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

Infarcted areas of rabbit myocardium show relatively higher inducible nitric oxide synthase activity, measured by the conversion of L-[14C]arginine to L-[14C]citrulline. The principal finding in this study is that dexamethasone (2 mg/kg) prevents the induction of inducible nitric oxide synthase in heart muscle when given before, or even 3 hr after coronary artery ligation. Additionally cyclic GMP levels remain unchanged following treatment with dexamethasone. It is possible that the enhanced production of nitric oxide by inducible nitric oxide synthase accounts, at least in part, for the depression of myocardial contractility seen in myocardial infarction and in other clinical conditions.
 ...
PMID:Dexamethasone inhibits the expression of an inducible nitric oxide synthase in infarcted rabbit myocardium. 751 19

Administration of whole-cell diphtheria and tetanus toxoids and pertussis vaccine adsorbed (DTP vaccine) caused marked depression in the expression of mRNA for isozymes of cytochrome P-450 in the livers of endotoxin-responsive and nonresponsive mice. The levels of expression of mRNA for a polycyclic aromatic hydrocarbon-inducible (CYP1A2) and an ethanol-inducible (CYP2E1) form of P-450 were reduced by 70% to 80% 8 to 12 hr after vaccination or Bordetella pertussis endotoxin administration. These effects are preceded by marked increases (threefold to sixfold) in mRNA expression for interleukin-6, interleukin-1 and tumor necrosis factor in both strains of mice, with maximal increases 1 to 2 hr after injection. This is the first demonstration that levels of cytokine mRNA are altered in the liver in response to DTP vaccine administration. The finding of increased cytokine mRNA in the livers of mice injected with vaccine supports a role for cytokines as mediators of the decreased levels of cytochrome P-450. In addition, inducible nitric oxide synthase mRNA expression is also increased after vaccine administration, with a peak at 4 hr. The temporal relationship of the increased cytokine mRNA expression, increased nitric oxide synthase and decreased expression of P-450 mRNAs suggests a mechanism by which cytokines mediate the induction of nitric oxide synthase, which increases nitric oxide and decreases the activities of some cytochromes P-450.
 ...
PMID:Modulation of hepatic mRNA levels after administration of lipopolysaccharide and diphtheria and tetanus toxoids and pertussis vaccine adsorbed (DTP vaccine) to mice. 752 68

The decreased contraction amplitude of isolated cardiac myocytes from guinea pigs exposed to lipopolysaccharide (LPS) was reported to be partially reversed by nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS) [Brady, et al., Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1963-H1966, 1992]. We have tested the potential involvement of NO formation in LPS-induced cardiac depression in the intact heart. Isolated perfused hearts of LPS-treated guinea pigs (4 mg/kg 4 h before organ removal) displayed a greatly decreased left ventricular pressure (LVP) when compared with untreated controls (48 +/- 11 vs. 93 +/- 18 mmHg, n = 6 hearts each), whereas heart rate and coronary flow were similar. Perfusion of LPS-treated hearts with L-NMMA or L-NAME (100 microM each) at constant flow did not increase LVP (50 +/- 14 and 44 +/- 11, respectively, vs. 52 +/- 14 mmHg). However, coronary resistance increased significantly. There was no difference between LPS-treated and control hearts in venous adenosine release (104 +/- 58 vs. 133 +/- 86 pmol.min-1.g-1). Measurement of the activities of the induced (iNOS) and constitutive forms of NOS revealed that there was no difference in total NOS activity (237 +/- 82 vs. 181 +/- 97 fmol.min-1.mg protein-1. There was no measurable induction of iNOS in the LPS-treated hearts either. Finally, cardiac energy status was studied by 31P nuclear magnetic resonance spectroscopy. There was no difference between LPS-treated and control hearts in myocardial ATP, creatine phosphate, pH, and free ADP (59 +/- 20 vs. 50 +/- 27 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Endotoxin-induced contractile dysfunction in guinea pig hearts is not mediated by nitric oxide. 754 61

Nitric oxide (NO), produced by either constitutive or inducible isoforms of NO synthase (cNOS or iNOS), influences myocardial inotropic and chronotropic responses. This pathway has been studied using NO donors or NOS inhibitors or by immune-mediated stimulation of iNOS. Although inhibition of constitutive NO activity in the heart does not influence indices of myocardial contractility, NO donors, in some species and preparations, may exert a negative inotropic effect as well as an enhancement of diastolic relaxation. The best documented cardiac action of NO is inhibition of the positive inotropic and chronotropic responses to beta-adrenergic receptor stimulation. Basal NO production, presumable via cNOS, appears to exert a mild tonic inhibition of beta-adrenergic responses. On the other hand, excessive NO production mediated by iNOS may contribute to the myocardial depression and beta-adrenergic hyporesponsiveness associated with conditions such as sepsis, myocarditis, cardiac transplant rejection, and dilated cardiomyopathy. Muscarinic cholinergic stimulation of the heart appears to stimulate NO production that mediates, at least partially, parasympathetic slowing of heart rate and inhibition of beta-adrenergic contractility. NO-stimulated production of 3',5'-cyclic guanosine monophosphate via guanylyl cyclase accounts for many of the observed physiological actions of NO. 3',5'-Cyclic guanosine monophosphate inhibits the beta-adrenergic-stimulated increase in the slow-inward calcium current and reduces the calcium affinity of the contractile apparatus, actions that could contribute to a negative inotropic effect, an abbreviation of contraction, and an enhancement of diastolic relaxation. Biochemical, immunocytochemical, and molecular biological techniques have been used to show the presence of both cNOS and iNOS within the myocardium. cNOS is expressed in myocytes, endothelial cells, and neurons in the myocardium, and there is evidence for iNOS in myocytes, small vessel endothelium, vascular smooth muscle cells, and immune cells that infiltrate the heart. Taken together, these observations suggest that NO influences normal cardiac physiology and may play an important role in the pathophysiology of certain disease states associated with cardiac dysfunction.
 ...
PMID:Role of nitric oxide in the regulation of myocardial function. 756 4

Nitric oxide is a short-lived reactive mediator that inhibits bone marrow (BM) cell proliferation induced by granulocyte-macrophage colony-stimulating factor (GM-CSF). The present studies show that nitric oxide also inhibits macrophage colony-stimulating factor (M-CSF)-induced growth of mouse BM cells, an effect that was dependent on the presence of an inflammatory mediator and blocked by the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMA). Treatment of mice with the hematotoxicant benzene (800 mg/kg, intraperitoneally, two times per day, for 2 days) resulted in a significant increase in nitric oxide production by BM cells stimulated with lipopolysaccharide (LPS) and interferon gamma alone or in combination with M-CSF or GM-CSF. Cells from benzene-treated mice also displayed increased sensitivity to the growth-promoting effects of M-CSF and GM-CSF. These results suggest that benzene treatment of mice primes BM cells to inducers of nitric oxide. Northern blot analysis showed that this was, at least in part, caused by increased expression of mRNA for inducible nitric oxide synthase (iNOS). Surprisingly, treatment of mice with L-NMA was found to cause a depression in BM cell proliferation and to potentiate benzene-induced decreases in BM cellularity and increases in nitric oxide production. L-NMA administration also augmented nitric oxide production by BM cells. These data indicate that L-NMA is hematotoxic and suggest that it may have actions distinct from inhibition of nitric oxide synthase in the BM.
 ...
PMID:Enhanced production of nitric oxide by bone marrow cells and increased sensitivity to macrophage colony-stimulating factor (CSF) and granulocyte-macrophage CSF after benzene treatment of mice. 819 60

1. We performed experiments to examine the effects of an anti-fungal imidazole compound, econazole, on the regulation and effects of lipopolysaccharide-inducible nitric oxide synthase (iNOS) activity in rat aortic rings and cultured J774 murine macrophage cells. 2. In endothelium-intact rings of thoracic aorta, phenylephrine caused a concentration-dependent contraction with EC50 of 1.9 +/- 0.15 x 10(-8) M (n = 5). Following incubation with lipopolysaccharide (LPS, 5 micrograms ml-1) for 8 h there was a right-shift in the concentration-response curve (EC50 3.1 +/- 0.28 x 10(-7) M, P < 0.05) with a depression in the maximum contraction from 1.44 +/- 0.25 g to 0.86 +/- 0.26 g (n = 4). Co-incubation of rings with econazole (1 x 10(-5) M) partially inhibited the LPS-induced loss of reactivity to phenylephrine (EC50 6.5 +/- 0.72 x 10(-8) M) and fully inhibited the reduction in maximum tension (1.49 +/- 0.19 g; n = 5). 3. In J774 cells, incubation with LPS (10 micrograms ml-1, 24 h) resulted in significant nitrite production that was inhibited by co-incubation with econazole (IC50 5.0 +/- 0.9 x 10(-6) M; n = 5). In cells stimulated with LPS, production of L-[3H]-citrulline from L-[3H]-arginine was 6.41 +/- 0.22 pmol mg-1 protein min-1 (n = 3). This was inhibited by 92 +/- 6% by addition of NG-monomethyl-L-arginine (L-NMMA, 1 x 10(-3) M; n = 3) to the homogenate but not by econazole (1 x 10(-5) M; n = 3). In contrast pretreatment of cells with econazole (1 x 10(-5) M) markedly reduced the LPS-induced [3H]-citrulline production (0.86 +/- 0.053 pmol mg-1 protein min-1; P < 0.01; n = 3). 4. In cells treated with LPS and econazole, L-[3H]-citrulline production was restored in a concentration-dependent manner by addition of calmodulin (1 x 10(-8)-3 x 10(-7) M) with an IC50 of 4.2 +/- 0.9 x 10(-8) M. 5. We have shown that econazole inhibits the functional and biochemical activity of iNOS in rat aortic rings and cultured J774 cells. Treatment of cells with econazole renders the NO synthase functionally inactive. In econazole-treated cells enzyme activity is restored by calmodulin suggesting that econazole may inhibit the binding of this essential co-factor to the enzyme following its production. These studies may have implications for the design of novel anti-inflammatory agents working through the L-arginine-nitric oxide pathway.
 ...
PMID:Functional effects of econazole on inducible nitric oxide synthase: production of a calmodulin-dependent enzyme. 888 96

Induction of the inducible isoform of nitric oxide (NO) synthase (iNOS) in the myocardium is implicated as a mechanism in the development of cardiac depression in immune activated states associated with an enhanced release of cytokines, such as septic shock. We evaluated the in vivo synthesis of NO and tetrahydrobiopterin (BH4), a cofactor of NOS, in the heart tissue using a model of LPS injection in rats (LPS: 10 mg/kg, i.v.). In control rats, iNOS activity or iNOS mRNA in the heart was negligible. Three hours after LPS administration, a marked induction of iNOS mRNA and activity was observed in the heart. A significant increase in BH4 content and GTP cyclohydrolase mRNA abundance was also observed in the heart from LPS-treated rats. Our results demonstrate induction of NO synthesis and parallel increase in BH4 concentration in the heart of rats after LPS treatment in vivo and may provide molecular evidence responsible for the increased production of BH4 which may up-regulate iNOS activity in the heart in vivo.
 ...
PMID:Co-induction of nitric oxide and tetrahydrobiopterin synthesis in the myocardium in vivo. 904 35

We have previously proposed that pro-inflammatory cytokines and nitric oxide (NO) contributed to reversible myocardial depression in patients with sepsis and congestive heart failure. Sepsis and heart failure are also associated with refractoriness to beta-adrenoceptor agonists. Therefore, the chronotropic effects of cytokines and the NO synthase inhibitor, NG-methyl-L-arginine (NMA), on beta-adrenoceptor stimulation of neonatal cardiac myocytes were studied. Tumor necrosis factor alpha, interleukin-1 beta and interleukin-6 but not interleukin-4 or interleukin-5 significantly enhanced spontaneous beating rates compared to untreated myocytes in serum-free media for 48 h (P < 0.01; n = 12 for each). NMA also significantly enhanced spontaneous beating rates (P < 0.01; n = 12 for each). Only interleukin-1 beta treatment resulted in significant nitrite production, immunohistochemical staining for inducible nitric oxide synthase and detection of inducible NO synthase messenger RNA by reverse transcriptase-polymerase chain reaction (RT-PCR). However, tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, and NMA each completely blocked the positive chronotropic effects of the beta-adrenoceptor agonist, isoproterenol (P < 0.01; n = 12 for each). These findings are most consistent with an inducible NO synthase-independent effect of cytokines and NMA on the chronotropic responses of neonatal cardiac myocytes to beta-adrenoceptor stimulation. This effect of cytokines and NMA on adrenergic signaling may involve a myocardial constitutive NO synthase or an NO-independent mechanism.
 ...
PMID:Cytokines and nitric oxide synthase inhibitor as mediators of adrenergic refractoriness in cardiac myocytes. 905 50

To evaluate the relationship between cardiovascular injury and the pathological significance of endothelial constitutive nitric oxide synthase (ecNOS) and inducible nitric oxide synthase (iNOS) in endotoxic shock, Wistar rats were injected intraperitoneally with 10 mg/kg Escherichia coli endotoxin and the resulting cardiovascular changes observed using immunohistochemistry, immunoelectron microscopy, the reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization at 4, 6, 8 and 10 h after endotoxin administration. Immunohistochemical and electron microscopic observations showed that ecNOS was localized in the cytoplasmic vesicles and rough endoplasmic reticulum of the endothelium of coronary arteries and intermyocardial capillaries in both control and endotoxin-treated rats. iNOS was localized in the cytoplasmic vesicles and endoplasmic reticulum of vascular endothelial cells, vascular smooth muscle cells and cardiomyocytes after endotoxin administration. The RT-PCR study confirmed the expression of ecNOS and iNOS mRNA in the heart tissues of all animals including controls. In situ hybridization showed that ecNOS mRNA was expressed in the cytoplasm of vascular endothelial cells in control and endotoxin-treated rats. After endotoxin administration, iNOS mRNA was strongly expressed in vascular endothelial cells, vascular smooth muscle cells, cardiomyocytes and a small number of macrophages. Bacterial lipopoly-saccharide induces rapid release of nitric oxide in the microvasculature and cardiomyocytes resulting in the depression of cardiomyocyte contraction. These findings may describe the cardiac response after endotoxin treatment.
 ...
PMID:Differential distribution of ecNOS and iNOS mRNA in rat heart after endotoxin administration. 929 May 78

The different cell types comprising cardiac muscle express one or more of the three isoforms (neuronal NOS, or nNOS; inducible NOS, or iNOS; and endothelial NOS, or eNOS) of nitric oxide synthase (NOS). nNOS is expressed in orthosympathetic nerve terminals and regulates the release of catecholamines in the heart. eNOS constitutively expressed in endothelial cells inhibits contractile tone and the proliferation of underlying vascular smooth muscle cells, inhibits platelet aggregation and monocyte adhesion, promotes diastolic relaxation, and decreases O2 consumption in cardiac muscle through paracrinally produced NO. eNOS is also constitutively expressed in cardiac myocytes from rodent and human species, where it autocrinally opposes the inotropic action of catecholamines after muscarinic cholinergic and beta-adrenergic receptor stimulation. iNOS gene transcription and protein expression are induced in all cell types after exposure to a variety of inflammatory cytokines. Aside from participating in the immune defense against intracellular microorganisms and viruses, the large amounts of NO produced autocrinally or paracrinally mediate the vasoplegia and myocardial depression characteristic of systemic immune stimulation and promote cell death through apoptosis. In cardiac myocytes, NO may regulate L-type calcium current and contraction through activation of cGMP-dependent protein kinase and cGMP-modulated phosphodiesterases. Other mechanisms independent of cGMP elevations may operate through interaction of NO with heme proteins, non-heme iron, or free thiol residues on target signaling proteins, enzymes, or ion channels. Given the multiplicity of NOS isoforms expressed in cardiac muscle and of the potential molecular targets for the NO produced, tight molecular regulation of NOS expression and activity at the transcriptional and posttranscriptional level appear to be needed to coordinate the many roles of NO in heart function in health and disease.
 ...
PMID:Nitric oxide synthases and cardiac muscle. Autocrine and paracrine influences. 935 45


1 2 3 4 5 6 7 8 9 10 Next >>