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S M McCann

Publications and source records attributed to S M McCann.

At least 19 recordsLinked to original sources
PubMed1997

Targeting transforming growth factor alpha expression to discrete loci of the neuroendocrine brain induces female sexual precocity.

Precocious puberty of cerebral origin is a poorly understood disorder of human sexual development, brought about by the premature activation of those neurons that produce luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual maturation. An increased production of transforming growth factor alpha (TGF alpha) in the hypothalamus has been implicated in the mechanism underlying both normal and precocious puberty. We have now used two gene delivery systems to target TGF alpha overexpression near LHRH neurons in immature female rats. Fibroblasts infected with a retroviral construct in which expression of the human TGF alpha gene is constitutively driven by the phosphoglycerate kinase promoter, or transfected with a plasmid in which TGF alpha expression is controlled by an inducible metallothionein promoter, were transplanted into several regions of the hypothalamus. When the cells were in contact with LHRH nerve terminals or in the vicinity of LHRH perikarya, sexual maturation was accelerated. These results suggest that precocious puberty of cerebral origin may result from a focal disorder of TGF alpha production within the confines of the LHRH neuron microenvironment.

3T3 Cells↗
PubMed1997

Oxytocin stimulates the release of luteinizing hormone-releasing hormone from medial basal hypothalamic explants by releasing nitric oxide.

Oxytocin induces mating behavior in rats of both sexes. Previous experiments revealed that progesterone-induced sex behavior in ovariectomized, estrogen-primed rats was caused by release of NO from NOergic neurons that stimulated the release of luteinizing hormone-releasing hormone (LHRH). The LHRH activated brain-stem neurons that initiated the lordosis reflex. We hypothesized that oxytocin might similarly release NO in the medial basal hypothalamic region that would stimulate release of LHRH into the hypophyseal portal vessels to release luteinizing hormone. To investigate this hypothesis, medial basal hypothalamic explants were preincubated in Krebs-Ringer bicarbonate buffer for 30 min, followed by a 30-min incubation in fresh Krebs-Ringer bicarbonate buffer containing the compounds to be tested. Oxytocin stimulated LHRH release 3- to 4-fold at the lowest concentration tested (10(-10) M). Values remained at a plateau as the concentration was increased to 10(-7) M and then declined in a concentration-dependent manner, so that there was no stimulation with a concentration of 10(-5) M. Oxytocin (10(-7) M) stimulated release of prostaglandin E2 into the medium, a finding consistent with a role of NO in the response. That NO indeed mediated the action of oxytocin was supported by blockade of the action of oxytocin by the competitive inhibitor of NO synthase (NOS), N(G)-monomethyl-L-arginine (300 microM). Furthermore, oxytocin (10(-9) to 10(-7) M) activated NOS as measured at the end of the experiments. Oxytocin appeared to act to stimulate norepinephrine terminals in the medial basal hypothalamus, which activated NOS by alpha1-adrenergic receptors, because prazocine, an alpha1 receptor blocker, inhibited the LHRH-releasing action of oxytocin. Finally, incubation of neural lobe explants with sodium nitroprusside, a NO releasor, revealed that nitroprusside (300-600 microM, but not 900 microM) inhibited oxytocin release. Therefore, the NO released by oxytocin also diffuses into the oxytocin neuronal endings and inhibits oxytocin release, forming a negative feedback loop. The results indicate that oxytocin is important not only in induction of mating, but also in stimulating LHRH release with subsequent luteinizing hormone discharge that plays a crucial role in reproduction.

Animals↗
PubMed1997

Role of leptin in hypothalamic-pituitary function.

A defect in the structure of the obese gene is responsible for development of obesity in the ob/ob mouse. The product of expression of the gene is the protein hormone leptin. Leptin causes weight loss in ob/ob and normal mice, it is secreted by adipocytes, and it is an important controller of the size of fat stores by inhibiting appetite. The ob/ob mouse is infertile and has a pattern of gonadotropin secretion similar to that of prepubertal animals. Consequently, we hypothesized that leptin might play a role in the control of gonadotropin secretion and initiated studies on its possible acute effects on hypothalamic-pituitary function. After a preincubation period, hemi-anterior pituitaries of adult male rats were incubated with leptin for 3 hr. Leptin produced a dose-related increase in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release, which reached peaks with 10(-9) and 10(-11) M leptin, respectively. Gonadotropin release decreased at higher concentrations of leptin to values indistinguishable from that of control pituitaries. On the other hand, prolactin secretion was greatly increased in a dose-related manner but only with leptin concentrations (10(-7)-10(-5) M). Incubation with leptin of median eminence-arcuate nuclear explants from the same animals produced significant increases in LH-releasing hormone (LHRH) release only at the lowest concentrations tested (10(-12)-10(-10) M). As the leptin concentration was increased, LHRH release decreased and was significantly less than control release at the highest concentration tested (10(-6) M). To determine if leptin can also release gonadotropins in vivo, ovariectomized females bearing implanted third ventricle cannulae were injected with 10 microg of estradiol benzoate s.c., followed 72 hr later by microinjection into the third ventricle of leptin (0.6 nmol in 5 microl) or an equal volume of diluent. There was a highly significant increase in plasma LH, which peaked 10-50 min after injection of leptin. Leptin had no effect on plasma FSH concentrations, and the diluent had no effect on either plasma FSH or LH. Thus, leptin at very low concentrations stimulated LHRH release from hypothalamic explants and FSH and LH release from anterior pituitaries of adult male rats in vitro and released LH, but not FSH, in vivo. The results indicate that leptin plays an important role in controlling gonadotropin secretion by stimulatory hypothalamic and pituitary actions.

Animals↗
PubMed1997

Interleukin (IL) 1beta, IL-1 receptor antagonist, IL-10, and IL-13 gene expression in the central nervous system and anterior pituitary during systemic inflammation: pathophysiological implications.

The pathophysiology of systemic inflammation and sepsis involves peripheral organs, causing gastrointestinal, renal, and cardiovascular alterations, as well as the central nervous system (CNS), affecting sleep, temperature regulation, behavior, and neuroendocrine function. The molecular basis of the CNS effects of systemic inflammation are not fully elucidated. Here we show that the CNS responds to systemic inflammation with pronounced IL-1beta gene expression and limited IL-1 receptor antagonist (IL-1ra), IL-10, and IL-13 gene expression. This pattern occurs throughout the CNS, including areas such as the subfornical organ, pineal gland, neurohypophysis, and hypothalamus. In contrast, in the anterior pituitary, we found limited IL-1beta gene expression but marked induction of the mRNA encoding for the secreted isoform of IL-1ra, secreted IL-1ra. We conclude that the central manifestations of peripheral inflammation are mediated by endogenous brain IL-1beta synthesized during systemic inflammation in the context of limited central cytokine counter regulation of IL-1. As IL-1beta is a potent stimulus for inducible nitric oxide synthase expression and activity, these findings explain our previous observation that systemic inflammation promotes inducible nitric oxide synthase gene expression in the brain and the spillover of NO metabolites into cerebrospinal fluid. The CNS transcription of the HIV-1 replication factor IL-1beta in the context of limited transcription of the IL-1 replication inhibitors IL-1ra, IL-10, and IL-13 might help explain the negative impact of systemic inflammation on the clinical course of AIDS. In addition, we propose that IL-1ra may be secreted by the anterior pituitary as a systemic anti-inflammatory hormone that is released in response to IL-1beta originated from multiple sources.

Animals↗
PubMed1997

Atrial natriuretic peptide in brain and pituitary gland.

The data reviewed establish the presence and important role in body fluid homeostasis of brain atrial natriuretic peptide (ANP) in all vertebrate-species examined. The peptide is localized in neurons in hypothalamic and brain stem areas involved in body fluid volume and blood pressure regulation, and its receptors are located in regions that contain the peptide. Most, if not all, of the actions of ANP are mediated by activation of particulate guanylyl cyclase with generation of guanosine 3',5'-cyclic monophosphate, which mediates its actions in brain as in the periphery. Although atrial stretch releases ANP from cardiac myocytes, the experiments indicate that the response to acute blood volume expansion is markedly reduced after elimination of neural control. Volume expansion distends baroreceptors in the right atria, carotid-aortic sinuses, and kidney, altering afferent input to the brain stem and hence the hypothalamus, resulting in stimulation via ANPergic neurons in the hypothalamus of oxytocin release from the neurohypophysis that circulates to the right atrium to stimulate ANP release. The ANP circulates to the kidney and induces natriuresis. Atrial natriuretic peptide also induces vasodilation compensating rapidly for increased blood volume by increased vascular capacity. Atrial natriuretic peptide released into hypophysial portal blood vessels inhibits release of adrenocorticotropic hormone (ACTH), thereby decreasing aldosterone release and enhancing natriuresis. Furthermore, the ANP neurons inhibit AVP release leading to diuresis and decreased ACTH release. Activation of hypothalamic ANPergic neurons via volume expansion also inhibits water and salt intake. These inhibitory actions may be partially mediated via ANP neurons in the olfactory system altering salt taste. Atrial natriuretic peptide neurons probably also alter fluid movement in the choroid plexus and in other brain vascular beds. Therefore, brain ANP neurons play an important role in modulating not only intake of body fluids, but their excretion to maintain body fluid homeostasis.

Animals↗
PubMed1997

Effect of somatostatin on the release of gonadotropins in male rats.

Since somatostatin, the growth hormone release-inhibiting hormone, has inhibitory actions in many cell types and is delivered to the anterior pituitary gland via the hypophysial portal vessels, as well as being synthesized by cells within the gland, we tested the hypothesis that it might inhibit the release of gonadotropins from anterior pituitaries in vitro. Consequently, the effect of somatostatin on gonadotropin release from incubated anterior pituitaries of male rats with and without the stimulatory action of luteinizing hormone-releasing hormone (LHRH) was studied. After a preincubation period of 1 hr, hemipituitaries from adult male rats were incubated in fresh Krebs-Ringer bicarbonate (KRB) buffer in a Dubnoff incubator with an atmosphere of 95% O(2)-5% CO2 at 37 degrees C for 3 hr. Incubation with somatostatin (10(-6), 10(-7), and 10(-8) M) had no effect on basal release of either LH or follicle-stimulating hormone (FSH). However, somatostatin (10(-6)-10(-8) M) suppressed LHRH (1.7 x 10(-8) M)-induced release of LH (P < 0.01 to P < 0.0001), but not FSH. Furthermore, somatostatin antiserum (1:1000) had no significant effect on basal LH or FSH release, whereas incubation with the antiserum plus LHRH (1.7 x 10(-9) or 1.7 x 10(-8) M) increased LH (P = 0.015 and P=.005, respectively), but not FSH release. In summary, our results suggest that somatostatin exerts a physiologically significant inhibitory effect on LH but not FSH release in the presence of LHRH in vitro. Presumably, somatostatin is secreted in vitro by pituitary cells since not only have anterior pituitaries of rats been shown to contain somatostatin, but also somatostatin mRNA. Somatostatin then diffuses to the LH gonadotropes, where it exerts its inhibitory action. However, the release of somatostatin is insufficient to alter basal in vitro release. On the other hand, at least at the concentrations employed, there was no significant effect either of somatostatin or the antiserum to alter basal or stimulated FSH release.

Animals↗
PubMed1996

Nitric oxide synthase content of hypothalamic explants: increase by norepinephrine and inactivated by NO and cGMP.

Release of luteinizing hormone (LH)-releasing hormone (LHRH), the hypothalamic peptide that controls release of LH from the adenohypophysis, is controlled by NO. There is a rich plexus of nitric oxide synthase (NOS)-containing neurons and fibers in the lateral median eminence, intermingled with terminals of the LHRH neurons. To study relations between NOS and LHRH in this brain region, we measured NOS activity in incubated medial basal hypothalamus (MBH). NOS converts [14C]arginine to equimolar quantities of [14C]citrulline plus NO, which rapidly decomposes. The [14C]citrulline serves as an index of the NO produced. NOS basal activity was suppressed by incubation of the tissue with an inhibitor of NOS, nitroarginine methyl ester (NAME) (10(-5) M). Furthermore, incubation of MBH explants for 30 min with norepinephrine (NE) increased NOS activity and the increase was prevented by prazosine (10(-5) M), an alpha 1-adrenergic receptor blocker; however, direct addition of NE to the tissue homogenate or to a preparation of MBH synaptosomes did not alter enzyme activity, which suggested that NE increased the content of NOS during incubation with the tissue. After purification of NOS, the increase in enzyme content induced by NE was still measurable. This indicates that within 30 min NE increased the synthesis of NOS in vitro. Incubation of MBH or the MBH homogenate with various concentrations of sodium nitroprusside (NP), a releaser of NO, reduced NOS activity at high concentrations (> or = 0.9 mM), which were associated with either a reduction of stimulation or a plateau of LHRH release. Finally, incubation of either MBH or the homogenate with cGMP, a major mediatior of NO action, at concentrations that increased LHRH release also reduced NOS activity. These results indicate that NO at high concentrations can inactivate NOS and that cGMP can also inhibit the enzyme directly. Therefore, the increased NOS activity induced by activation of alpha 1 receptors by NE is inhibited by NO itself and a principal product of its activity, cGMP, providing negative feedback on NOS. In central nervous system (CNS) infections with high concentrations of inducible NOS produced by glial elements, the high concentrations of NO and cGMP produced may suppress LHRH release, resulting in decreased gonadotropin and gonadal steroid release.

Animals↗
PubMed1996

Role of dopamine in the inhibitory control of growth hormone and prolactin release by gastrin-releasing peptide.

The ability of gastrin-releasing peptide to inhibit the release of growth hormone and prolactin by a hypothalamic mechanism has been previously reported. To determine whether or not these effects involved the hypothalamic dopaminergic neurons, ovariectomized female rats were pretreated with the dopamine receptor blocker, pimozide (0.6 mg/kg, SC), or the diluent 35 min prior to administration of gastrin-releasing peptide (2 micrograms in 2 microliters 0.9% NaCl) into the third ventricle. The elevation in plasma growth hormone in response to growth hormone-releasing factor (GRF; 1 microgram/kg, i.v.) was blocked by gastrin-releasing peptide as previously reported following pretreatment with the diluent, but occurred following the injection of pimozide, reversing the inhibitory action of gastrin-releasing peptide. Some control animals that were injected with the pimozide vehicle exhibited elevated plasma prolactin levels compared to levels in uninjected controls. Gastrin-releasing peptide significantly lowered plasma prolactin concentrations in this group of animals. As expected, plasma prolactin levels were elevated following pimozide treatment due to the removal of inhibitory dopaminergic control. Prolactin concentrations were unresponsive to gastrin-releasing peptide treatment in this paradigm and remained elevated throughout the 40-min duration of sampling. We interpret these data to indicate that gastrin-releasing peptide exerts its inhibitory actions on the release of growth hormone and prolactin through a dopaminergic mechanism. Gastrin-releasing peptide may elicit the release of dopamine from tuberoinfundibular neurons, which a) stimulates release of somatostatin, thus inhibiting the release of growth hormone, and b) reaches the pituitary directly via the hypophysial portal vessels to inhibit the release of prolactin from the lactotropes.

Animals↗
PubMed1996

Inducible nitric oxide synthase gene expression in the brain during systemic inflammation.

Inducible nitric oxide synthase (iNOS) is a transcriptionally regulated enzyme that synthesizes nitric oxide from L-arginine that has a key role in the pathophysiology of systemic inflammation and sepsis. Transgenic animals with a null mutation for the iNOS gene are resistant to hypotension and death caused by Escherichia coli lipopolysaccharide (LPS). The regulation of peripheral iNOS has been well studied in sepsis, but little is known about iNOS regulation in the brain during systemic inflammation or sepsis. We know that at baseline there is no detectable iNOS gene expression in the brain, but a detailed neuroanatomical study reveals that early in the course of systemic inflammation there is a profound induction of iNOS messenger RNA in vascular, glial and neuronal structures of the rat brain, accompanied by the production of nitric oxide (NO) metabolites in brain parenchyma and cerebrospinal fluid (CSF). We propose that the spillover of nitrite into the CSF has the potential to be a diagnostic marker for systemic inflammation and sepsis. Pharmacological interventions aimed at regulating iNOS function in the brain might represent a new treatment strategy in sepsis. Brain iNOS may be relevant to the pathophysiology, diagnosis and treatment of systemic inflammation and sepsis.

Animals↗
PubMed1996

Role of neuromedin B in the in vitro thyrotropin release in response to thyrotropin-releasing hormone from anterior pituitaries of eu-, hypo-, and hyperthyroid rats.

A role of neuromedin B (NB), a bombesin-like peptide, as an inhibitory paracrine/autocrine regulator of thyrotropin secretion has been suggested. We previously reported (10) that basal thyroid-stimulating hormone (TSH) release in vitro was decreased by NB and increased in the presence of a highly potent antiserum against NB (aNB). In these experiments, we studied the effects of NB (10(-11) - 10(-7) M) and antiserum against NB (aNB, 1:2000 dilution) on basal TSH release and the response to thyrotropin-releasing hormone (TRH) (0.5 x 10(-8) M) from incubated anterior pituitaries from eu-, hypo-, and hyperthyroid rats. As expected, in euthyroid rats NB decreased basal and TRH-stimulated TSH release, but only at the highest concentration tested (10(-7) M). Incubation of the pituitaries from euthyroid rats with the antiserum against NB increased basal TSH release above that from glands of normal rabbit serum-incubated controls, as anticipated based on the concept that NB inhibits TSH release from the pituitary glands of euthyroid animals. The antiserum did not augment the response to TRH, suggesting that NB released in this situation, although suppressing basal release, had no effort on the stimulated release induced by TRH. Glands from hypothyroid rats had a slightly lower basal TSH release and decreased response to TRH than glands from euthyroid rats. They responded with a decrease in basal TSH release at a much lower concentration of NB (10(-9) M) than pituitaries from euthyroid animals. Surprisingly, pituitaries from hypothyroid rats showed a paradoxical increased release of TSH in response to the lowest concentration of NB (10(-11) M), which decreased with increasing concentrations and was not distinguishable from control release in the presence of TRH at the highest concentration of NB (10(-7) M). We hypothesize that the increased responsiveness to the inhibition of basal TSH release by NB in the hypothyroid pituitaries may be related to an upregulation of NB receptors in this situation, in which the release of NB is diminished because of loss of feedback via thyroid hormones. The view that NB secretion was reduced in the hypothyroid situation was supported by the fact that there was no change in TSH release or the response to TRH following treatment with aNB in these animals. Remarkably, in the glands from the hyperthyroid rats, although basal TSH secretion was significantly lower than that from euthyroid pituitaries and response to TRH was also decreased, NB (10(-11)-10(-7) M) instead of decreasing TSH release augmented it significantly. Also, the response to TRH was significantly augmented but only at the lowest concentration of NB tested (10(-11 M). That NB was probably being secreted in vitro from the hyperthyroid pituitaries was indicated by an increased basal TSH release as well as a higher TSH medium concentration after TRH in the presence of the aNB. These results support the concept that the glands from the hyperthyroid animals secrete more NB because of positive feedback of thyroid hormones directly on the thyrotropes to increase NB synthesis and release which downregulates NB receptors on the gland. This downregulation of receptors in some manner reverses the inhibitory action of NB on basal and TRH-stimulated TSH release. In conclusion, the results provide further evidence for an important role of NB as an autocrine regulator of TSH release, which is modulated by increased release of NB induced by thyroid hormones.

Animals↗
PubMed1995

In vivo and in vitro effects of neuropeptide K and neuropeptide gamma on the release of growth hormone.

There is anatomical and experimental evidence suggesting that tachykinins have a role in the regulation of secretion of anterior pituitary hormones. In this investigation, the effects of neuropeptide K and neuropeptide gamma on the secretion of GH were studied in vivo and in vitro. Injections of neuropeptide K into the third ventricle of freely moving, ovariectomized rats resulted in a significant increase of plasma GH, but neuropeptide gamma induced no significant changes in these levels, although it did induce a significant increase in GH pulse height. In vitro, neither neuropeptide K nor neuropeptide gamma had any apparent effect on GH release from hemipituitaries incubated for 2 h. These results suggest that neuropeptide K may have a modulatory function in the regulation of GH secretion from the anterior pituitary, through an action exerted at the hypothalamic level, and the effects of neuropeptide gamma seem to be more marginal.

Animals↗
PubMed1995

Nitric oxide inhibits the release of norepinephrine and dopamine from the medial basal hypothalamus of the rat.

Previous research indicates that norepinephrine and dopamine stimulate release of luteinizing hormone (LH)-releasing hormone (LHRH), which then reaches the adenohypophysis via the hypophyseal portal vessels to release LH. Norepinephrine exerts its effect via alpha 1-adrenergic receptors, which stimulate the release of nitric oxide (NO) from nitricoxidergic (NOergic) neurons in the medial basal hypothalamus (MBH). The NO activates guanylate cyclase and cyclooxygenase, thereby inducing release of LHRH into the hypophyseal portal vessels. We tested the hypothesis that these two catecholamines modulate NO release by local feedback. MBH explants were incubated in the presence of sodium nitroprusside (NP), a releaser of NO, and the effect on release of catecholamines was determined. NP inhibited release of norepinephrine. Basal release was increased by incubation of the tissue with the NO scavenger hemoglobin (20 micrograms/ml). Hemoglobin also blocked the inhibitory effect of NP. In the presence of high-potassium (40 mM) medium to depolarize cell membranes, norepinephrine release was increased by a factor of 3, and this was significantly inhibited by NP. Hemoglobin again produced a further increase in norepinephrine release and also blocked the action of NP. When constitutive NO synthase was inhibited by the competitive inhibitor NG-monomethyl-L-arginine (NMMA) at 300 microM, basal release of norepinephrine was increased, as was potassium-evoked release, and this was associated in the latter instance with a decrease in tissue concentration, presumably because synthesis did not keep up with the increased release in the presence of NMMA. The results were very similar with dopamine, except that reduction of potassium-evoked dopamine release by NP was not significant. However, the increase following incubation with hemoglobin was significant, and hemoglobin, when incubated with NP, caused a significant elevation in dopamine release above that with NP alone. In this case, NP increased tissue concentration of dopamine along with inhibiting release, suggesting that synthesis continued, thereby raising the tissue concentration in the face of diminished release. When the tissue was incubated with NP plus hemoglobin, which caused an increase in release above that obtained with NP alone, the tissue concentration decreased significantly compared with that in the absence of hemoglobin, indicating that, with increased release, release exceeded synthesis, causing a fall in tissue concentration. When NO synthase was blocked by NMMA, the release of dopamine, under either basal or potassium-evoked conditions, was increased. Again, in the latter instance the tissue concentration declined significantly, presumably because synthesis did not match release. Therefore, the results were very similar with both catecholamines and indicate that NO acts to suppress release of both amines. Since both catecholamines activate the release of LHRH, the inhibition of their release by NO serves as an ultra-short-loop negative feedback by which NO inhibits the release of the catecholamines, thereby reducing the activation of the NOergic neurons and decreasing the release of LHRH. This may be an important means for terminating the pulses of release of LHRH, which generate the pulsatile release of LH that stimulates gonadal function in both male and female mammals.

Animals↗
PubMed1995

Oxytocin mediates atrial natriuretic peptide release and natriuresis after volume expansion in the rat.

Our previous studies have shown that stimulation of the anterior ventral third ventricular region increases atrial natriuretic peptide (ANP) release, whereas lesions of this structure, the median eminence, or removal of the neural lobe of the pituitary block ANP release induced by blood volume expansion (BVE). These results indicate that participation of the central nervous system is crucial in these responses, possibly through mediation by neurohypophysial hormones. In the present research we investigated the possible role of oxytocin, one of the two principal neurohypophysial hormones, in the mediation of ANP release. Oxytocin (1-10 nmol) injected i.p. caused significant, dose-dependent increases in urinary osmolality, natriuresis, and kaliuresis. A delayed antidiuretic effect was also observed. Plasma ANP concentrations increased nearly 4-fold (P < 0.01) 20 min after i.p. oxytocin (10 nmol), but there was no change in plasma ANP values in control rats. When oxytocin (1 or 10 nmol) was injected i.v., it also induced a dose-related increase in plasma ANP at 5 min (P < 0.001). BVE by intra-atrial injection of isotonic saline induced a rapid (5 min postinjection) increase in plasma oxytocin and ANP concentrations and a concomitant decrease in plasma arginine vasopressin concentration. Results were similar with hypertonic volume expansion, except that this induced a transient (5 min) increase in plasma arginine vasopressin. The findings are consistent with the hypothesis that baroreceptor activation of the central nervous system by BVE stimulates the release of oxytocin from the neurohypophysis. This oxytocin then circulates to the right atrium to induce release of ANP, which circulates to the kidney and induces natriuresis and diuresis, which restore body fluid volume to normal levels.

Animals↗
PubMed1995

Ethanol inhibits luteinizing hormone-releasing hormone (LHRH) secretion by blocking the response of LHRH neuronal terminals to nitric oxide.

It has previously been shown that alcohol can suppress reproduction in humans, monkeys, and small rodents by inhibiting release of luteinizing hormone (LH). The principal action is via suppression of the release of LH-releasing hormone (LHRH) both in vivo and in vitro. The present experiments were designed to determine the mechanism by which alcohol inhibits LHRH release. Previous research has indicated that the release of LHRH is controlled by nitric oxide (NO). The proposed pathway is via norepinephrine-induced release of NO from NOergic neurons, which then activates LHRH release. In the present experiments, we further evaluated the details of this mechanism in male rats by incubating medial basal hypothalamic (MBH) explants in vitro and examining the release of NO, prostaglandin E2 (PGE2), conversion of arachidonic acid to prostanoids, and production of cGMP. The results have provided further support for our theory of LHRH control. Norepinephrine increased the release of NO as measured by conversion of [14C]arginine to [14C]citrulline, and this increase was blocked by the alpha 1 receptor blocker prazosin. Furthermore, the release of LHRH induced by nitroprusside (NP), a donor of NO, is related to the activation of soluble guanylate cyclase by NO since NP increased cGMP release from MBHs and cGMP also released LHRH. Ethanol had no effect on the production of NO by MBH explants or the increased release of NO induced by norepinephrine. Therefore, it does not act at that step in the pathway. Ethanol also failed to affect the increase in cGMP induced by NP. On the other hand, as might be expected from previous experiments indicating that LHRH release was brought about by PGE2, NP increased the conversion of [14C]arachidonic acid to its metabolites, particularly PGE2. Ethanol completely blocked the release of LHRH induced by NP and the increase in PGE2 induced by NP. Therefore, the results support the theory that norepinephrine 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. The increase in cGMP increases intracellular free calcium, activating phospholipase A2 to provide arachidonic acid, the substrate for conversion by the activated cyclooxygenase to PGE2, which then activates the release of LHRH. Since alcohol inhibits the conversion of labeled arachidonic acid to PGE2, it must act either directly to inhibit cyclooxygenase or perhaps it may act by blocking the increase in intracellular free calcium induced by cGMP, which is crucial for activation of of both phospholipase A2 and cyclooxygenase.

Animals↗