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)

Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impaired bioavailability and/or responsiveness to endogenous NO has been implicated in the pathogenesis of cardiovascular and other diseases. Current therapies that involve the use of organic nitrates and other NO donors have limitations, including non-specific interactions of NO with various biomolecules, lack of response and the development of tolerance following prolonged administration. Compounds that activate sGC in an NO-independent manner might therefore provide considerable therapeutic advantages. Here we review the discovery, biochemistry, pharmacology and clinical potential of haem-dependent sGC stimulators (including YC-1, BAY 41-2272, BAY 41-8543, CFM-1571 and A-350619) and haem-independent sGC activators (including BAY 58-2667 and HMR-1766).
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PMID:NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. 1695 67

Natriuretic peptides are regulatory autacoids in the mammalian myocardium whose functions, mediated via particulate guanylyl cyclase/cGMP, may include cytoprotection against ischaemia-reperfusion injury. Previous work has identified that B-type natriuretic peptide (BNP) limits infarct size when administered prior to and during coronary occlusion through a K(ATP) channel-dependent mechanism. The present study examined the hypothesis that the protection afforded by BNP is mediated specifically at reperfusion in a postconditioning-like manner. Langendorff-perfused rat hearts were subjected to 35 min coronary artery occlusion and 120 min reperfusion, and infarct size was determined by tetrazolium staining. Postconditioning was effected by applying six 10-second periods of global ischaemia at the onset of reperfusion.Treatment with either BNP 10 nM or the NO donor S-nitroso-N-acetylpenicillamine (SNAP) 1-10 microM was commenced 5 min prior to reperfusion and continued until 10 min after reperfusion. Control infarct size (% of ischaemic risk zone) was 40.8 +/- 3.7%.BNP at reperfusion induced a significant limitation of infarct size (BNP 22.9 +/- 4.1% P<0.05 vs. control). Co-treatment at reperfusion with BNP and the K(ATP) channel blockers 5-hydroxydecanote (5HD, 100 microM), glibenclamide (Glib; 10 microM) or HMR1098 (10 microM) abolished the infarct-limiting effect of BNP (BNP + 5HD 41.0 +/- 3.9%, BNP + Glib 39.8 +/- 5.6%, BNP + HMR 1098 46.0 +/- 7.1%,P < 0.05 vs. BNP). BNP given together with L-NAME (100 microM) at reperfusion resulted in a marked loss of protection (BNP + L-NAME 53.1 +/- 3.8% P < 0.001 vs. BNP). In a second series of experiments, SNAP (1-10 microM) given at reperfusion was found not to be protective (SNAP 1 microM 30.2 +/- 4.9%, SNAP 2 microM 27.5 +/- 9.5%, SNAP 5 microM 39.2 +/- 5.7%, SNAP 10 microM 33.7 +/- 6.4%, not significant vs. control). In a third series of experiments, postconditioning significantly limited infarct size (14.9 +/- 3.6 % vs. control 34.5 +/- 4.9%, P < 0.01) and this effect of postconditioning was abolished in the presence of isatin (100 microM), a non-specific blocker of particulate guanylyl cyclases (35.1 +/- 6%, P < 0.05 vs. postconditioning). In conclusion, pharmacological activation of pGC by BNP can effectively induce protection against reperfusion injury, by mechanisms involving K(ATP) channel opening and endogenous NO synthase activation. Furthermore, endogenous activation of pGC could play a role in the mechanism of postconditioning.
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PMID:B-type natriuretic peptide at early reperfusion limits infarct size in the rat isolated heart. 1789 17

Soluble guanylyl cyclase (sGC), a ubiquitously expressed heme-containing receptor for nitric oxide (NO), is a key mediator of NO-dependent processes. In addition to NO, a number of synthetic compounds that target the heme-binding region of sGC and activate it in a NO-independent fashion have been described. We report here that dicyanocobinamide (CN2-Cbi), a naturally occurring intermediate of vitamin B(12) synthesis, acts as a sGC coactivator both in vitro and in intact cells. Heme depletion or heme oxidation does not affect CN2-Cbi-dependent activation. Deletion mutagenesis demonstrates that CN2-Cbi targets a new regulatory site and functions though a novel mechanism of sGC activation. Unlike all known sGC regulators that target the N-terminal regulatory regions, CN2-Cbi directly targets the catalytic domain of sGC, resembling the effect of forskolin on adenylyl cyclases. CN2-Cbi synergistically enhances sGC activation by NO-independent regulators 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (BAY41-2272), 4-[((4-carboxybutyl){2-[(4-phenethylbenzyl)oxy]phenethyl}amino) methyl [benzoic]-acid (cinaciguat or BAY58-2667), and 5-chloro-2-(5-chloro-thiophene-2-sulfonylamino-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide sodium salt (ataciguat or HMR-1766). BAY41-2272 and CN2-Cbi act reciprocally by decreasing the EC(50) values. CN2-Cbi increases intracellular cGMP levels and displays vasorelaxing activity in phenylephrine-constricted rat aortic rings in an endothelium-independent manner. Both effects are synergistically potentiated by BAY41-2272. These studies uncover a new mode of sGC regulation and provide a new tool for understanding the mechanism of sGC activation and function. CN2-Cbi also offers new possibilities for its therapeutic applications in augmenting the effect of other sGC-targeting drugs.
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PMID:Cobinamides are novel coactivators of nitric oxide receptor that target soluble guanylyl cyclase catalytic domain. 2217 Oct 90