Effect of Nitric Oxide Pathway Inhibition on the Evolution of Anaphylactic Shock in Animal Models: A Systematic Review

Abstract

Nitric oxide (NO) induces vasodilation in various types of shock. The effect of pharmacological modulation of the NO pathway in anaphylactic shock (AS) remains poorly understood. Our objective was to assess, through a systematic review, whether inhibition of NO pathways (INOP) was beneficial for the prevention and/or treatment of AS. A predesigned protocol for this systematic review was published in PROSPERO (CRD42019132273). A systematic literature search was conducted till March 2022 in the electronic databases PubMed, EMBASE, Scopus, Cochrane and Web of Science. Heterogeneity of the studies did not allow meta-analysis. Nine hundred ninety unique studies were identified. Of 135 studies screened in full text, 17 were included in the review. Among six inhibitors of NO pathways identified, four blocked NO synthase activity and two blocked guanylate cyclase downstream activity. Pre-treatment was used in nine studies and post-treatment in three studies. Five studies included both pre-treatment and post-treatment models. Overall, seven pre-treatment studies from fourteen showed improvement of survival and/or arterial blood pressure. Four post-treatment studies from eight showed positive outcomes. Overall, there was no strong evidence to conclude that isolated blockade of the NO/cGMP pathway is sufficient to prevent or restore anaphylactic hypotension. Further studies are needed to analyze the effect of drug combinations in the treatment of AS.

Keywords: anaphylactic shock; cyclic guanosine monophosphate; guanylate cyclase; nitric oxide; nitric oxide synthase.

Figure 1

Representative sections of lung tissue. (A) Control group, showing lung tissue with patent alveolar spaces and bronchial passages and unremarkable blood vessels. (B–H) show anaphylactic changes in the lung. (B) Heavy mixed inflammatory cell infiltration of lung parenchyma with widening of interalveolar spaces (arrowheads), perivascular cellular infiltrates (thin arrows) and peribronchial inflammation (thick arrows). (C,D) Perivascular edema and heavy inflammatory cell infiltrate consisting predominantly of mast cells (thin arrows) and eosinophils (arrowheads). (E,F) Narrowing of the bronchial lumen with sloughing of respiratory epithelium (thick arrow), epithelial injury (arrowhead) and fallen dead cells in the lumen (curved arrow). (G) Heavy perivascular eosinophil infiltration (thin arrow). (H) Severe perivascular edema (thin arrow). This figure with explanatory text is obtained from an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited [8].

Figure 2

Binding of PAF and histamine to their respective receptors, which are G protein-linked, leads to activation of Gq/G11.This leads to the activation of the guanine nucleotide exchange factor, Trio, which in sequence activates small GTPases such as RhoA, which then activate the serine/threonine kinase, ROCK, which in turn phosphorylates myosin light chain phosphatase (MLCP), inhibiting its activity. Receptor binding activates phospholipase C which then catalyzes PIP2 (phosphatidyl inositol 4,5-bisphophate) hydrolysis to form DAG (diacyl glycerol) and IP3 (inositol triphosphate). Calcium-dependent activation of MLC kinase (MLCK) now occurs, resulting in increased actomyosin contractility and contributing to changing actin bundle orientation (induction of radial actin stress fibers), with the latter switching from being parallel to the junctions to perpendicular, thereby inducing junctional stress and disrupting integrity and vascular leakiness. Meanwhile, nitric oxide (NO), produced not by inducible nitric oxide synthase (iNOS), but by the constitutive endothelial form (eNOS) that is rapidly activated via the PI3K/Akt pathway. NO induces the formation of cGMP in smooth muscle cells from guanylyl cyclase (sGC), which then activates PKG, leading to a reuptake of calcium (Ca²⁺) from the cytosol by the sarcoplasmic reticulum (SER), as well as diminished calcium influx via voltage-dependent calcium channels (VDCC). This, combined with the opening of potassium channels and the exit of calcium from the cell leads to drop in intracellular calcium concentrations, inactivation of calmodulin and a resultant failure to activate MLCK. MLC phosphatase activity also increases correspondingly, leading to disruption of the actin–myosin cross-bridge and causing vasodilatation of blood vessels. Smooth muscle cells (SMC), immunoglobulin E (IgE), receptor (R). This figure was obtained from an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. Authors slightly adapted the figure [4].

Figure 3

PRISMA 2020 flow diagram [17]. The number of studies identified from databases, screened for eligibility and the final included papers in the systematic review. This flow diagram is obtained from an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited [17].

Figure 4

Evaluation of bias; risk of bias (RoB).

Figure 5

Molecular processes involved in the production of NO in endothelial cells and induction of vasodilation in smooth muscle cells.In response to environmental, neuronal, humoral or mechanical stimuli (e.g., ACh, bradykinin or shear stress), NO is synthesized in endothelial cells (EC) from l-arginine (l-Arg) by the activated form of endothelial NO synthase. NO diffuses to neighboring vascular smooth muscle cells (VSMC) where it activates soluble guanylate cyclase (sGC), which subsequently increases the intracellular cGMP production from GTP. B, basal form; 6c, 6-coordinate form; 5c, 5-coordinate form (fully activated). NO may directly (or via a pathway other than producing cGMP) regulate certain target proteins (e.g., Ca²⁺-activated K⁺ (KCa) channel). cGMP activates cGMP-dependent protein kinase (PKG), which regulates numerous target proteins, e.g., KCa channel current (IKCa), L-type Ca²⁺ channel current (ICaL), sarcolemma Ca²⁺-ATPase pump (ICaP), and myosin light chain phosphatase (MLCP), which leads to VSMC relaxation. cGMP is degraded into GMP by cyclic nucleotide phosphodiesterases (PDEs). Contractile kinetics shows that Ca²⁺ and cGMP co-mediated MLC phosphorylation and cross-bridge attachment. M, fraction of the free form of myosin light chain; Mp, fraction of phosphorylated myosin, AMp, fraction of myosin attached to actin filament; AM, fraction of attached myosin cross-bridges but dephosphorylated, namely, latch state. Total myosin is conserved, i.e., M + Mp + AMp + AM = 1. Note that VSMC is connected to EC via myoendothelial gap junctions. R, hormone receptors on EC membrane; CaM, calmodulin; MLCK, myosin light chain kinase; Iup, sarcoplasmic reticulum Ca²⁺ uptake current; Irel, sarcoplasmic reticulum Ca²⁺ release current; IP3, inositol 1,4,5-trisphosphate. Drugs blocking the production of NO (L-NAME, NG-nitro-L-arginine methyl ester; indigo carmine) and soluble guanylate cyclase, sGC (ODQ, 1H-[1,2,4] Oxadiazole [4,3-a] quinoxalin-1-one; methylene blue); cyclic adenosine monophosphate (cAMP). Aminoguanidine hydrochloride blocks inducible NOS. 7-Nitroindazole (7-NI) inhibits neuronal NOS. Copyright authorization for the figure and explanatory text re-use was requested through Copyright Clearance Center and granted by the American Physiological Society (APS). The paper is cited in reference [38]. We adapted the figure by adding the drugs that inhibit different NO pathways.