The vasodilator action of organic nitrates is thought to be mediated by an increase in the level of cGMP following stimulation of the cytosolic enzyme guanylate cyclase in the vascular smooth muscle cell. However, direct evidence for the formation of the putative active metabolite, nitric oxide (NO) within the different compartments of the vascular wall is still missing. We here demonstrate for the first time that cultured vascular smooth muscle cells as well as endothelial cells from different species actively metabolize organic nitrates to NO. We furthermore present evidence for an outward transport of cGMP from both cell types following stimulation of soluble guanylate cyclase. The rate of NO release closely correlated with the rate of cGMP egression. Biotransformation of organic nitrates to NO appeared to comprise at least two different components, a heat-sensitive enzymatic pathway which is short-lived and prone to rapid desensitization and a second non-enzymatic component which is apparently unsaturable and longer lasting. The marked decrease in the release of NO and cGMP upon the repeated administration of organic nitrates suggests that the phenomenon of "nitrate tolerance" is mainly due to an impaired biotransformation. We propose that the metabolism of nitrates to NO may have important implications for the prevention of atherosclerosis and the therapeutic modulation of blood cell function.
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"Different types of NO-releasing agents have been developed and are commercially available, such as sodium nitroprusside (SNP), firstly described as a vasodilator, which is used to manage acute hypertensive crisis; or molsidomine, used in the therapy of angina pectoris and heart failure. SIN-1, another NO donor, is known as both NO and ONOO− donor mainly because during NO release from SIN-1 superoxide is also generated [144, 145]. A wide range of NO-releasing drug classes have been developed recently. "
[Show abstract][Hide abstract] ABSTRACT: The finding that neural stem cells (NSCs) are able to divide, migrate, and differentiate into several cellular types in the adult brain raised a new hope for restorative neurology. Nitric oxide (NO), a pleiotropic signaling molecule in the central nervous system (CNS), has been described to be able to modulate neurogenesis, acting as a pro- or antineurogenic agent. Some authors suggest that NO is a physiological inhibitor of neurogenesis, while others described NO to favor neurogenesis, particularly under inflammatory conditions. Thus, targeting the NO system may be a powerful strategy to control the formation of new neurons. However, the exact mechanisms by which NO regulates neural proliferation and differentiation are not yet completely clarified. In this paper we will discuss the potential interest of the modulation of the NO system for the treatment of neurodegenerative diseases or other pathological conditions that may affect the CNS.
"However, one difficulty with these studies has been an inability to detect NO as a byproduct of GTN metabolism . Moreover, the generation of NO was observed when the concentrations of GTN exceeded therapeutic values [93–98]. A potential solution has been proposed that once GTN is bioactivated within the mitochondria, nitrite or an additional action of mtALDH generates the vasodilatory NO bioactivity . "
[Show abstract][Hide abstract] ABSTRACT: The heme-protein soluble guanylyl cyclase (sGC) is the intracellular receptor for nitric oxide (NO). sGC is a heterodimeric enzyme with α and β subunits and contains a heme moiety essential for binding of NO and activation of the enzyme. Stimulation of sGC mediates physiologic responses including smooth muscle relaxation, inhibition of inflammation, and thrombosis. In pathophysiologic states, NO formation and bioavailability can be impaired by oxidative stress and that tolerance to NO donors develops with continuous use. Two classes of compounds have been developed that can directly activate sGC and increase cGMP formation in pathophysiologic conditions when NO formation and bioavailability are impaired or when NO tolerance has developed. In this report, we review current information on the pharmacology of heme-dependent stimulators and heme-independent activators of sGC in animal and in early clinical studies and the potential role these compounds may have in the management of cardiovascular disease.
Full-text · Article · Feb 2012 · Critical care research and practice
"To some of the wells, 200 mM 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III) (FeTPPS; Calbiochem, Merck ), 1.0 mM S-nitroso-N-acetyl-penicillamine (SNAP) (Molecular Probes/Invitrogen) or 0.8 mM 3-morpholi- nosydnonimine hydrochloride (SIN-1) (Molecular Probes) was added. One millimolar SNAP generates 14 mM NO min 21 and 1 mM SIN-1 generates 10 mM ONOO 2 min 21 (Feelisch & Kelm, 1991). The ferric chelator deferoxamine (DFO) was added at a concentration of 400 mM 30 min before addition of bacteria. "
[Show abstract][Hide abstract] ABSTRACT: Francisella tularensis is a highly virulent intracellular bacterium capable of rapid multiplication in phagocytic cells. Previous studies have revealed that activation of F. tularensis-infected macrophages leads to control of infection and reactive nitrogen and oxygen species make important contributions to the bacterial killing. We investigated the effects of adding S-nitroso-acetyl-penicillamine (SNAP), which generates nitric oxide, or 3-morpholinosydnonimine hydrochloride, which indirectly leads to formation of peroxynitrite, to J774 murine macrophage-like cell cultures infected with F. tularensis LVS. Addition of SNAP led to significantly increased colocalization between LAMP-1 and bacteria, indicating containment of F. tularensis in the phagosome within 2 h, although no killing occurred within 4 h. A specific inhibitory effect on bacterial transcription was observed since the gene encoding the global regulator MglA was inhibited 50-100-fold. F. tularensis-infected J774 cells were incapable of secreting TNF-α in response to Escherichia coli LPS but addition of SNAP almost completely reversed the suppression. Similarly, infection with an MglA mutant did not inhibit LPS-induced TNF-α secretion of J774 cells. Strong staining of nitrotyrosine was observed in SNAP-treated bacteria, and MS identified nitration of two ribosomal 50S proteins, a CBS domain pair protein and bacterioferritin. The results demonstrated that addition of SNAP initially did not affect the viability of intracellular F. tularensis LVS but led to containment of the bacteria in the phagosome. Moreover, the treatment resulted in modification by nitration of several F. tularensis proteins.
Full-text · Article · Jun 2011 · Journal of Medical Microbiology