Jeffrey A Kline1, Michael A Puskarich2, Jonathan W Pike3, John Zagorski3, Nathan J Alves3. 1. Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address: jefkline@iu.edu. 2. Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, MN, United States; Department of Emergency Medicine, University of Minnesota, Minneapolis, MN, United States. 3. Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, United States.
Abstract
BACKGROUND: We test if inhaled nitric oxide (NO) attenuates platelet functional and metabolic hyper-reactivity in subjects with submassive pulmonary embolism (PE). METHODS:Participants with PE were randomized to either 50 ppm NO + O2 or O2 only for 24 h with blood sampling at enrollment and after treatment; results were compared with healthy controls. Platelet metabolic activity was assessed by oxygen consumption (basal and uncoupled) and reactivity was assessed with agonist-stimulated thromboelastography (TEG) and fluorometric measurement of agonist-stimulated cytosolic [Ca++] without and with pharmacological soluble guanylate (sGC) modulation. RESULTS:Participants (N = 38 per group) were well-matched at enrollment for PE severity, comorbidities as well as TEG parameters and platelet O2 consumption. NO treatment doubled the mean plasma [NO3-] (P < 0.001) indicating successful delivery, but placebo treatment produced no change. After 24 h, neither TEG nor O2 consumption parameters differed significantly between treatment groups. Platelet cytosolic [Ca++] was elevated with PE versus controls, and was decreased by treatment with cinaciguat (an sGC activator), but not riociguat (an sGC stimulator). Stimulated platelet lysatesGC activity was increased with PE compared with controls. CONCLUSIONS: In patients with acute submassive PE, despite evidence of adequate drug delivery, inhaled NO had no major effect on platelet O2 consumption or agonist-stimulated parameters on TEG. Pharmacological activation, but not stimulation, of sGC effectively decreased platelet cytosolic [Ca++], and platelet sGC activity was increased with PE, confirming the viability of sGC as a therapeutic target.
RCT Entities:
BACKGROUND: We test if inhaled nitric oxide (NO) attenuates platelet functional and metabolic hyper-reactivity in subjects with submassive pulmonary embolism (PE). METHODS:Participants with PE were randomized to either 50 ppm NO + O2 or O2 only for 24 h with blood sampling at enrollment and after treatment; results were compared with healthy controls. Platelet metabolic activity was assessed by oxygen consumption (basal and uncoupled) and reactivity was assessed with agonist-stimulated thromboelastography (TEG) and fluorometric measurement of agonist-stimulated cytosolic [Ca++] without and with pharmacological soluble guanylate (sGC) modulation. RESULTS:Participants (N = 38 per group) were well-matched at enrollment for PE severity, comorbidities as well as TEG parameters and platelet O2 consumption. NO treatment doubled the mean plasma [NO3-] (P < 0.001) indicating successful delivery, but placebo treatment produced no change. After 24 h, neither TEG nor O2 consumption parameters differed significantly between treatment groups. Platelet cytosolic [Ca++] was elevated with PE versus controls, and was decreased by treatment with cinaciguat (an sGC activator), but not riociguat (an sGC stimulator). Stimulated platelet lysate sGC activity was increased with PE compared with controls. CONCLUSIONS: In patients with acute submassive PE, despite evidence of adequate drug delivery, inhaled NO had no major effect on platelet O2 consumption or agonist-stimulated parameters on TEG. Pharmacological activation, but not stimulation, of sGC effectively decreased platelet cytosolic [Ca++], and platelet sGC activity was increased with PE, confirming the viability of sGC as a therapeutic target.
Authors: C C Helms; M Marvel; W Zhao; M Stahle; R Vest; G J Kato; J S Lee; G Christ; M T Gladwin; R R Hantgan; D B Kim-Shapiro Journal: J Thromb Haemost Date: 2013-12 Impact factor: 5.824
Authors: Mark T Gladwin; Gregory J Kato; Debra Weiner; Onyinye C Onyekwere; Carlton Dampier; Lewis Hsu; R Ward Hagar; Thomas Howard; Rachelle Nuss; Maureen M Okam; Carole K Tremonti; Brian Berman; Anthony Villella; Lakshmanan Krishnamurti; Sophie Lanzkron; Oswaldo Castro; Victor R Gordeuk; Wynona A Coles; Marlene Peters-Lawrence; James Nichols; Mary K Hall; Mariana Hildesheim; William C Blackwelder; James Baldassarre; James F Casella Journal: JAMA Date: 2011-03-02 Impact factor: 56.272
Authors: Jeffrey A Kline; Michael A Puskarich; Alan E Jones; Ronald A Mastouri; Cassandra L Hall; Anthony Perkins; Emily E Gundert; Tim Lahm Journal: Nitric Oxide Date: 2019-01-08 Impact factor: 4.427
Authors: Jeffrey A Kline; Cassandra L Hall; Alan E Jones; Michael A Puskarich; Ronald A Mastouri; Tim Lahm Journal: Am Heart J Date: 2017-01-27 Impact factor: 4.749
Authors: Lai Wen; Susanne Feil; Markus Wolters; Martin Thunemann; Frank Regler; Kjestine Schmidt; Andreas Friebe; Marcus Olbrich; Harald Langer; Meinrad Gawaz; Cor de Wit; Robert Feil Journal: Nat Commun Date: 2018-10-16 Impact factor: 14.919
Authors: Tanya K Marvi; William B Stubblefield; Benjamin F Tillman; Mark W Tenforde; Leora R Feldstein; Manish M Patel; Wesley H Self; Carlos G Grijalva; Todd W Rice Journal: Crit Care Explor Date: 2021-03-17
Authors: Andrea Vernerova; Luiz Felipe Garcia-Souza; Ondrej Soucek; Milan Kostal; Vit Rehacek; Lenka Kujovska Krcmova; Erich Gnaiger; Ondrej Sobotka Journal: Biomedicines Date: 2021-12-08