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Pharmacology of the lower urinary tract
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
LUT smooth muscle can be relaxed by drugs increasing the intracellular concentrations of cAMP or cGMP.15,201,203 Multiple types of adenylyl cyclases exist, which catalyze the formation of cAMP.204,205 In LUT smooth muscles, increases in cAMP seem to have a main role in bladder relaxation, whereas cGMP is important for urethral relaxation.15,202,203,206. Several agents, acting through different receptors linked to adenylyl cyclase, or directly stimulating the enzyme, have been shown to relax the bladder and simultaneously to increase the intracellular concentrations of cAMP. Many endogenous agents as well as drugs have cGMP as their common mediator in eliciting different physiological responses. There are multiple types of soluble and particulate guanylyl cyclases that catalyze cGMP synthesis.207 Soluble guanylyl cyclase is the target of NO, which binds to its heme moiety and activates the enzyme with resulting increase in cGMP. cGMP, in turn, regulates protein phosphorylation, ion channel conductivity, and phosphodiesterase (PDE) activity.
Circulation of fluid between plasma, interstitium and lymph
Published in Neil Herring, David J. Paterson, Levick's Introduction to Cardiovascular Physiology, 2018
Neil Herring, David J. Paterson
The increased cytosolic Ca2+ raises the Ca2+-calmodulin level, which stimulates endothelial NO synthase activity (Section 9.4). Although small amounts of NO can lower permeability (by scavenging toxic O2 radicals), high levels of NO are pro-inflammatory (Figure 11.28). NO activates soluble guanylyl cyclase, which produces cyclic guanosine monophosphate (cGMP). cGMP is a permeability-raising messenger that activates phosphodiesterase 2 (PDE2) (Figure 11.30). Because PDE2 is more abundant in venular than arterial endothelium, this helps localize the inflammatory response to venules. PDE2 degrades cyclic adenosine monophosphate (cAMP), an anti-inflammatory, barrierenhancing messenger, so a fall in cAMP raises permeability. Conversely, cAMP-raising agonists, such as the β adrenergic receptor agonists isoprenaline and terbutaline, attenuate gap formation and inflammation. The anti-inflammatory action of cAMP is mediated by two pathways: (1) cAMP activates protein kinase A (PKA), which inhibits myosin contraction (Section 9.7); (2) cAMP activates the factor exchange protein directly activated by cAMP 1 (EPAC1), which activates pathways that stabilize the junctional strands and actin cyto- skeleton. A fall in cAMP therefore favours gap formation by loosening the intercellular junction and by endothelial contraction (retraction). In intact venules, junction loosening seems the more important factor because inhibitors of myosin light chain kinase, a key initiator of contraction, do not block the inflammatory response. By contrast, active contraction is important in cultured endothelial cells, a much used but potentially misleading research ‘model’.
Nitrous anhydrase activity of carbonic anhydrase II: cysteine is required for nitric oxide (NO) dependent phosphorylation of VASP in human platelets
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Dimitrios Tsikas, Stepan Gambaryan
Nitrite and nitrate are metabolites of NO endogenously produced from L-arginine by the catalytic action of NO synthase (NOS). Exogenous nitrite and nitrate are also present in foods and drinking water and represent a considerable source of NO bioactivity via bacterial nitrate reductase activity in mouth and gut flora. Pharmacological nitrite, an NOS-independent source of NO, has protective effects in the cardiovascular system by decreasing blood pressure and inhibiting platelet activation5. Administration of nitrite has been reported to lower blood pressure and to inhibit platelet aggregation in vivo in humans and mice6,7. In contrast, nitrite added to washed human or mice platelets in vitro was found not to activate soluble guanylyl cyclase (sGC) and not to inhibit platelet activation7,8. We supposed that the different effects of nitrite in vivo and in washed platelets in vitro might be connected with the absence of extra-cellular L-cysteine in washed platelet preparations. In our experiments with washed human platelets we tested this hypothesis and used L-cysteine at physiological concentrations.
Myeloperoxidase: a potential therapeutic target for coronary artery disease
Published in Expert Opinion on Therapeutic Targets, 2020
Thanat Chaikijurajai, W. H. Wilson Tang
Furthermore, another AZM198 study from Cheng et al. [12] showed that mice treated with AZM198 had better endothelial function and decreased enzymatic activity of MPO measured by LC-MS/MS compared with the control group. Notably, there was no significant difference in plasma MPO levels and inflammatory cytokines, suggesting that AZM198 selectively attenuates the effects of MPO on endothelial dysfunction and atherosclerosis. The mechanism by which AZM198 improves endothelial function was described as an increase in cyclic guanosine monophosphate (cGMP) observed in the treatment group, which suggested that there was improved activity of soluble guanylyl cyclase (sGC) as a result of increased NO bioavailability from MPO inhibition. These findings showed the possibility that AZM198 could be an MPO inhibitor to promote plaque stabilization and improve endothelial function, which could subsequently reduce the risk of CAD. However, those results were from young mice as well as the studies on thiouracil derivatives, and further investigation on the atheroprotective effects of 2-thioxanthine derivatives is warranted.
Genetic background of coronary artery disease: clinical implications and perspectives
Published in Expert Review of Precision Medicine and Drug Development, 2020
Massimiliano Camilli, Giulia Iannaccone, Marco G. Del Buono, Filippo Crea, Nadia Aspromonte
GUCY1A1, together with GUCY1B1 (GUCY1B3), forms soluble guanylyl cyclase (sGC), an enzyme responsible for platelet aggregation inhibition under nitric oxide stimulation [28]. Nitric oxide is a potent vasodilator, inhibits platelet activation and thrombus formation, and platelet release of nitric oxide may be attenuated in the setting of unstable coronary syndromes [31]. Several GWAS studies revealed an increase in CAD/myocardial infarction (MI) risk associated with sGC mutations and a relevant alteration of their inhibitory effect on platelet aggregation [27,28,32]. Erdmann J et al. used a large family with a history of unstable coronary syndromes at a young age and identified two gene mutations in GUCYIA3 and CCT7 (encoding a molecular chaperone necessary for folding of newly synthetized cellular proteins and stabilizing soluble guanylyl cyclase). These mutations could further impair sGC-dependent nitric oxide signaling and predispose to acute coronary disease [33]Despite the limitations in the functional studies, the concept that platelet activity in the setting of thrombosis may be heritable is relevant and lacking of extensive data.