Quantification of recombinant and platelet P2Y1 receptors utilizing a [125I]-labeled high-affinity antagonist 2-iodo-N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate ([125I]MRS2500)

The ADP-activated P2Y1 receptor is broadly expressed and plays a crucial role in ADP-promoted platelet aggregation. We previously synthesized 2-iodo-N6-methyl–(N)-methanocarba-2′-deoxyadenosine 3′,5′-bisphosphate (MRS2500), as a selective, high affinity, competitive antagonist of this receptor. Here we report utilization of a trimethylstannyl precursor molecule for the multistep radiochemical synthesis of a [125I]-labeled form of MRS2500. [125I]MRS2500 bound selectively to Sf9 insect cell membranes expressing the human P2Y1 receptor but did not specifically bind to membranes isolated from empty vector-infected cells. Binding of [125I]MRS2500 to P2Y1 receptors was saturable with a Kd of 1.2 nM. Known agonists and antagonists of the P2Y1 receptor inhibited [125I]MRS2500 binding to P2Y1 receptor-expressing membranes with potencies in agreement with those previously observed in functional assays of this receptor. A high-affinity binding site for [125I]MRS2500 also was observed on intact human platelets (Kd = 0.61 nM) and mouse platelets (Kd = 1.20 nM) that exhibited the pharmacological selectivity of the P2Y1 receptor. The densities of sites observed were 151 sites/platelet and 229 sites/platelet in human and mouse platelets, respectively. In contrast, specific binding was not observed in platelets isolated from P2Y1 receptor (−/−) mice. Taken together, these data illustrate the synthesis and characterization of a novel P2Y1 receptor radioligand and its utility for examining P2Y1 receptors natively expressed on human and mouse platelets

P2Y receptors in GtoPdb v.2023.1

P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5, 189]) are activated by the endogenous ligands ATP, ADP, UTP, UDP, UDP-glucose and adenosine. The eight mammalian P2Y receptors are activated by distinct nucleotides: P2Y1, P2Y11, P2Y12 and P2Y13 are activated by adenosine-nucleotides; P2Y2, P2Y4 can be activated by both adenosine and uridine nucleotides, with some species-specific differences; P2Y6 is mainly activated by UDP; P2Y14 is preferentially activated by sugar-uracil nucleotides. The missing numbers in the receptor nomenclature refer either to non-mammalian orthologs or receptors having some sequence homology to P2Y receptors but for which there is no functional evidence of responsiveness to nucleotides [380]. Based on their G protein coupling P2Y receptors can be divided into two subfamilies: P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11 receptors couple via Gq proteins to stimulate phospholipase C followed by increases in inositol phosphates and mobilization of Ca2+ from intracellular stores. P2Y11 receptors couple in addition to Gs proteins followed by increased adenylate cyclase activity. In contrast, P2Y12, P2Y13, and P2Y14 receptors signal primarily through activation of Gi proteins and inhibition of adenylate cyclase activity or control of ion channel activity [380]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 receptor subtype, approved in Japan and South Korea for the management of dry eye disease [238], and the P2Y12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 320]

P2Y receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned receptors to endogenously expressed receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y receptor' or 'P2Y1-like', etc., until further, as yet undefined, corroborative criteria can be applied [46, 109, 187, 375, 388].Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 receptor subtype, approved in Japan for the management of dry eye disease [236], and the P2Y12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 316]

P2Y receptors in GtoPdb v.2021.3

P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5, 192]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned receptors to endogenously expressed receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y receptor' or 'P2Y1-like', etc., until further, as yet undefined, corroborative criteria can be applied [47, 110, 190, 383, 396]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 receptor subtype, approved in Japan for the management of dry eye disease [241], and the P2Y12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [53, 323]

Functionalized Congeners of P2Y 1 Receptor Antagonists: 2-Alkynyl ( N )-Methanocarba 2′-Deoxyadenosine 3′,5′-Bisphosphate Analogues and Conjugation to a Polyamidoamine (PAMAM) Dendrimer Carrier

The P2Y1 receptor is a prothrombotic G protein-coupled receptor (GPCR) activated by ADP. Preference for the North (N) ring conformation of the ribose moiety of adenine nucleotide 3′,5′-bisphosphate antagonists of the P2Y1 receptor was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute. A series of covalently linkable N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphates containing extended 2-alkynyl chains was designed and binding affinity at the human (h) P2Y1 receptor determined. The chain of these functionalized congeners contained hydrophilic moieties, a reactive substituent, or biotin, linked via an amide. Variation of the chain length and position of an intermediate amide group revealed high affinity of carboxylic congener 8 (Ki 23 nM) and extended amine congener 15 (Ki 132 nM), both having a 2-(1-pentynoyl) group. A biotin conjugate 18 containing an extended ε-aminocaproyl spacer chain exhibited higher affinity than a shorter biotinylated analogue. Alternatively, click coupling of terminal alkynes of homologous 2-dialkynyl nucleotide derivatives to alkyl azido groups produced triazole derivatives that bound to the P2Y1 receptor following deprotection of the bisphosphate groups. The preservation of receptor affinity of the functionalized congeners was consistent with new P2Y1 receptor modeling and ligand docking. Attempted P2Y1 antagonist conjugation to PAMAM dendrimer carriers by amide formation or palladium-catalyzed reaction between an alkyne on the dendrimer and a 2-iodopurine-derivatized nucleotide was unsuccessful. A dialkynyl intermediate containing the chain length favored in receptor binding was conjugated to an azide-derivatized dendrimer, and the conjugate inhibited ADP-promoted human platelet aggregation. This is the first example of attaching a strategically functionalized P2Y receptor antagonist to a PAMAM dendrimer to produce a multivalent conjugate exhibiting a desired biological effect, i.e. antithrombotic action

The P2Y1 receptor is involved in the maintenance of glucose homeostasis and in insulin secretion in mice

Pancreatic β cells express several P2 receptors including P2Y1 and the modulation of insulin secretion by extracellular nucleotides has suggested that these receptors may contribute to the regulation of glucose homeostasis. To determine whether the P2Y1 receptor is involved in this process, we performed studies in P2Y1 mice. In baseline conditions, P2Y1-mice exhibited a 15% increase in glycemia and a 40% increase in insulinemia, associated with a 10% increase in body weight, pointing to a role of the P2Y1 receptor in the control of glucose metabolism. Dynamic experiments further showed that P2Y1-mice exhibited a tendency to glucose intolerance. These features were associated with a decrease in the plasma levels of free fatty acid and triglycerides. When fed a lipids and sucrose enriched diet for 15 weeks, the two genotypes no longer displayed any significant differences. To determine whether the P2Y1 receptor was directly involved in the control of insulin secretion, experiments were carried out in isolated Langerhans islets. In the presence of high concentrations of glucose, insulin secretion was significantly greater in islets from P2Y1-mice. Altogether, these results show that the P2Y1 receptor plays a physiological role in the maintenance of glucose homeostasis at least in part by regulating insulin secretion

Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy

Objective: We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype–phenotype correlations. Methods: We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed. Results: We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3′ and 5′ exons. Seizures in patients with mutations in exons 4–5 were more pharmacoresponsive than in patients with mutations in exons 8–15. Conclusions: SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

TRY plant trait database – enhanced coverage and open access

Plant traits—the morphological, anatomical, physiological, biochemical and phenological characteristics of plants—determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits—almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.Rest of authors: Decky Junaedi, Robert R. Junker, Eric Justes, Richard Kabzems, Jeffrey Kane, Zdenek Kaplan, Teja Kattenborn, Lyudmila Kavelenova, Elizabeth Kearsley, Anne Kempel, Tanaka Kenzo, Andrew Kerkhoff, Mohammed I. Khalil, Nicole L. Kinlock, Wilm Daniel Kissling, Kaoru Kitajima, Thomas Kitzberger, Rasmus Kjøller, Tamir Klein, Michael Kleyer, Jitka Klimešová, Joice Klipel, Brian Kloeppel, Stefan Klotz, Johannes M. H. Knops, Takashi Kohyama, Fumito Koike, Johannes Kollmann, Benjamin Komac, Kimberly Komatsu, Christian König, Nathan J. B. Kraft, Koen Kramer, Holger Kreft, Ingolf Kühn, Dushan Kumarathunge, Jonas Kuppler, Hiroko Kurokawa, Yoko Kurosawa, Shem Kuyah, Jean-Paul Laclau, Benoit Lafleur, Erik Lallai, Eric Lamb, Andrea Lamprecht, Daniel J. Larkin, Daniel Laughlin, Yoann Le Bagousse-Pinguet, Guerric le Maire, Peter C. le Roux, Elizabeth le Roux, Tali Lee, Frederic Lens, Simon L. Lewis, Barbara Lhotsky, Yuanzhi Li, Xine Li, Jeremy W. Lichstein, Mario Liebergesell, Jun Ying Lim, Yan-Shih Lin, Juan Carlos Linares, Chunjiang Liu, Daijun Liu, Udayangani Liu, Stuart Livingstone, Joan Llusià, Madelon Lohbeck, Álvaro López-García, Gabriela Lopez-Gonzalez, Zdeňka Lososová, Frédérique Louault, Balázs A. Lukács, Petr Lukeš, Yunjian Luo, Michele Lussu, Siyan Ma, Camilla Maciel Rabelo Pereira, Michelle Mack, Vincent Maire, Annikki Mäkelä, Harri Mäkinen, Ana Claudia Mendes Malhado, Azim Mallik, Peter Manning, Stefano Manzoni, Zuleica Marchetti, Luca Marchino, Vinicius Marcilio-Silva, Eric Marcon, Michela Marignani, Lars Markesteijn, Adam Martin, Cristina Martínez-Garza, Jordi Martínez-Vilalta, Tereza Mašková, Kelly Mason, Norman Mason, Tara Joy Massad, Jacynthe Masse, Itay Mayrose, James McCarthy, M. Luke McCormack, Katherine McCulloh, Ian R. McFadden, Brian J. McGill, Mara Y. McPartland, Juliana S. Medeiros, Belinda Medlyn, Pierre Meerts, Zia Mehrabi, Patrick Meir, Felipe P. L. Melo, Maurizio Mencuccini, Céline Meredieu, Julie Messier, Ilona Mészáros, Juha Metsaranta, Sean T. Michaletz, Chrysanthi Michelaki, Svetlana Migalina, Ruben Milla, Jesse E. D. Miller, Vanessa Minden, Ray Ming, Karel Mokany, Angela T. Moles, Attila Molnár V, Jane Molofsky, Martin Molz, Rebecca A. Montgomery, Arnaud Monty, Lenka Moravcová, Alvaro Moreno-Martínez, Marco Moretti, Akira S. Mori, Shigeta Mori, Dave Morris, Jane Morrison, Ladislav Mucina, Sandra Mueller, Christopher D. Muir, Sandra Cristina Müller, François Munoz, Isla H. Myers-Smith, Randall W. Myster, Masahiro Nagano, Shawna Naidu, Ayyappan Narayanan, Balachandran Natesan, Luka Negoita, Andrew S. Nelson, Eike Lena Neuschulz, Jian Ni, Georg Niedrist, Jhon Nieto, Ülo Niinemets, Rachael Nolan, Henning Nottebrock, Yann Nouvellon, Alexander Novakovskiy, The Nutrient Network, Kristin Odden Nystuen, Anthony O'Grady, Kevin O'Hara, Andrew O'Reilly-Nugent, Simon Oakley, Walter Oberhuber, Toshiyuki Ohtsuka, Ricardo Oliveira, Kinga Öllerer, Mark E. Olson, Vladimir Onipchenko, Yusuke Onoda, Renske E. Onstein, Jenny C. Ordonez, Noriyuki Osada, Ivika Ostonen, Gianluigi Ottaviani, Sarah Otto, Gerhard E. Overbeck, Wim A. Ozinga, Anna T. Pahl, C. E. Timothy Paine, Robin J. Pakeman, Aristotelis C. Papageorgiou, Evgeniya Parfionova, Meelis Pärtel, Marco Patacca, Susana Paula, Juraj Paule, Harald Pauli, Juli G. Pausas, Begoña Peco, Josep Penuelas, Antonio Perea, Pablo Luis Peri, Ana Carolina Petisco-Souza, Alessandro Petraglia, Any Mary Petritan, Oliver L. Phillips, Simon Pierce, Valério D. Pillar, Jan Pisek, Alexandr Pomogaybin, Hendrik Poorter, Angelika Portsmuth, Peter Poschlod, Catherine Potvin, Devon Pounds, A. Shafer Powell, Sally A. Power, Andreas Prinzing, Giacomo Puglielli, Petr Pyšek, Valerie Raevel, Anja Rammig, Johannes Ransijn, Courtenay A. Ray, Peter B. Reich, Markus Reichstein, Douglas E. B. Reid, Maxime Réjou-Méchain, Victor Resco de Dios, Sabina Ribeiro, Sarah Richardson, Kersti Riibak, Matthias C. Rillig, Fiamma Riviera, Elisabeth M. R. Robert, Scott Roberts, Bjorn Robroek, Adam Roddy, Arthur Vinicius Rodrigues, Alistair Rogers, Emily Rollinson, Victor Rolo, Christine Römermann, Dina Ronzhina, Christiane Roscher, Julieta A. Rosell, Milena Fermina Rosenfield, Christian Rossi, David B. Roy, Samuel Royer-Tardif, Nadja Rüger, Ricardo Ruiz-Peinado, Sabine B. Rumpf, Graciela M. Rusch, Masahiro Ryo, Lawren Sack, Angela Saldaña, Beatriz Salgado-Negret, Roberto Salguero-Gomez, Ignacio Santa-Regina, Ana Carolina Santacruz-García, Joaquim Santos, Jordi Sardans, Brandon Schamp, Michael Scherer-Lorenzen, Matthias Schleuning, Bernhard Schmid, Marco Schmidt, Sylvain Schmitt, Julio V. Schneider, Simon D. Schowanek, Julian Schrader, Franziska Schrodt, Bernhard Schuldt, Frank Schurr, Galia Selaya Garvizu, Marina Semchenko, Colleen Seymour, Julia C. Sfair, Joanne M. Sharpe, Christine S. Sheppard, Serge Sheremetiev, Satomi Shiodera, Bill Shipley, Tanvir Ahmed Shovon, Alrun Siebenkäs, Carlos Sierra, Vasco Silva, Mateus Silva, Tommaso Sitzia, Henrik Sjöman, Martijn Slot, Nicholas G. Smith, Darwin Sodhi, Pamela Soltis, Douglas Soltis, Ben Somers, Grégory Sonnier, Mia Vedel Sørensen, Enio Egon Sosinski Jr, Nadejda A. Soudzilovskaia, Alexandre F. Souza, Marko Spasojevic, Marta Gaia Sperandii, Amanda B. Stan, James Stegen, Klaus Steinbauer, Jörg G. Stephan, Frank Sterck, Dejan B. Stojanovic, Tanya Strydom, Maria Laura Suarez, Jens-Christian Svenning, Ivana Svitková, Marek Svitok, Miroslav Svoboda, Emily Swaine, Nathan Swenson, Marcelo Tabarelli, Kentaro Takagi, Ulrike Tappeiner, Rubén Tarifa, Simon Tauugourdeau, Cagatay Tavsanoglu, Mariska te Beest, Leho Tedersoo, Nelson Thiffault, Dominik Thom, Evert Thomas, Ken Thompson, Peter E. Thornton, Wilfried Thuiller, Lubomír Tichý, David Tissue, Mark G. Tjoelker, David Yue Phin Tng, Joseph Tobias, Péter Török, Tonantzin Tarin, José M. Torres-Ruiz, Béla Tóthmérész, Martina Treurnicht, Valeria Trivellone, Franck Trolliet, Volodymyr Trotsiuk, James L. Tsakalos, Ioannis Tsiripidis, Niklas Tysklind, Toru Umehara, Vladimir Usoltsev, Matthew Vadeboncoeur, Jamil Vaezi, Fernando Valladares, Jana Vamosi, Peter M. van Bodegom, Michiel van Breugel, Elisa Van Cleemput, Martine van de Weg, Stephni van der Merwe, Fons van der Plas, Masha T. van der Sande, Mark van Kleunen, Koenraad Van Meerbeek, Mark Vanderwel, Kim André Vanselow, Angelica Vårhammar, Laura Varone, Maribel Yesenia Vasquez Valderrama, Kiril Vassilev, Mark Vellend, Erik J. Veneklaas, Hans Verbeeck, Kris Verheyen, Alexander Vibrans, Ima Vieira, Jaime Villacís, Cyrille Violle, Pandi Vivek, Katrin Wagner, Matthew Waldram, Anthony Waldron, Anthony P. Walker, Martyn Waller, Gabriel Walther, Han Wang, Feng Wang, Weiqi Wang, Harry Watkins, James Watkins, Ulrich Weber, James T. Weedon, Liping Wei, Patrick Weigelt, Evan Weiher, Aidan W. Wells, Camilla Wellstein, Elizabeth Wenk, Mark Westoby, Alana Westwood, Philip John White, Mark Whitten, Mathew Williams, Daniel E. Winkler, Klaus Winter, Chevonne Womack, Ian J. Wright, S. Joseph Wright, Justin Wright, Bruno X. Pinho, Fabiano Ximenes, Toshihiro Yamada, Keiko Yamaji, Ruth Yanai, Nikolay Yankov, Benjamin Yguel, Kátia Janaina Zanini, Amy E. Zanne, David Zelený, Yun-Peng Zhao, Jingming Zheng, Ji Zheng, Kasia Ziemińska, Chad R. Zirbel, Georg Zizka, Irié Casimir Zo-Bi, Gerhard Zotz, Christian Wirth.Max Planck Institute for Biogeochemistry; Max Planck Society; German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig; International Programme of Biodiversity Science (DIVERSITAS); International Geosphere-Biosphere Programme (IGBP); Future Earth; French Foundation for Biodiversity Research (FRB); GIS ‘Climat, Environnement et Société'.http://wileyonlinelibrary.com/journal/gcbhj2021Plant Production and Soil Scienc

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570