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By Norepinephrine and Inactivated by NO and Cgmp (Medial Basal Hypothalami/Luteinizing Hormone-Releasing Hormone/Camp/Arginine/Nitroarginine Methyl Ester) G

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By Norepinephrine and Inactivated by NO and Cgmp (Medial Basal Hypothalami/Luteinizing Hormone-Releasing Hormone/Camp/Arginine/Nitroarginine Methyl Ester) G Proc. Natl. Acad. Sci. USA Vol. 93, pp. 4246-4250, April 1996 Physiology Nitric oxide synthase content of hypothalamic explants: Increased by norepinephrine and inactivated by NO and cGMP (medial basal hypothalami/luteinizing hormone-releasing hormone/cAMP/arginine/nitroarginine methyl ester) G. CANTEROS*, V. RErroRI*, A. GENARO*, A. SUBURO*, M. GIMENO*, AND S. M. MCCANNtt *Centro de Estudios Farmacologicos y Botanicos, Consejo Nacional de Investigaciones Cientificas y Tecnicas, Serrano 665, 1414 Buenos Aires, Argentina; and tPennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808-4124 Contributed by S. M. McCann, December 26, 1995 ABSTRACT Release of luteinizing hormone (LH)- pituitary gland. There it releases LH, which induces ovulation releasing hormone (LHRH), the hypothalamic peptide that and ovarian steroid secretion in females and testosterone controls release of LH from the adenohypophysis, is con- secretion in males (3). Since NO controls LHRH release in the trolled by NO. There is a rich plexus of nitric oxide synthase arcuate nucleus-median eminence region, where axons of (NOS)-containing neurons and fibers in the lateral median LHRH neurons terminate on the portal capillaries (2), we eminence, intermingled with terminals of the LHRH neurons. expected to find NOergic neurons in this region. Indeed, in the To study relations between NOS and LHRH in this brain present study we found a large number of NOergic cell bodies region, we measured NOS activity in incubated medial basal and fibers in the arcuate-median eminence region. hypothalamus (MBH). NOS converts [l4C]arginine to equimo- This study was initiated to determine if we could measure lar quantities of [14C]citrulline plus NO, which rapidly decom- NOS activity in incubated medial basal hypothalami (MBHs) poses. The [14C]citrulline serves as an index ofthe NO produced. by the citrulline method (4) and study the effect of various NOS basal activity was suppressed by incubation of the tissue transmitters controlling LHRH release on the activity of the with an inhibitor of NOS, nitroarginine methyl ester (NAME) enzyme. We report details of the evidence that demonstrates (10-5 M). Furthermore, incubation of MBH explants for 30 min that norepinephrine (NE) increased the content of NOS in the with norepinephrine (NE) increased NOS activity and the in- MBH. We also show that concentrations of NO released crease was prevented by prazosine (10-5 M), an al-adrenergic high direct addition of NE to the tissue by sodium nitroprusside (NP) can directly inactivate NOS, receptor blocker, however, an feedback on the en- homogenate or to a preparation of MBH synaptosomes did not providing ultra-short-loop negative alter enzyme activity, which suggested that NE increased the zyme. This feedback can inhibit NO-induced activation of content of NOS during incubation with the tissue. After purifi- LHRH release. Furthermore, cGMP, released from the tissue cation ofNOS, the increase in enzyme content induced by NE was by NO, can directly lower NOS activity. In CNS infections, with still measurable. This indicates that within 30 min NE increased high concentrations of NO produced by inducible NOS in glial the synthesis of NOS in vitro. Incubation of MBH or the MBH cells, NO and cGMP may inhibit LHRH release induced by homogenate with various concentrations of sodium nitroprus- NO leading to decreased gonadotropin release. side (NP), a releaser of NO, reduced NOS activity at high concentrations (20.9 mM), which were associated with either a MATERIALS AND METHODS reduction of stimulation or a plateau of LHRH release. Finally, incubation of either MBH or the homogenate with cGMP, a Male rats of the Wister strain (200-250 g) from our colony major mediatior of NO action, at concentrations that increased were used. All rats were kept in group cages in a light LHRH release also reduced NOS activity. These results indicate (0500-1900 hr) and temperature (23-25°C)-controlled room that NO at high concentrations can inactivate NOS and that with free access to laboratory chow and water. cGMP can also inhibit the enzyme directly. Therefore, the In Vitro Studies. After decapitation and removal of the increased NOS activity induced by activation of al receptors by brain, the MBH was dissected from each brain (5). The NE is inhibited by NO itselfand a principal product ofits activity, hypothalami were preincubated in a Dubnoff metabolic shaker cGMP, providing negative feedback on NOS. In central nervous (50 cycles per minute; 95% 02/5% CO2) for 30 min in system (CNS) infections with high concentrations of inducible Krebs-Ringer bicarbonate buffer (pH 7.4) containing 0.1% NOS produced by glial elements, the high concentrations of NO glucose before replacement with fresh medium or medium and cGMP produced may suppress LHRH release, resulting in containing the substances to be tested. The incubation con- decreased gonadotropin and gonadal steroid release. tinued for 30 min, followed by removal of the medium and storage of samples at -20°C before assay for LHRH. LHRH Nitric oxide synthase (NOS)-containing neurons, termed NO- was measured by RIA using highly specific LHRH antiserum ergic neurons, have been localized in various parts of the kindly provided by A. Barnea (University of Texas Southwest- central nervous system (CNS) of the rat. In particular, NOergic ern Medical Center, Dallas). The sensitivity of the assay was neurons occur in the hypothalamus where the perikarya are 0.2 pg per tube and the curve was linear up to 100 pg of LHRH. located in paraventricular and supraoptic nuclei; their axons Determination of NOS Activity. For determination of NO project to the neural lobe of the pituitary gland, the structure release from the incubated MBH explants, we first used the that contains the largest quantity of NOS of any organ in the method of Bredt and Snyder (4) that measures the conversion body (1). NO has recently been found to control release of of [14C]arginine incubated with tissue into [14C]citrulline. luteinizing hormone (LH)-releasing hormone (LHRH) from Since citrulline remains in the whereas the the hypothalamus (2). LHRH is released into hypophyseal sample, equimolar portal capillaries through which it is carried to the anterior Abbreviations: LH, luteinizing hormone (lutropin); LHRH, LH- releasing hormone; NOS, nitric oxide synthase; MBH, medial basal The publication costs of this article were defrayed in part by page charge hypothalamus; NP, sodium nitroprusside; NE, norepinephrine; CNS, payment. This article must therefore be hereby marked "advertisement" in central nervous system. accordance with 18 U.S.C. §1734 solely to indicate this fact. *To whom reprint requests should be addressed. 4246 Downloaded by guest on September 30, 2021 Physiology: Canteros et al. Proc. Natl. Acad. Sci. USA 93 (1996) 4247 amounts of NO produced are rapidly destroyed, the method indirectly measures NO production, an index of NOS activity. After preincubation (15 min) in Krebs-Ringer bicarbonate buffer (equilibrated with 95% 02/5% CO2) at 37°C, MBH explants (2 per tube) were incubated in medium with the addition of [14C]arginine (0.3 ,uCi; 1 Ci = 376Bq) with or without test substances for 30 min. After the incubation the hypothalami were homogenized in 0.4 ml of 20 mM Hepes (pH 7.4), 2 mM NADPH, 0.10 mM Ca2+. After 30 min of incuba- tion at 37°C, the homogenates were centrifuged at 10,000 x g for 10 min at 4°C and the supernatants were applied to 2-ml columns of Dowex AG WX-8 (Na+ form) and eluted with 3 ml of double distilled water. [14C]citrulline was quantified by I..i. liquid scintillation counting. In the modified method we used, the only change was to add the [14C]arginine to the homogenate or to a synaptosomal A preparation instead of the incubated tissue. Purification of NOS. The enzyme was purified by the method of Bredt and Snyder (6). Fractions containing NOS activity were incubated in a buffer that contained 20 mM Hepes, 10 ,tM [14C]arginine (0.3 ,tCi), 1 mM NADPH, 1.25 mM CaCl2, 1 mM EDTA, and 10 ,ug/ml calmodulin in 200 tlI of incubation volume. After 10 min incubation at 37°C, the reaction was stopped by adding 1 ml of ice-cold 10 mM EGTA, 1 mM citrulline, 100 mM Pipes, pH 5.5. Then, [14C]citrulline formation was measured as indicated above. Effect of Sodium NP and cGMP on NOS Activity. To deter- mine if NP, a releaser of NO, or cGMP, an active metabolite ~j t~ d- I produced in tissue by the action of NO, would alter NOS activity, iS: S. { various concentrations of each of these compounds were added to either incubated MBH explants or to the homogenates as just described; the effect on NOS activity was determined by the B modified [14C]citrulline method. Localization of NOS. For serial FIG. 1. Consecutive sections (30 ,um) from the basal hypothalamus immunohistochemistry, immunostained for LHRH and neuronal NOS. (A) Numerous fine coronal frozen sections (25 ,um) were cut through the hypo- fibers showing LHRH immunoreactivity were observed in the lateral thalamus and median eminence and processed for immuno- region of the median eminence. Fibers were also present around the histochemistry (7). After blockade of endogenous peroxidase ventricular lumen in the region of the arcuate nucleus. (B) The lateral activity, consecutive sections were incubated in rabbit antisera portion of the median eminence contained a large number of NOS-ir to neuronal NOS from rat brain (8) or LHRH (a gift from A. fibers. Similar fibers were also observed close to the midline. Isolated Barnea, University of Texas Southwestern Medical Center). fibers were found around meningeal vessels. Comparison ofA and B Bound antibodies were detected with biotinylated goat anti- shows that the lateral area occupied by NOS-ir fibers includes the rabbit serum and avidin-biotin-peroxidase complex (Vec- smaller area containing the lateral cluster of LHRH-ir fibers.
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