by NE, indicating that it did not act on NOS. Earlier experiments indicated that prostaglandin E2 (PGE2) was important in releasing LHRH. PGE2 is produced by activation of cyclooxygenase by NO since this occurred following addition of the NO donor, NP. Not only does NP increase PGE2 release, but it also increases the conversion of [14C]arachidonic acid to its metabolites, particularly PGE2, by activating cyclooxygenase. NP also activated lipoxygenase as indicated by increased release of leukotrienes, which also stimulate LHRH release. Ethanol acts at this step, because it completely blocked the release of PGE2, leukotrienes, and LHRH induced by NP. Therefore, the results support the theory that NE acts to stimulate NO release from NOergic neurons. This NO diffuses to the LHRH terminals, where it activates guanylate cyclase, leading to an increase in cGMP. At the same time, it also activates cyclooxygenase and lipoxygenase. The increase in cGMP increases intracellular free calcium, required for activation of phospholipase A2. Phospholipase A2 converts membrane phospholipids into arachidonic acid, the substrate for conversion by the activated cyclooxygenase and lipoxygenase to PGE2 and leukotrienes that activate the release of LHRH. Because alcohol inhibits conversion of labeled arachidonic acid to PGE2 and leukotrienes, it must act either directly to inhibit cyclooxygenase and lipoxygenase or by some other mechanism which, in turn, inhibits the enzyme. We initially believed that the action of alcohol was exerted directly on the LHRH terminals; however, our recent experiments indicate that alcohol suppresses LHRH release, at least in part, by stimulating beta-endorphinergic neurons that inhibit the release of NE, which drives the NOergic release of LHRH.

Animals↗

PubMed1998

Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women.

Leptin, an adipocyte hormone, is a trophic factor for the reproductive system; however, it is still unknown whether there is a dynamic relation between fluctuations in circulating leptin and hypothalamic-pituitary-ovarian (HPO) axis hormones. To test the hypothesis that fluctuations in plasma leptin concentrations are related to the levels of luteinizing hormone (LH) and estradiol, we sampled plasma from six healthy women every 7 min for 24 h during days 8-11 of the menstrual cycle. Cross-correlation analysis throughout the 24-h cycle revealed a relation between release patterns of leptin and LH, with a lag of 42-84 min but no significant cross-correlation between LH and estradiol. The ultradian fluctuations in leptin levels showed pattern synchrony with those of both LH and estradiol as determined by cross-approximate entropy (cross-ApEn). At night, as leptin levels rose to their peak, the pulsatility profiles of LH changed significantly and became synchronous with those of leptin. LH pulses were fewer, of longer duration, higher amplitude, and larger area than during the day. Moreover, the synchronicity of LH and leptin occurred late at night, at which time estradiol and leptin also exhibited significantly stronger pattern coupling than during the day. We propose that leptin may regulate the minute-to-minute oscillations in the levels of LH and estradiol, and that the nocturnal rise in leptin may determine the change in nocturnal LH profile in the mid-to-late follicular phase that precedes ovulation. This may explain the disruption of hypothalamic-pituitary-ovarian function that is characteristic of states of low leptin release, such as anorexia nervosa and cachexia.

Activity Cycles↗