Nitric oxide guanylyl cyclase activation

Activation of brain H receptors also stimulates cGMP synthesis [19]. Outside the brain, histamine is known to relax vascular smooth muscle by activation of endothelial H receptors, thereby increasing endothelial Ca2+ concentrations and stimulating the synthesis and release of nitric oxide. The latter, a diffusible agent, then activates the smooth muscle guanylyl cyclase [30]. Although less is known about these mechanisms in the CNS, there is evidence that brain H receptor activation can produce effects that depend on guanylyl cyclase activity [19]. 

Mechanism of action of nitrates, nitrites, and other substances that increase the concentration of nitric oxide (NO) in smooth muscle cells. (MLCK, activated myosin light chain kinase [see Figure 12-1] guanylyl cyclase, activated guanylyl cyclase , unknown intermediate steps. Steps leading to relaxation are shown with heavy arrows.)... 

Sodium nitroprusside is used for the short-term control of severe hypertension and can improve cardiac function in patients with left ventricular failure see Chapter 34). Nitroprusside acts by releasing nitric oxide (NO). NO activates the guanylyl cyclase-cyclic GMP-PKG pathway, leading to vasodilation. The mechanism of release of NO likely involves both enzymatic and nonenzymatic pathways. Tolerance does not develop to nitroprusside. Nitroprusside dilates both arterioles and venules the hemodynamic response results from a combination of venous pooling and reduced arterial impedance. In subjects with normal left ventricular function, venous pooling affects cardiac output more than does the reduction of afterload cardiac output thus tends to fall. In patients with severely impaired left ventricular function and diastolic ventricular distention, the reduction of arterial impedance leads to a rise in cardiac output see Chapter 33). Sodium nitroprusside is a nonselective vasodilator, and regional distribution of blood flow is little affected by the drug. In... 

Mery, P.-F., Pavoine, C., Belhassen, L., Pecker, F., and Fischmeister, R. (1993). Nitric oxide regulates cardiac Ca current Involvement of cGMP-inhibited and cGMP-stimulated phosphodiesterases through guanylyl cyclase activation. J. Biol. Chem. 268, 26286-26295. 

Ferrero R, Rodriguez-Pascual F (2000) Nitric oxide-sensitive guanylyl cyclase activity inhibition through cyclic GMP-dependent dephosphorylation. J Neurochem 75 2029-2039... 

Synthesized by soluble guanylyl cyclase and particulate guanylyl cyclase from guanosine triphosphate (GTP). Nitric oxide activates soluble guanylyl cyclase to enhance cyclic GMP production that contributes to various NO actions. Cyclic GMP is hydrolyzed by phosphodiesterases. Cyclic GMP binds to and activates cGMP-dependent protein kinase, phosphodiesterases, and Cyclic Nucleotide-regulated Cation Channels. 

Guanylyl cyclases (GC) are a family of enzymes (EC 4.6.1.2) that catalyse the formation of the second messenger cyclic GMP (cGMP) from guanosine triphosphate (GTP). GCs are subdivided in soluble GCs and GCs that are membrane-bound and linked to a receptor. Activation occurs by nitric oxide (NO) and pqrtide hormones, respectively [1,2]. 

Cyclic GMP is made from GTP by the enzyme gua-nylyl cyclase, which exists in soluble and membrane-bound forms. Each of these isozymes has unique physiologic properties. The atriopeptins, a family of peptides produced in cardiac atrial tissues, cause natriuresis, diuresis, vasodilation, and inhibition of aldosterone secretion. These peptides (eg, atrial natriuretic factor) bind to and activate the membrane-bound form of guanylyl cyclase. This results in an increase of cGMP by as much as 50-fold in some cases, and this is thought to mediate the effects mentioned above. Other evidence links cGMP to vasodilation. A series of compounds, including nitroprusside, nitroglycerin, nitric oxide, sodium nitrite, and sodium azide, all cause smooth muscle re-... 

Soluble forms of guanylyl cyclase are activated by nitric oxide 370 Nitric oxide functions as an intracellular second messenger 370... 

Soluble forms of guanylyl cyclase are activated by nitric oxide. These enzymes are homologous to the catalytic domains of the membrane-bound forms of GC. They are considered heterodimers because they appear to exist, under physiological conditions, as complexes of a and P subunits, each with Mr of 70-80 kDa. Both types of soluble GC contain three primary domains an amino-terminus heme domain responsible for binding nitric oxide (NO), a dimerization domain and a carboxy terminus catalytic domain. The aP heterodimer is required for enzyme activity [35]. This can be seen as similar to the situation for AC, which contains two catalytic entities within a single polypeptide chain (Fig. 21-5). 

Fig. 9.1 Nitric oxide mediated inhibition of platelet activation. Abbreviations used NO, nitric oxide EDRF, endothelium-derived relaxing factor GC, guanylyl cyclase PDE, phosphodiesterase cGMP-PK, GMP-dependent protein kinase Raplb, small GTPase Raplb ...

Vasodilation is attributable to nitric oxide (NO), which is produced either directly from the nitroester or liberated by decomposition of NO intermediates (Feelisch and Noack 1987). Either glutathione in cells of vascular tissue or sulfhydryl groups of proteins in these tissues may be responsible for converting nitrates to NO. Nitric oxide activates guanylyl cyclase, which increases intracellular levels of cyclic guanosine 3 5 -monophosphate and thereby produces vasodilation (Kelly and Smith 1996 Robertson and Robertson 1996). 

Muscarinic agonists release endothelium-derived relaxing factor, identified as nitric oxide (NO), from the endothelial cells. The NO diffuses to adjacent vascular smooth muscle, where it activates guanylyl cyclase and increases cGMP, resulting in relaxation (see Figure 12-2). Isolated vessels prepared with the endothelium preserved consistently reproduce the... 

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