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)

Epidermal growth factor (EGF) is released from platelets during aggregation. Because we thought that EGF played a role in vascular tone, we investigated its vascular reactivity using isolated rat aortic strips with and without the endothelium. In the presence of endothelium, EGF relaxed vascular smooth muscle precontracted with 40 mM K+, 10(-5) M prostaglandin F2 alpha or 10(-6) M norepinephrine. The relaxation induced by EGF was more prominent on the prostaglandin F2 alpha- and norepinephrine-induced contractions than on the K(+)-induced contraction. Atropine (10(-5) M) and aspirin (10(-5) M) had no effect on the EGF-induced relaxation, but methylene blue (10(-5) M) partly abolished the relaxation evoked by EGF. These results suggest that EGF relaxes vascular smooth muscle in the presence of the endothelium. They also suggest that EGF has an effect on the endothelium to produce relaxing factor independent of cyclooxygenase; the releasing factor activates soluble guanylate cyclase, resulting in relaxation of vascular smooth muscle through the production of cyclic GMP.
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PMID:Vascular smooth muscle relaxation induced by epidermal growth factor is endothelium-dependent. 236 6

Epidermal growth factor (EGF) increases DNA synthesis and cell division both in vivo and in vitro. The mechanism by which EGF increases growth and DNA synthesis is unknown. Since the intracellular messenger cGMP stimulates DNA synthesis, the present investigation was designed to determine if EGF might have part of its mechanism of action through activating guanylate cyclase [EC 4.6.1.2], the enzyme that catalyzes the formation of cGMP. EGF enhanced soluble and particulate guanylate cyclase activities as well as cGMP levels 2- to 3-fold in hypophysectomized and nonhypophysectomized tissues both in vivo and in vitro. EGF increased guanylate cyclase activity 0.5 h after ip injection in mice, and this increased activity was still present 12 h later. Guanylate cyclase activity was increased to a greater extent secondary to EGF in hypophysectomized cecum compared to nonhypophysectomized cecum. Dose-response curves revealed that maximal stimulation of guanylate cyclase by EGF occurred at 1 nM. There was no augmented guanylate cyclase activity when the concentration of EGF was decreased to 0.01 nM. The data in this investigation suggest that guanylate cyclase may play a role in the mechanism of action of EGF.
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PMID:Epidermal growth factor enhances guanylate cyclase activity in vivo and in vitro. 285 73

To investigate whether atrial natriuretic factor regulates the growth of hepatocytes and to determine the receptor subtype involved in such modulation, we studied the effect of atrial natriuretic factor 103-126 and clearance receptor binding analogs of atrial natriuretic factor, (des-(Q116, S117, G118, L119, G120) atrial natriuretic factor 102-121 and des-(C105,121) atrial natriuretic factor 104-126) on growth of human hepatoblastoma cells. Atrial natriuretic factor 103-126 and des-(Q116, S117, G118, L119, G120) atrial natriuretic factor 102-121 inhibited thymidine incorporation into human hepatoblastoma cells cultured in the presence of bovine serum albumin and epidermal growth factor but not in cells cultured in bovine serum albumin alone. Moreover, atrial natriuretic factor 103-126, des-(Q116, S117, G118, L119, G120) atrial natriuretic factor 102-121 and des-(C105,121) atrial natriuretic factor 104-126, in a concentration-dependent manner, inhibited thymidine incorporation and cell proliferation. As monitored by the ability of des-(Q116, S117, G118, L119, G120) atrial natriuretic factor 102-121 to displace 125I-labeled atrial natriuretic factor, epidermal growth factor increased the expression of cell surface clearance receptors. Epidermal growth factor also transiently increased the cellular content of atrial natriuretic factor clearance receptor messenger RNA without altering the levels of guanylyl cyclase-linked atrial natriuretic factor receptor messenger RNA levels. Maximal increase in atrial natriuretic factor clearance receptor messenger RNA coincided with the maximal increase in des-(Q116, S117, G118, L119, G120) atrial natriuretic factor 102-121-displaceable 125I-atrial natriuretic factor binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Atrial natriuretic peptide inhibits growth of hepatoblastoma (HEP G2) cells by means of activation of clearance receptors. 768 82

Pulmonary arterial hypertension (PAH) is a devastating disease that is characterized by a high mortality. The pathogenesis of PAH is multifactorial. In addition to hereditary factors (e. g., BMPR2 mutations), numerous environmental factors may trigger the onset and progression of the disease. An imbalance between vasoconstrictive and vasodilative factors leads to vasoconstriction in the pulmonary circuit, resulting in an increase of pulmonary vascular resistance and pulmonary artery pressure. Alterations of several signaling pathways (i. e.; endothelin, nitric oxide and prostacyclin pathways) contribute to an increase of pulmonary vascular tone, and these pathways represent the targets of the current therapeutic interventions. However, PAH is increasingly recognized as a chronic proliferative disease particularly of the small pulmonary arteries, that is primarily characterized by morphological changes of the vascular wall ("vascular remodeling"). These changes are particularly induced by peptide growth factors such as platelet-derived growth factor (PDGF) that elicit their signals via activation of membrane-bound receptor tyrosine kinases (RTK). Accordingly, there is both experimental and clinical evidence for a therapeutic efficacy of tyrosine kinase inhibitors (TKI), which provide the basis for "reverse remodeling" strategies and indeed represent a promising novel approach for the treatment of PAH. Epidermal growth factor (EGF), soluble guanylate cyclase (sGC), and phosphodiesterase type 1 (PDE1) may represent additional future target molecules. PAH leads to progressive right heart failure which determines the outcome of PAH patients. The pathomechanisms of right heart failure should therefore also be considered for the development of novel therapeutic concepts.
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PMID:[Novel concepts in the pathobiology of pulmonary arterial hypertension]. 1881 87