Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) exerts neurotrophic and neurotoxic effects on dopamine (DA) function in primary midbrain cultures. We investigate herein the role of glutathione (GSH) homeostasis in the neurotrophic effects of NO. Fetal midbrain cultures were pretreated with GSH synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO), 24 h before the addition of NO donors (diethylamine/nitric oxide-complexed sodium and S-nitroso-N-acetylpenicillamine) at doses tested previously as neurotrophic. Under these conditions, the neurotrophic effects of NO disappeared and turned on highly toxic. Reduction of GSH levels to 50% of baseline induced cell death in response to neurotrophic doses of NO. Soluble guanylate cyclase (sGC) and cyclic GMP-dependent protein kinase (PKG) inhibitors protected from cell death for up to 10 h after NO addition; the antioxidant ascorbic acid also protected from cell death but its efficacy decreased when it was added after NO treatment (40% protection 2 h after NO addition). The pattern of cell death was characterized by an increase in chromatin condensed cells with no DNA fragmentation and with breakdown of plasmatic membrane. The inhibition of RNA and protein synthesis and of caspase activity also protected from cell death. This study shows that alterations in GSH levels change the neurotrophic effects of NO in midbrain cultures into neurotoxic. Under these conditions, NO triggers a programmed cell death with markers of both apoptosis and necrosis characterized by an early step of free radicals production followed by a late requirement for signalling on the sGC/cGMP/PKG pathway.
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PMID:Glutathione depletion switches nitric oxide neurotrophic effects to cell death in midbrain cultures: implications for Parkinson's disease. 1175 59

Ten-day administration of the glutamate-cysteine ligase inhibitor L-buthionine-[S,R]-sulfoximine (BSO; 20 or 30 mM in drinking water) to adult male Sprague-Dawley rats induced 50-60% glutathione depletion (p<0.001) and elevated aortic ring reactive oxygen species release and tissue and plasma H2O2 concentrations (p<0.001) compared to control animals (CON) that consumed normal drinking water. In contrast to previous studies using tail cuff plethysmography methods, BSO had no significant effect on systolic blood pressure assessed by indwelling femoral artery catheters in conscious animals (10-day values, 119+/-3 mn Hg vs 122+/-4 mm Hg in CON vs BSO, respectively). Thoracic aorta rings were excised for in vitro assessment of vasomotor function. BSO shifted the phenylephrine (PE) dose-response curve to the left (p=0.003), lowering the EC50 for PE contraction (from -6.752+/-0.056 to -7.056+/-0.055 log units; p=0.001). Endothelium-dependent relaxation to acetylcholine (ACh) was significantly blunted (p=0.019) and the EC50 for ACh relaxation was significantly increased (from -7.428+/-0.117 to -7.129+/-0.048 log units; p=0.02) in BSO vs CON. Endothelium-independent vasorelaxation to sodium nitroprusside was similar in BSO and CON groups. Thoracic aorta immunoblot analyses revealed increases in endothelial nitric oxide synthase, superoxide dismutase 1 and 2, and soluble guanylate cyclase in BSO vs CON (all p<0.01). Thus, enhanced PE contraction, blunted endothelium-dependent relaxation, and adaptations in nitric oxide bioavailability pathways provide the first evidence of chronic, in vivo BSO-induced, oxidative stress-mediated direct effects on the vasomotor function of arteries.
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PMID:Glutathione depletion in vivo enhances contraction and attenuates endothelium-dependent relaxation of isolated rat aorta. 1645 98