Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We observed in rats the changes in cochlear blood flow (CoBF) and cutaneous blood flow of the abdominal wall (AbBF) after the administration of the NO synthase inhibitor, N-nitro-L-arginine-methyl ester (L-NAME). Ten minutes after i.v. infusion of L-NAME (0.2, 1, 5, 10 mg/kg), L-arginine, which is a substrate of NO, was infused (100 mg/kg) i.v. Employing a laser Doppler flowmeter, the changes in blood flow were recorded from the basal turn of the right cochlea or the abdominal wall and blood pressure (BP) was recorded from the left femoral artery simultaneously. Vascular conductance (VC) was calculated from CoBF/mean BP (cochlear VC) or AbBF/mean BP (abdominal VC). The findings in rats generally agreed with those in guinea pigs [Brechtelsbauer et al., Hear. Res. 77 (1994) 38-42]. Intravenous infusion of L-NAME produced a dose-dependent depression of cochlear VC at 0.2 mg/kg (-18.9), 1 mg/kg (-37.9%), 5 mg/kg (-45.8%) and 10 mg/kg (-48.3%). AbBF also decreased after infusion of L-NAME (5 mg/kg) but to a lesser degree (-41.1% in VC) with no significance compared to CoBF (5 mg/kg). Infusion of L-arginine partially reversed the CoBF decrease caused by L-NAME. The group of 0.2 mg/kg infusion of L-NAME showed the largest degree of recovery with L-arginine, while the 10 mg/kg group showed the smallest. The decrease in AbBF did not recover substantially with L-arginine, the degree being less than that of each group in the CoBF experiment. It was suggested that the NO/soluble guanylate cyclase/cGMP system is more active in the cochlear microcirculation. With the round window (RW) application of 1% L-NAME (2 microl), cochlear VC was decreased by 21.6%, which was closest to that of the 0.2 mg/kg group of L-NAME i.v. infusion. The cochlear VC depression after local application of L-NAME did not show any recovery (-0.3%) by RW application of 5% L-arginine (2 microl) 25 min after L-NAME application; a slight gradual increase was observed when a higher concentration (20%) of L-arginine was applied to the RW. We propose that i.v. infusions of L-NAME and L-arginine primarily affect the precapillary arteriole of the spiral modiolar artery which effectively regulates microcirculation as a resistance vessel, and that RW application affects the vessels of the lateral wall, not the spiral modiolar artery because of the difficulty of substance diffusion.
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PMID:Effects of nitric oxide synthase inhibitor on cochlear blood flow. 1220 47

We evaluated the contribution of peroxynitrite to the fatal cardiovascular depression induced by overproduction of nitric oxide (NO) after activation of inducible NO synthase (iNOS) in the rostral ventrolateral medulla (RVLM), the origin of sympathetic vasomotor tone. In Sprague-Dawley rats maintained under propofol anesthesia, microinjection of E. coli lipopolysaccharide (LPS) bilaterally into the RVLM elicited significant hypotension, bradycardia, reduction in sympathetic vasomotor tone and mortality. There was also a discernible elevation of iNOS expression in the ventrolateral medulla, followed by a massive production of nitrotyrosine, an experimental index for peroxynitrite. Co-administration bilaterally into the RVLM of the selective iNOS inhibitor, S-methylisothiourea (50, 100 or 250 pmol), an active peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis- (N-methyl-4'-pyridyl)-porphyrinato iron (III) (10 or 50 pmol), a peroxynitrite scavenger, L-cysteine (5, 50 or 100 pmol), or a superoxide dismutase mimetic, Mn(III)-tetrakis-(4-benzoic acid) porphyrin (1 or 10 pmol), significantly prevented mortality, reduced nitrotyrosine production and reversed the NO-induced cardiovascular suppression after application of LPS into the RVLM. We conclude that the formation of peroxynitrite by a reaction between superoxide anion and NO is primarily responsible for the fatal cardiovascular depression induced by overproduction of NO after activation of iNOS at the RVLM.
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PMID:Contribution of peroxynitrite to fatal cardiovascular depression induced by overproduction of nitric oxide in rostral ventrolateral medulla of the rat. 1238 74

SSRI-induced sexual dysfunction affects 30% to 50% or more of individuals who take these drugs for depression. Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5HT2 and 5HT3 receptors; decreased dopamine; blockade of cholinergic and alpha-1 adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels. Five approaches to treatment include conservative approaches such as wait and see, decrease dosage, and drug holidays. More aggressive strategy for treating SSRI-induced sexual dysfunction are changing antidepressants and augmentation.
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PMID:Mechanisms and treatments of SSRI-induced sexual dysfunction. 1238 82

To understand cyclic nucleotide dynamics in intact cells, we used the patch-cramming method with cyclic nucleotide-gated channels as real-time biosensors for cGMP. In neuroblastoma and sympathetic neurons, both muscarinic agonists and nitric oxide (NO) rapidly elevate cGMP. However, muscarinic agonists also elicit a long-term (2 hr) suppression (LTS) of subsequent cGMP responses. Muscarinic agonists elevate cGMP by triggering Ca2+ mobilization, which activates NO synthase to produce NO, leading to the activation of soluble guanylate cyclase (sGC). Here we examine the mechanism of LTS. Experiments using direct intracellular cGMP injection demonstrate that enhancement of phosphodiesterase (PDE) activity, rather than depression of sGC activity, is responsible for LTS. Biochemical measurements show that both cGMP and cAMP content is suppressed, consistent with the involvement of a nonselective PDE. Application of pharmacological agents that alter Ca2+ mobilization from intracellular stores and experiments involving injection of the Ca2+ chelator BAPTA show that Ca2+ mobilization is necessary and sufficient for LTS induction but also show that LTS maintenance is Ca2+-independent. Protein phosphatase injection reverses LTS, and specific inhibitors of Ca2+/calmodulin kinase II (CaMKII) prevent induction and inhibit maintenance. The switch between the Ca2+ dependence of LTS induction to the Ca2+ independence of LTS maintenance is consistent with CaMKII autophosphorylation, similar to proposed mechanisms of hippocampal long-term potentiation. Because the molecular machinery underlying LTS is common to many cells, LTS may be a widespread mechanism for long-term silencing of cyclic nucleotide signaling.
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PMID:Patch cramming reveals the mechanism of long-term suppression of cyclic nucleotides in intact neurons. 1238 88

Stress and depression have a significant impact on modern society. Even though their symptomatology is well characterized, little is known about the molecular mechanisms underlying these disturbing disorders. While the role of neurotransmitters such as serotonin, norepinephrine (NE), dopamine (DA), corticotropin-releasing hormone (CRH), and arginine vasopressin (AVP) has been extensively studied, new evidence suggests a role for the unique neurotransmitter nitric oxide (NO). This highly diffusible and reactive molecule is synthesized by at least three enzyme subtypes of NO synthase (NOS). The commonly known neuronal NOS subtype is localized in areas of the brain related to stress and depression. The limbic-hypothalamic-pituitary-adrenal (LHPA) axis is the core of this system. These interrelated pathways have in common the production, and negative feedback, of glucocorticoids. Within these areas, NO is suggested to play a role in modulating the release of other neurotransmitters, acting as a cellular communicator in plasticity and development, and/or acting as a vasodilator in regulation of blood flow. This article summarizes some of the recent advances in the understanding of the role of NO in stress and depression.
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PMID:Nitric oxide, stress, and depression. 1239 68

Repetitive transcranial magnetic stimulation (rTMS) has been applied for treatment of several diseases such as depression. However, the safety and biological effects of rTMS have not been fully elucidated. In this study, the effects of rTMS on the levels of inflammatory mediators in the central nervous system (CNS), which may be involved in neurodegenerative disorders, were investigated in comparison with the electric convulsive model. Long-term rTMS (1500 pulses at 30 Hz/day for series of 7 days) stimulation, which did not elicit convulsion, was given to rats (rTMS rats). Single high-frequency electrical stimulation (100 Hz, 0.5-ms pulse width, 1 s duration, 50 mA), which induced convulsion, was given to rats (ES rats). mRNA levels of interleukin (IL)-1beta, IL-6, cyclooxygenase (COX)-2 and inducible nitric oxide synthetase (iNOS) in the brain were evaluated by reverse transcription-polymerase chain reaction before and after these stimulations. mRNA of IL-1beta, IL-6 and COX-2 was induced in the brains of ES rats but not in the brains of long-term rTMS rats. mRNA of iNOS was not induced in the brain of long-term rTMS rats. These results suggest that long-term rTMS may safe and modulate neural function without up-regulation of inflammatory mediators, which may be involved in neurodegenerative disorders.
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PMID:The long-term high-frequency repetitive transcranial magnetic stimulation does not induce mRNA expression of inflammatory mediators in the rat central nervous system. 1244 77

The role of inducible nitric-oxide synthase (iNOS) in the pathogenesis of heart failure is still a matter of controversy. In contrast to early reports favoring a contribution of iNOS because of the negative inotropic and apoptotic potential of NO, more recent clinical and experimental data question a causative role. Here we report that transgenic mice with cardiac specific iNOS-overexpression and concomitant myoglobin-deficiency (tg-iNOS+/myo-/-) develop signs of heart failure with cardiac hypertrophy, ventricular dilatation, and interstitial fibrosis. In addition, reactivation of the fetal gene expression program typical for heart failure occurs. The structural and molecular changes are accompanied by functional depression such as reduced contractility, ejection fraction, and cardiac energetics. Our findings indicate that excessive cardiac NO formation can cause heart failure; however, under normal circumstances myoglobin constitutes the important barrier that efficiently protects the heart from nitrosative stress.
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PMID:Myoglobin protects the heart from inducible nitric-oxide synthase (iNOS)-mediated nitrosative stress. 1266 3

Neurogenic ATP and nitric oxide (NO) may play important roles in the physiological control of gastrointestinal motility. However, the interplay between purinergic and nitrergic neurons in mediating the inhibitory neurotransmission remains uncertain. This study investigated whether neurogenic NO modulates the purinergic transmission to circular smooth muscles of the hamster proximal colon. Electrical activity was recorded from circular muscle cells of the hamster proximal colon by using the microelectrode technique. Intramural nerve stimulation with a single pulse evoked a fast purinergic inhibitory junction potential (IJP) followed by a slow nitrergic IJP. The purinergic component of the second IJP evoked by paired stimulus pulses at pulse intervals between 1 and 3 s became smaller than that of the first IJP. This purinergic IJP depression could be observed at pulse intervals <3 s, but not at longer ones, and failed to occur in the presence of NO synthase inhibitor. Exogenous NO (0.3-1 microM), at which no hyperpolarization is produced, inhibited purinergic IJPs, without altering the nitrergic IJP and exogenously applied ATP-induced hyperpolarization. In the presence of both purinoceptor antagonist and nitric oxide synthase (NOS) inhibitor, intramural nerve stimulation with 5 pulses at 20 Hz evoked vasoactive intestinal peptide (VIP)-associated IJPs, suggesting that VIP component may be masked in the IJPs of the hamster proximal colon. Our results suggest that neurogenic NO may modulate the purinergic transmission to circular smooth muscles of the hamster proximal colon via a prejunctional mechanism. In addition, VIP may be involved in the neurotransmitter in the hamster proximal colon.
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PMID:Nitrergic prejunctional inhibition of purinergic neuromuscular transmission in the hamster proximal colon. 1274 Mar 97

Using histochemical reaction demonstrating NADPH-diaphorase (NADPH-d), the dynamics of NO synthesis was studied in the rat brain raphe nuclei following intravenous injection of morphine hydrochloride. In normal conditions NADPH-d activity was demonstrated in neurons of all raphe nuclei. Acute and chronic administration of morphine in different doses (0.5 mg/kg and 5 mg/kg) was found to inhibit NO-ergic activity of the major part of raphe nuclei neurons. The depression of NADPH-d activity was unequal in different nuclei. The NO-ergic changes are caused by an activation of opiate receptors, as they depend on morphine dose, while the application of opiate antagonist naloxone restores the NO-ergic function of raphe neurons. Formation of tolerance to opiate analgetic effect is accompanied by a significant, though short-lasting increase of NO synthesis activity. It is suggested that the changes in NO-ergic function of raphe neurons may influence brain serotonin balance after opiate administration.
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PMID:[NO-ergic rat brain commissural neurons in the norm and during opiate administration]. 1289 74

We investigated the role of nitric oxide (NO) in the control of myocardial O2 consumption in Fischer 344 rats. In Fischer rats at 4, 14, and 23 mo of age, we examined cardiac function using echocardiography, the regulation of cardiac O2 consumption in vitro, endothelial NO synthase (eNOS) protein levels, and potential mechanisms that regulate superoxide. Aging was associated with a reduced ejection fraction [from 75 +/- 2% at 4 mo to 66 +/- 3% (P < 0.05) at 23 mo] and an increased cardiac diastolic volume [from 0.60 +/- 0.04 to 1.00 +/- 0.10 ml (P < 0.01)] and heart weight (from 0.70 +/- 0.02 to 0.90 +/- 0.02 g). The NO-mediated control of cardiac O2 consumption by bradykinin or enalaprilat was not different between 4 mo (36 +/- 2 or 34 +/- 3%) and 14 mo (29 +/- 1 or 25 +/- 3%) but markedly (P < 0.05) reduced in 23-mo-old Fischer rats (15 +/- 3 or 7 +/- 2%). The response to the NO donor S-nitroso-N-acetyl penicillamine was not different across groups (35%, 35%, and 44%). Interestingly, the eNOS protein level was not different at 4, 14, and 23 mo. The addition of tempol (1 mmol/l) to the tissue bath eliminated the depression in the control of cardiac O2 consumption by bradykinin (25 +/- 3%) or enalaprilat (28 +/- 3%) in 23-mo-old Fischer rats. We next examined the levels of enzymes involved in the production and breakdown of superoxide. The expression of Mn SOD, Cu/Zn SOD, extracellular SOD, and p67phox, however, did not differ between 4- and 23-mo-old rats. Importantly, there was a marked increase in gp91phox, and apocynin restored the defect in NO-dependent control of cardiac O2 consumption at 23 mo to that seen in 4-mo-old rats, identifying the role of NADPH oxidase. Thus increased biological activity of superoxide and not decreases in the enzyme that produces NO are responsible for the altered control of cardiac O2 consumption by NO in 23-mo-old Fischer rats. Increased oxidant stress in aging, by decreasing NO bioavailability, may contribute not only to changes in myocardial function but also to altered regulation of vascular tone and the progression of cardiac or vascular disease.
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PMID:NAD(P)H oxidase-generated superoxide anion accounts for reduced control of myocardial O2 consumption by NO in old Fischer 344 rats. 1291 88


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