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.
ABSTRACT
The natriuretic peptide (NP) system counter-regulates the renin-angiotensin system (RAS), so enhancing the activity of natriuretic peptides (NPs) may be beneficial in conditions when RAS is activated such as ischemia-reperfusion injury (IRI). Neprilysin is the key enzyme responsible for the degradation of NPs. The effects of neprilysin inhibition or the combination of neprilysin inhibition and RAS inhibition on renal IRI-induced renal dysfunction have not been investigated yet. To investigate this, rats underwent sham surgery or bilateral IRI for 20 min. G-Als, G-Scb, and G-Als+Scb underwent similar protocol but received aliskiren (renin inhibitor), sacubitril (neprilysin inhibitor) or a combination of both pre- and post-IRI, respectively. IRI caused significant alterations in all renal functional parameters, markers of acute renal injury, pro-inflammatory and pro-fibrotic cytokines, and histological features. All these alterations were significantly attenuated in G-Als, G-Scb, and G-Als+Scb. The attenuations in the alterations in serum creatinine, creatinine clearance, and histological features were larger in G-Als+Scb compared to either G-Als or G-Scb. We conclude that RAS blockade by a renin inhibitor (aliskiren) or neprilysin inhibition by sacubitril separately led to significant attenuation in the renal IRI-induced renal dysfunction. The combination of aliskiren and sacubitril was more effective than either one alone.
