Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2023.05.16.540941

Effect of AT1 receptor blockade on cardiovascular outcome after cardiorespiratory arrest: an experimental study in rats

Fernandes de Araujo Filho, E. A.
View original source ↗Export metadata ↓

Abstract

BackgroundAT1 angiotensin II receptor (ATI) antagonists are beneficial in focal ischemia/reperfusion (I/R) cases. However, in cases of global I/R, such as cardiorespiratory arrest (CRA), ATI blockers effects are still unknown. MethodsRats were allocated into four groups: Sham group (SG) - animals submitted to surgical interventions, without CRA; Control group (CG) - animals submitted to CRA and ventricular fibrillation; Group AT1 (GAT1) - like CG, plus 0.2 mg/kg of Candesartan; Vehicle Group (VG): animals equally induced to CRA, and administration of 0.2 ml/kg of dimethyl sulfoxide. The rate of return of spontaneous circulation (ROSC), survival, hemodynamic variables, histopathology, and markers of tissue injury were analyzed. ResultsCompared to CG, the GAT1 group had a higher rate of ROSC (62.5% vs. 42.1%, p<0.0001), survival (100% vs. 62.5%, CI: 0.014-0.034; p = 0.027), lower incidence of arrhythmia after 10 minutes of ROSC, (10% vs. 62.5%, p=0.000) and lower neuronal and cardiac injury scores (p=0.025 and p=0.021, respectively). The groups did not differ regarding CRA duration, number of adrenaline doses, or number of defibrillations. ConclusionATI receptor blockade was responsible for higher rates of ROSC and survival, in addition to demonstrating neuronal and myocardial protection. HighlightsO_LIAT1 receptor block was responsible per higher rates of ROSC and survival in intervention group. C_LIO_LIThe AT1 receptor block can be neuroprotector in ischemic injury caused by CPR. C_LIO_LIThe candesartan administration during CPR can contribute with reduction of ventricular arrythmias. C_LI

Explore related subjects

pharmacology and toxicologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Fernandes de Araujo Filho, E. A.. 2023-05-18. Effect of AT1 receptor blockade on cardiovascular outcome after cardiorespiratory arrest: an experimental study in rats. https://doi.org/10.1101/2023.05.16.540941

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Lipid-ASO therapeutics exhibit differential tissue targeted delivery upon systemic or local CNS administration

Antisense oligonucleotides (ASOs) are a powerful therapeutic modality, but their full potential is hindered by pharmacokinetic properties that affect tissue and cellular delivery. Lipid conjugation is increasingly used to modulate ASO's biodistribution and promote extrahepatic activity, yet lipid dependent effects on in vivo functional delivery, particularly in the central nervous system (CNS), remain less explored. Here, we performed a side by side in vivo comparison of cholesterol, palmitic acid (C16:0), docosanoic acid (C22:0), and eicosapentaenoic acid (C20:5) conjugated to a fully phosphorothioated 3 10 3 LNA gapmer ASO targeting the Malat1 long non coding RNA. Lipid-ASO conjugates were administered systemically or locally in the brain of mice and evaluated for tissue level and cellular level distribution by imaging, qPCR and single-cell RNA sequencing, simultaneously annotating cell origin and global transcriptional changes within the cell. Following systemic administration in mice, lipid conjugation improved overall multi organ efficacy compared to unconjugated ASO, but with pronounced tissue specific differences. Single cell sequencing of liver and heart transcriptomes revealed lipid dependent cellular uptake patterns and transcriptional responses distinct from administration of unconjugated ASO. After intracerebroventricular administration, selected fatty acid conjugates enhanced silencing in deep brain regions such as the striatum, whereas cholesterol conjugation impaired functional delivery despite increased CNS retention. Light-sheet microscopy showed restricted parenchymal penetration of cholesterol ASOs compared with broader but heterogeneous distribution of palmitic acid conjugate. Together, these findings demonstrate that lipid identity critically determines ASO efficacy, productive cellular uptake, and regional CNS engagement, emphasizing the need for context specific lipid design in ASO therapeutic development.

pharmacology and toxicology↗
bioRxiv2026

Novel Dissymmetric Ionizable Lipid-Assembled Lipid Nanoparticles for Delivery of Ferroptosis-Related siRNA in Diabetic Treatment

Small interfering RNA (siRNA) enables precise post-transcriptional gene silencing for refractory diseases, yet its clinical translation remains limited by the lack of safe and efficient delivery vectors. Inspired by the dissymmetric alkyl chain architecture of natural membrane phospholipids, we designed and synthesized 34 novel ionizable lipids with dissymmetric hydrophobic tails and formulated them into lipid nanoparticles (LNPs). Through systematic physicochemical and biological assessments, we established clear structure-activity relationships and identified two lead LNPs (O14-LNP, H18a-LNP) with superior endosomal escape capacity, enhanced in vivo gene silencing potency, and favorable biosafety relative to the clinical benchmark MC3-LNP. In both streptozotocin-induced and spontaneous db/db type 2 diabetes (T2D) mouse models, lead LNPs delivering ferroptosis-related siRNAs effectively ameliorated glucose and lipid metabolic disorders, restored islet function, and alleviated hepatic steatosis. This study not only lays a theoretical foundation for the rational design of novel ionizable lipids, but also validates the therapeutic potential of siRNA therapy targeting ferroptosis, providing a versatile delivery platform and targeted therapeutic strategy for the treatment of T2D.

pharmacology and toxicology↗
bioRxiv2023

Sida cordifolia, a medicinal plant is efficacious in models of Huntingtons disease, by reducing ER stress

Background and aimHuntingtons Disease is a severe neurodegenerative disorder caused by misfolded mutant huntingtin proteins with expanded stretches of polyglutamines aggregating and destroying cells in the nervous system. Sida cordifolia and Acorus calamus are medicinal plants used in traditional Ayurvedic medicine to treat neurological disorders. Here, we tested the effectiveness of extracts of both medicinal plants in decreasing aggregation of mutant huntingtin protein in models of Huntingtons Disease and explored the mode of action. Experimental procedureWe used two models, the nematode Caenorhabditis elegans and a transgenic mouse neuroblastoma cell line, both expressing mutant huntingtin proteins with elongated polyglutamines. We assessed the effect of Sida cordifolia and Acorus calamus on mutant huntingtin protein aggregation in both models, and additionally used the cell line for mechanistic studies to identify cellular pathways underlying the effects of treatment. Results and conclusionHere, we show that an extract of Sida cordifolia inhibits aggregation of mutant huntingtin proteins. In the C. elegans model, the extract prolonged life span and improved motility of the nematode by reducing aggregation of the mutant huntingtin protein. Acorus calamus did not exhibit these effects. In the transgenic mouse neuroblastoma cell line, the extract decreased aggregation of the mutant huntingtin protein by suppressing key pathways in the ER stress response caused by the mutant protein. Our results highlight the potential therapeutic value of Sida cordifolia and its promise as a source for novel medications. HighlightsO_LISida cordifolia extract reduces aggregates in HD model of transgenic worms C_LIO_LIReduction in aggregates leads to improved motility and longevity C_LIO_LISida cordifolia extract reduces ER stress in cells expressing mHTT protein C_LIO_LIFirst report on the pharmacology of Sida cordifolia in neurodegeneration C_LI

pharmacology and toxicology↗