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)

To investigate the effect of cadmium on guanyl cyclase activity, urine levels of the nucleotide cGMP were measured in patients with bone and renal lesions resulting from chronic cadmium exposure, in patients with osteoarthritis and in a normal age-matched control population. The effects of cadmium, zinc and mercury salts on blood mononuclear cell cGMP production were also studied in vitro. The two patient groups exhibited clear differences in cGMP excretion. Lower urine cGMP (59%, P less than 0.01) and creatinine values (43%, P less than 0.01) were found in cadmium-exposed patients and higher cGMP values (56%, P less than 0.05) in patients with osteoarthritis, compared to the control group. Creatinine adjusted cGMP values were also lower in cadmium-exposed patients (28%, P less than 0.05) and higher in patients with osteoarthritis (130%, P less than 0.01). In vitro, a 10 h exposure of mononuclear cells to cadmium or mercury salts depressed guanyl cyclase activity in most experiments. At 10(-4) M, mercury was consistently more inhibitory in all cultures (95%, P less than 0.01). As cadmium has a potential for inhibiting guanyl cyclase activity in human tissue, the low urine cGMP values found in patients with cadmium disease may be attributable to chronic cadmium exposure. High guanyl cyclase activity in patients with osteoarthritis may be associated with inflammation.
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PMID:cGMP levels in chronic cadmium disease and osteoarthritis. 287 27

The mechanism of endothelin-1 (ET-1)-induced nitric oxide (NO) production, MMP-1 production and MMP-13 production was investigated in human osteoarthritis chondrocytes. The cells were isolated from human articular cartilage obtained at surgery and were cultured in the absence or presence of ET-1 with or without inhibitors of protein kinase or LY83583 (an inhibitor of soluble guanylate cyclase and of cGMP). MMP-1, MMP-13 and NO levels were then measured by ELISA and Griess reaction, respectively. Additionally, inducible nitric oxide synthase (iNOS) and phosphorylated forms of p38 mitogen-activated protein kinase, p44/42, stress-activated protein kinase/Jun-N-terminal kinase and serine-threonine Akt kinase were determined by western blot. Results show that ET-1 greatly increased MMP-1 and MMP-13 production, iNOS expression and NO release. LY83583 decreased the production of both metalloproteases below basal levels, whereas the inhibitor of p38 kinase, SB202190, suppressed ET-1-stimulated production only. Similarly, the ET-1-induced NO production was partially suppressed by the p38 kinase inhibitor and was completely suppressed by the protein kinase A kinase inhibitor KT5720 and by LY83583, suggesting the involvement of these enzymes in relevant ET-1 signalling pathways. In human osteoarthritis chondrocytes, ET-1 controls the production of MMP-1 and MMP-13. ET-1 also induces NO release via iNOS induction. ET-1 and NO should thus become important target molecules for future therapies aimed at stopping cartilage destruction.
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PMID:Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production. 1574 80

Nitric oxide (NO) is a simple but pluripotent molecule that is mainly released from vascular endothelial cells where it is formed intracellularly by nitric oxide synthase from L-arginine in response to several stimuli, including shear stress or muscarinic receptor stimulation. NO stimulates guanylyl cyclase to form cyclic guanosine monophosphate, which results in relaxation and vasodilatation of vascular smooth muscle cells (VSMCs). In addition, NO prevents adhesion and aggregation of platelets, and it possesses anti-inflammatory, antiproliferative, and antimigratory effects on leukocytes, endothelial cells, and VSMCs, thus offering protection from atherosclerosis. Dysfunction of the vascular endothelium has been documented in most conditions that promote or are associated with atherosclerosis and is characterized by a reduced bioavailability of NO. The healthy endothelium prevents adhesion and migration of leukocytes, proliferation of VSMCs, and platelet adhesion and aggregation. Maintaining the balance of blood flow and thrombus formation is also a major task of the vascular endothelium. It has been shown that both NO and prostacyclin, a cyclooxygenase-derived relaxing factor, inhibit activation of platelets and regulate vasomotion. Reduced NO and prostacyclin levels can result in endothelial dysfunction, which is recognized as the first step in the atherogenic process. It is of note that chronic inflammation conditions, such as rheumatoid arthritis, are associated with endothelial dysfunction. The reduced NO bioavailability may therefore explain the increased risk for cardiovascular events in patients with chronic low-grade inflammation, such as rheumatoid arthritis and osteoarthritis. Thus, this article provides an overview of the impact of inflammation and anti-inflammatory treatment with cyclooxygenase inhibitors on endothelial function.
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PMID:Cyclooxygenase-2 and nitric oxide. 1678 25