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Immune Modulation In Sepsis
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Janet M. J. Hammond, Peter D. Potgieter
Nitric Oxide Nitric oxide is a low-molecular-weight, membrane-permeable gas [90] that functions as a neurotransmitter [91], regulates vascular tone by activating soluble guanylate cyclase in vascular smooth muscle cells and causing an increase in the level of intracellular cyclic guanosine monophosphate [92], and inhibits platelet aggregation [93], and leukocyte adhesion [94]. In addition, at concentrations higher than those required for intercellular communication, NO has antitumor and antimicrobial activity [95]. Nitric oxide release is thought to be the final common pathway that leads to the hypotension and vascular dysregulation seen in septic shock.
Neuroactive Substances in the Control of Cardiovascular and Visceral Responses: An Overview
Published in I. Robin A. Barraco, Nucleus of the Solitary Tract, 2019
A role for soluble guanylate cyclase in central cardiovascular regulation has also been studied. We have used the guanylate cyclase inhibitor, methylene blue, to impede activation of the enzyme either by endogenous agents released upon activation of cardiovascular reflexes or by injection of putative transmitters into NTS. These studies have suggested that soluble guanylate cyclase may be a second messenger in neurons that participate in cardiopulmonary reflexes.69,138 Furthermore, our studies suggest that the enzyme may be linked to receptors that are themselves linked to ion channels, such as the NMDA, AMPA, and KA receptor.139 Interestingly, inhibition of soluble GC has no effect on responses to exogenously administered QUIS.139 The potential role of soluble guanylate cyclase in cardiovascular reflexes in NTS is particularly intriguing in light of its apparent link to neurotransmission or modulation by excitatory amino acids and by the novel neural messengers, nitric oxide and related compounds.69,140-143
Pharmacokinetic/Pharmacodynamic Correlations of Selected Vasodilators
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Tsang-Bin Tzeng, Ho-Leung Fung
This model takes into account biochemical evidence that suggests nitrates to partition between the bathing medium (in this case, the incubation buffer) and the vascular smooth muscle cell, where it is metabolically activated, through catalysis with a yet unknown factor X (possibly a thiol-containing compound or protein), to produce NO.7 Subsequently, the NO generated would stimulate soluble guanylate cyclase, increasing the cellular accumulation of cGMP,8 which initiates muscle relaxation. Several rate constants are incorporated into this model to describe the various kinetic processes.
Novel therapeutic approaches in the management of chronic kidney disease: a narrative review
Published in Postgraduate Medicine, 2023
Panagiotis Theofilis, Aikaterini Vordoni, Rigas G. Kalaitzidis
The administration of guanylate cyclase (GC) activators could also be efficacious in improving the treatment targets in diabetic CKD. In humans, soluble guanylate cyclase is a receptor for nitric oxide (NO). It is an important and established target in improving cardiovascular and renal diseases. It is expressed in the arterial system of the kidneys and neuroendocrine cells, contributing to the regulation of renal perfusion and renin excretion [56]. GC is activated by NO and induces the production of cyclic guanin monophosphate (cGMP) from guanosine triphosphate [57]. The complex NO/cGMP has an important effect on renal blood flow, along with anti-inflammatory, anti-fibrotic, and anti-proliferative actions in vascularized and non-vascularized regions of the renal cortex [58]. The dysregulation of NO-GC-cGMP is associated with an increased risk of CKD. It is believed that targeting the NO-sGC-cGMP axis is a potential therapeutic target, which may confer renal protection in experimental models. sGC can also be activated pharmacologically through specialized stimulators and activators, such as BI 685,509. Several trials are underway (NCT04750577, NCT04736628), and the role of this drug class in renal protection is still to be determined.
The state of the art of fetal hemoglobin-inducing agents
Published in Expert Opinion on Drug Discovery, 2022
Aline Renata Pavan, Juliana Romano Lopes, Jean Leandro Dos Santos
Another pathway that regulates γ-globin gene expression is the guanylate cyclase and the ⋅NO/cGMP signaling pathway. Soluble guanylate cyclase (sGC) converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), which is an important second messenger that mediates several physiological processes, such as smooth muscle relaxation and platelet adhesion [86]. To demonstrate the role of sGC in γ-globin gene expression, researchers evaluated the level of expression of the subunits (α and β) that compose the enzyme in K562 cells. The results demonstrated that these cells expressed high levels of the α and β subunits, comparable to the levels found in the lungs and the brain cells. Also, a positive correlation was found between the expression of the α subunit and the expression of γ-globin. Furthermore, an sGC activator increased the γ-globin mRNA levels by five-fold to six-fold, and this effect disappeared when the cells were pre-treated with an sGC inhibitor. Similar results were found after the treatment of K562 cells and primary erythroblasts from healthy individuals and β-thalassemic patients with a cGMP analog (8-Br-cGMP), which indicated that modulation of sGC might be performed to regulate γ-globin gene expression and HbF induction [87].
Individualizing the treatment of patients with heart failure with reduced ejection fraction: a journey from hospitalization to long-term outpatient care
Published in Expert Opinion on Pharmacotherapy, 2022
Carlos Escobar, Juan Luis-Bonilla, Maria G. Crespo-Leiro, Alberto Esteban-Fernández, Nuria Farré, Ana Garcia, Julio Nuñez
Activation of the RAAS and sympathetic nervous system has been traditionally involved in the pathogenesis of HFrEF [28–31]. In this context, the main target of HFrEF treatment was largely limited to inhibition of these systems (using RAAS inhibitors and beta blockers) [32]. However, the pathogenesis of HFrEF is more complex and challenging, with the implication of several neurohormonal systems, including activation of deleterious pathways, such as RAAS, the sympathetic nervous system, and the sodium-glucose cotransporter-2 (SGLT2) system, and the inhibition of protective pathways, such as the natriuretic peptide pathway and the guanylate cyclase system (Figure 1) [33–41]. Although these neurohormonal systems are designed to maintain cardiovascular homeostasis in the short term, chronic activation/inhibition of the pathways induces deleterious changes in the heart, kidneys, and vasculature, and this translates into impairment of HF [30]. For example, HFrEF is associated with nitric oxide deficiency, decreased soluble guanylate cyclase activity, and cGMP production, which can damage the cardiovascular and renal systems. Stimulation of soluble guanylate cyclase with vericiguat will improve/reverse these alterations [35–38]. Therefore, the etiopathogenesis of HFrEF is complex, as many neurohormonal systems are implicated. As a result, HF burden can be reduced only through a comprehensive approach that targets all these systems [42,43].