PubMed Health⌕ Search

Biomedical subjects

D S Bredt

Publications and source records attributed to D S Bredt.

At least 91 records · Page 5Linked to original sources
PubMed1994

NOS induction by NGF in basal forebrain cholinergic neurones: evidence for regulation of brain NOS by a neurotrophin.

Nerve growth factor (NGF) acts through trkA receptors to serve as a trophic factor for cholinergic neurones in the medial septal nucleus (MSN) and vertical limb of the diagonal band (VDB). Herein, we show that brain nitric oxide synthase (NOS), which synthesizes the neuromodulator nitric oxide, is selectively expressed in a large fraction of trkA-containing neurones in the MSN and VDB. Axotomy of these neurones gave evidence that NOS expressing cholinergic neurones innervate the hippocampus. NGF infusion induced a robust, specific increase in NOS expression in basal forebrain cholinergic neurones. These results indicate that brain NOS can be regulated by a neurotrophic factor and suggest that NGF influences forebrain function by regulating production of nitric oxide as well as acetylcholine.

Animals↗
PubMed1994

Localization and actions of nitric oxide in the cat carotid body.

An extensive plexus of nerve fibers capable of synthesizing nitric oxide was demonstrated in the cat carotid body by immunocytochemical and biochemical studies of nitric oxide synthase. Denervation experiments indicated that the axons originate from: (i) microganglial neurons located within the carotid body and along the glossopharyngeal and carotid sinus nerves, whose ramifications primarily innervate carotid body blood vessels; and (ii), sensory neurons in the petrosal ganglion, whose terminals end in association with lobules of type I cells. In the in vitro superfused cat carotid body, the nitric oxide synthase substrate, L-arginine, induced a dose-dependent inhibition of carotid sinus nerve discharge evoked by hypoxia. In contrast, the nitric oxide synthase inhibitor, L-NG-nitroarginine methylester, augmented the chemoreceptor response to hypoxia, and this effect was markedly enhanced when the preparation was both perfused and superfused in vitro. The nitric oxide donor, nitroglycerine, inhibited carotid sinus nerve discharge, and immunocytochemistry revealed that this drug stimulated the formation of cyclic 3',5'-guanosine monophosphate in both type I cells and blood vessels. Our data indicate that nitric oxide is an inhibitory neuronal messenger in the carotid body, which affects the process of chemoreceptor transduction/transmission via actions on both the receptor elements and their associated blood vessels.

Amino Acid Oxidoreductases↗
PubMed1994

Rat spinal cord neurons contain nitric oxide synthase.

We describe the distribution and characteristics of nitric oxide synthase-containing neurons in rat spinal cord using a polyclonal affinity-purified antibody against rat cerebellar nitric oxide synthase. Numerous neurons were stained throughout the entire rostrocaudal extent of the spinal cord. Cell bodies, dendrites and axons stained in a uniform manner. Nitric oxide synthase immunoreactivity was intense in neurons of laminae I-IV and X throughout the entire spinal cord. Neurons in the intermediolateral cell column of the thoracic and lumbar spinal cord were also intensely stained for nitric oxide synthase. The sacral cord demonstrated substantial nitric oxide synthase immunostaining within lamina VII. For the entire cord, scattered neurons in laminae V, VI, VII, and VIII were weakly positive. In addition, punctate nitric oxide synthase staining throughout laminae I, III and surrounding some large motor neurons in the ventral horn suggested the presence of nitric oxide synthase at synapses. Axons and dendritic terminals located in the gray and white matter were also stained. The majority of nitric oxide synthase positive neurons in the intermediolateral cell column were double-labelled by subcutaneously injected FluoroGold confirming that these cells were preganglionic autonomic neurons. Most NADPH-diaphorase-stained neurons were also nitric oxide synthase-positive. The distribution of nitric oxide synthase-containing neurons in spinal cord suggests that nitric oxide plays a role in spinal cord neurotransmission including: preganglionic sympathetic and parasympathetic, somatosensory, visceral sensory and possibly motor pathways. In particular, the autonomic nervous system appears enriched with nitric oxide synthase immunoreactivity. The precise role of each neuron type remains to be demonstrated in physiologic and pathophysiologic paradigms.

Amino Acid Oxidoreductases↗
PubMed1994

Nitric oxide mediates the formation of synaptic connections in developing and regenerating olfactory receptor neurons.

Nitric oxide (NO) is a diffusible free radical that functions as a second messenger and neurotransmitter. NO synthase (NOS) is highly and transiently expressed in neurons of the developing olfactory epithelium during migration and establishment of primary synapses in the olfactory bulb. NOS is first expressed at E11 in cells of the presumptive nervous layer of the olfactory placode. NOS immunoreactivity persists in the descendants of these cells that differentiate into embryonic olfactory receptor neurons (ORNs). Olfactory NOS expression in the ORN and in its afferents rapidly declines after birth and is undetectable by P7. Following bulbectomy, NOS expression is rapidly induced in the regenerating ORN and is particularly enriched in their outgrowing axons. Immunoblot and Northern blot analyses similarly demonstrate an induction of NOS protein and mRNA expression, respectively, the highest levels of which coincide with peaks of ORN regeneration. These data argue against a role for NO in odorant-sensitive signal transduction, but suggest a prominent function for NO in activity-dependent establishment of connections in both developing and regenerating olfactory neurons.

Amino Acid Oxidoreductases↗
PubMed1994

Transient nitric oxide synthase neurons in embryonic cerebral cortical plate, sensory ganglia, and olfactory epithelium.

Neuronal nitric oxide synthase (NOS), visualized immunohistochemically or with NADPH diaphorase histochemistry, is transiently expressed in discrete areas of the developing rat nervous system. In the brain transient NOS expression occurs in the cerebral cortical plate. At E15-E19, the majority of cells in the plate stain, with their processes extending through the corpus striatum to the thalamus. This staining decreases after birth and vanishes by the 15th postnatal day. Neurons in olfactory epithelium also express NOS from E15 till early postnatal life. In embryonic sensory ganglia virtually all neuronal cells are NOS positive, whereas by early adulthood only 1% express NOS. By contrast to these areas of transient NOS expression, in other neuronal sites NOS staining appears after cell bodies cease dividing and cells extend processes, and the staining persists in adult life. The transient expression of neuronal NOS may reflect a role in developmental processes such as programmed cell death.

Age Factors↗
PubMed1994

Ultrastructural localization of nitric oxide synthase in canine small intestine and colon.

The ultrastructural distribution and subcellular localization of nitric oxide synthase (NOS) immunoreactivity and its possible colocalization with vasoactive intestinal polypeptide (VIP) and substance P in the muscularis externa in canine ileum and colon were studied by using polyclonal antisera raised against VIP, substance P, and cerebellar NOS. Immunogold staining, with or without silver enhancement, was carried out directly on ultrathin sections using single and two-faced double immunogold methods. NOS immunoreactivity was observed in nerve profiles in myenteric plexus and circular muscle layer. Immunoreactivity was occasionally detected in smooth muscle cells and interstitial cells of Cajal. The double immunostaining revealed NOS and VIP in the same nerve varicosities but never in the same organelles. NOS was localized in electron-dense material of undetermined nature, whereas VIP was associated with large granular vesicles. Substance P and NOS were never found in the same nerves. These results indicate that NOS is present in the enteric nerves containing VIP but in different organelles and that nitric oxide release probably does not occur by an exocytotic mechanism.

Amino Acid Oxidoreductases↗
PubMed1994

Human uterine arterial relaxation induced by nitroxidergic nerve stimulation.

Uterine arterial strips obtained from humans responded to nicotine with a contraction, which was abolished by prazosin. In the arteries treated with the alpha 1-receptor antagonist and partially contracted with serotonin, nicotine produced a relaxation that was not influenced by treatment with atropine or timolol and endothelium denudation but was abolished by hexamethonium, oxyhemoglobin, and NG-nitro-L-arginine (L-NNA). The inhibitory effect of L-NNA was reversed by L- but not D-arginine. Relaxations induced by nitroglycerin and nitric oxide (NO) were not affected by L-NNA but were abolished by oxyhemoglobin. Transmural electrical stimulation relaxed the arterial strips treated with prazosin; this response was abolished by L-NNA and restored by L-arginine. Histochemical study with NO synthase antiserum demonstrated the presence of immunoreactive nerve fibers in the adventitia. It may be concluded that human uterine arteries are innervated by vasodilator nerves that liberate NO as a neurotransmitter after chemical or electrical stimulation. Predominant vasoconstriction due to nerve stimulation appears to be associated with activation of alpha 1-adrenoceptors by neurogenic norepinephrine.

Adult↗
PubMed1994

Inhibition of sphincter of Oddi function by the nitric oxide carrier S-nitroso-N-acetylcysteine in rabbits and humans.

Nitric oxide (NO) is an inhibitor of gastrointestinal smooth muscle. Model systems of the gut predict the NO will complex with biological thiol (SH) groups, yielding S-nitrosothiols (RS-NO), which may limit the propensity to form mutagenic nitrosamines. The inhibitory effects of NO and its biologically relevant adducts on sphincter of Oddi (SO) motility have been inferred from animal studies; however, their importance in regulating human SO is not known. The objectives of this study were to (a) provide histologic confirmation of nitric oxide synthase (NOS) in human SO; (b) characterize the pharmacology of S-nitroso-N-acetylcysteine (SNAC), an exemplary S-nitrosothiol, on SO motility in a rabbit model; and (c) study the effects of topical SNAC on SO motility in humans. Immunocytochemical and histochemical identification of NOS was performed in human SO. The pharmacologic response of SNAC was defined in isolated rabbit SO using a standard bioassay. Topical SNAC was then applied to the duodenal papilla in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) and biliary manometry. NOS was localized to nerve fibers and bundles of the SO in rabbits and humans. SNAC inhibited spontaneous motility (frequency and amplitude) as well as acetylcholine-induced elevations in SO basal pressure in the rabbit model. In patients undergoing ERCP and biliary manometry, topical SNAC inhibited SO contraction freqency, basal pressure, and duodenal motility. NOS is localized to neural elements in human SO, implicating a role for NO in regulating SO function. Supporting this concept, SNAC is an inhibitor of SO and duodenal motility when applied topically to humans during ERCP. Our data suggest a novel clinical approach using local NO donors to control gastrointestinal motility and regulate sphincteric function.

Acetylcysteine↗
PubMed1993

Targeted disruption of the neuronal nitric oxide synthase gene.

By homologous recombination, we have generated mice that lack the neuronal nitric oxide synthase (NOS) gene. Neuronal NOS expression and NADPH-diaphorase (NDP) staining are absent in the mutant mice. Very low level residual catalytic activity suggests that other enzymes in the brain may generate nitric oxide. The neurons normally expressing NOS appear intact, and the mutant NOS mice are viable, fertile, and without evident histopathological abnormalities in the central nervous system. The most evident effect of disrupting the neuronal NOS gene is the development of grossly enlarged stomachs, with hypertrophy of the pyloric sphincter and the circular muscle layer. This phenotype resembles the human disorder infantile pyloric stenosis, in which gastric outlet obstruction is associated with the lack of NDP neurons in the pylorus.

Amino Acid Oxidoreductases↗
PubMed1993

Enhanced expression of nitric oxide synthase by rat retina following pterygopalatine parasympathetic denervation.

Removal of the pterygopalatine ganglion enhanced the expression of nitric oxide synthase (NOS) in the ipsilateral rat retina and optic nerve by immunohistochemical and biochemical criteria. The denervation procedure did not alter the apparent histochemical reactivity of retinal cells normally immunoreactive for NOS but did induce expression in retinal ganglion cells and their axons in the retinal nerve fiber layer and optic nerve. After denervation, the induced NOS immunohistochemical reactivity was consistently visualized by day 7, reached a maximum intensity during days 14 to 28, and thereafter gradually attenuated to become barely detectable by microscopy at 10 weeks. Biochemical assays performed two weeks after pterygopalatine denervation confirmed the immunohistochemical observations, especially with regard to the optic nerve. The induced enzyme activity in both retina and optic nerve showed calcium dependency. These results point towards interactions of the ocular parasympathetic innervation and the retina, between which no known neuronal connections exist.

Amino Acid Oxidoreductases↗
PubMed1993

Nitric oxide synthase-immunoreactive nerve fibers in dog cerebral and peripheral arteries.

Nitric oxide synthase (NOS)-immunoreactive fibers innervating the dog arterial wall were histochemically determined by the use of NOS antiserum. NOS-immunoreactive fibers were consistently found in every arterial wall examined. In a whole-mount preparation, NOS-positive fibers were detectable in the small pial artery having a diameter of about 100 microns as well as the proximal middle cerebral artery. Further detailed analyses in thin cryostat sections indicated that in middle cerebral, basilar, temporal, mesenteric and femoral arteries, fine NOS-positive fibers were detected in outer zones of the media in addition to many thicker fibers in the adventitia. However, in the coronary artery, many thick fibers were situated in the adventitia, and fine NOS-positive fibers were not found in the media. Injection of ethanol to the pterygopalatine ganglion markedly decreased or abolished the NOS immunoreactivity in nerve cells and fibers and abolished the innervation of NOS-positive fibers in the wall of middle cerebral artery of the ipsilateral side. Together with findings in our previous publications concerning the functional role of nitroxidergic nerve in the control of arterial tone, we conclude that perivascular nerves containing NOS are crucial in eliciting the neurally induced, NO-mediated arterial relaxation.

Amino Acid Oxidoreductases↗
PubMed1993

Neurons synthesizing nitric oxide innervate the mammalian carotid body.

The carotid body is an arterial chemoreceptor organ sensitive to blood levels of O2, CO2 and pH. The present immunocytochemical and neurochemical study has demonstrated the presence of an extensive plexus of nitric oxide (NO)-synthesizing nerve fibers in this organ. These nitric oxide synthase (NOS)-containing axons are closely associated with parenchymal type I cells and with blood vessels in the carotid body. Denervation and retrograde tracing experiments have revealed that these fibers arise from NOS-immunoreactive and nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase-positive neuronal cell bodies located in the petrosal ganglion and the carotid body, and dispersed along the glossopharyngeal and carotid sinus nerves (CSN). Within the petrosal ganglion, these neurons are topographically segregated from the catecholaminergic cells, and they contain the neuropeptide, substance P. NOS-positive autonomic microganglial cells in the carotid body and CSN also exhibit choline acetyltransferase (ChAT) immunoreactivity. Our results suggest that nitric oxide may be a novel neuronal messenger in the mammalian carotid body involved in the modulation of chemosensory transduction and transmission in this organ.

Amino Acid Oxidoreductases↗
PubMed1993

The distribution of nitric oxide synthase-containing autonomic preganglionic terminals in the rat.

Nitric oxide synthase (NOS)-immunoreactivity was co-localised with NADPH diaphorase activity in preganglionic sympathetic neurons and in their terminals in pre- and paravertebral sympathetic ganglia. The density of NOS-containing terminals varied between ganglia. Reactive terminals were densest in the superior cervical, stellate and inferior mesenteric ganglia, where the majority of the neurons were surrounded by reactive fibres, and the coeliac and superior mesenteric ganglia, where about half the postganglionic somata were surrounded by reactive terminals. Fibres were least abundant in the pelvic ganglia and thoracic and lumbar sympathetic chain ganglia. NOS reactivity did not coincide with the distribution of calcitonin gene related peptide immunoreactivity, a marker for the terminals of NOS-containing sensory neurons in the rat. The distribution of nerve cells and terminals suggests that NOS is present in more than one functional subpopulation of sympathetic preganglionic neurons.

Amino Acid Oxidoreductases↗
PubMed1993

The localization of nitric oxide synthase in the rat eye and related cranial ganglia.

Nitric oxide synthase is the biosynthetic enzyme for the free radical neurotransmitter nitric oxide. Using an affinity-purified antiserum, nitric oxide synthase was found to be localized to peripheral ocular nerve fibers, related cranial ganglia, and the retina of the rat. In the eye, nitric oxide synthase-like immunoreactive peripheral nerve fibers were visualized mainly in the choroid and about limbal blood vessels. The anterior uvea was quite sparsely innervated, and the cornea was negative. Many principal neurons in the pterygopalatine ganglion were immunoreactive for nitric oxide synthase while very few cells stained in the superior cervical and trigeminal ganglia. Virtually all nitric oxide synthase-like immunoreactive pterygopalatine cells were also immunostained for vasoactive intestinal polypeptide; nitric oxide synthase also partially co-localized with neuropeptide Y in some of the neurons of this ganglion. Pterygopalatine ganglionectomy significantly reduced the number of peripheral nitric oxide synthase-like immunoreactive nerve fibers in the eye. A variety of immunoreactive retinal cells were seen. Most cells in the inner nuclear layer or ganglion cell layer corresponded morphologically to amacrine cells and displaced amacrine cells. Interplexiform cells and occasional faintly stained cells in the outer portion of the inner nuclear layer also were visualized. Nicotinamide adenine dinucleotide phosphate diaphorase histochemistry generally stained cells of similar distribution but did reveal somewhat more extensive localizations in peripheral ocular tissues, the ciliary ganglion, and the retina, compared with nitric oxide synthase immunohistochemistry. Nitric oxide synthase thus localizes to peripheral ocular nerve fibers, chiefly parasympathetic in nature and derived from the pterygopalatine ganglion, and to several cell types in the retina. Nitric oxide probably acts as a choroidal vasodilator of parasympathetic origin in the eye; the neuropeptide co-localizations in the pterygopalatine ganglion suggest complex neuromodulatory interactions. The retinal localizations imply potential neurotransmitter functions for nitric oxide in this tissue.

Amino Acid Oxidoreductases↗
PubMed1993

Immunohistochemical localization of nitric oxide synthase in the autonomic innervation of the human penis.

An improved understanding of the physiology of penile erection has resulted from recent evidence that implicates nitric oxide as the principal mediator of erectile function. Previously, the neuroanatomy of erection in man was established with descriptions of the autonomic innervation of the pelvic organs and external genitalia. The basis upon which novel physiological concepts of erection relate to earlier neuroanatomical principles remains to be determined. In the present study these relationships were explored with nitric oxide synthase immunohistochemistry and reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry of select pelvic tissue specimens obtained from 4 men (3 at radical prostatectomy and 1 at autopsy). Nitric oxide synthase, the enzyme that catalyzes nitric oxide production, was identified in discrete neuronal locations, including the pelvic plexus, cavernous nerves and their terminal endings within the corporeal erectile tissue, branches of the dorsal penile nerves and nerve plexuses in the adventitia of the deep cavernous arteries. This distribution of nitric oxide synthase-containing nerves suggests that nitric oxide neuronally modulates local vascular smooth musculature of the penis. On this basis, nitric oxide is identified as a neuronal mediator of penile erection in man.

Aged↗
PubMed1993

Possible origins and distribution of immunoreactive nitric oxide synthase-containing nerve fibers in cerebral arteries.

The distribution of perivascular nerve fibers expressing nitric oxide synthase (NOS)-immunoreactivity was examined in Sprague-Dawley and Long-Evans rats using affinity-purified rabbit antisera raised against NOS from rat cerebellum. NOS immunoreactivity was expressed within the endothelium and adventitial nerve fibers in both rat strains. Labeled axons were abundant and dense in the proximal anterior and middle cerebral arteries, but were less numerous in the caudal circle of Willis and in small pial arteries. The sphenopalatine ganglia were the major source of positive fibers in these vessels. Sectioning postganglionic parasympathetic fibers from both sphenopalatine ganglia reduced the density of NOS-immunoreactive (IR) nerve fibers by > 75% in the rostral circle of Willis. Moreover, NOS-IR was present in 70-80% of sphenopalatine ganglion cells. Twenty percent of these neurons also contained vasoactive intestinal polypeptide (VIP)-immunoreactivity. By contrast, the superior cervical ganglia did not contain NOS-IR cells. In the trigeminal ganglion, NO-IR neurons were found chiefly within the ophthalmic division; approximately 10-15% of neurons were positively labeled. Colocalization with calcitonin gene-related peptide (CGRP) was not observed. Sectioning the major trigeminal branch innervating the circle of Willis decreased positive fibers by < or = 25% in the ipsilateral vessels. In the nodose ganglion, 20-30% of neurons contained NOS-immunoreactivity, whereas less than 1% were in the C2 and C3 dorsal root ganglia. Three human circles of Willis obtained at autopsy showed sparse immunoreactive fibers, chiefly within vessels of the posterior circulation. Postmortem delay accounted for some of the reduced density. Our findings indicate that nerve fibers innervating cerebral arteries may serve as a nonendothelial source of the vasodilator nitric oxide (NO). The coexistence of NOS and VIP within sphenopalatine ganglion cells raises the possibility that two vasodilatory agents, one, a highly diffusable short-lived, low-molecular-weight molecule, and the other, a polar 28 amino acid-containing peptide, may serve as coneuromediators within the cerebral circulation.

Amino Acid Oxidoreductases↗