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Jonathan P Wisor, 1 Nils Henrik Holmedahl, 2 Ingvild West Saxvig, 3 Odd-Magne Fjeldstad, 2 Eddie Weitzberg, 4 Janne Grønli, 5 Harald Kåre Engan 6 1Sleep and Performance Research Center and Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA; 2Section of Lung Rehabilitation, Department of Rehabilitation and Lifestyle Medicine, LHL-Hospital Gardermoen, Jessheim, Norway; 3Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Bergen, Norway; 4Department of Physiology and Pharmacology, Karolinska Institutet and Department of Perioperative Medicine and Intensive Care, Karolinska Hospital, Stockholm, Sweden; 5Department of Biological and Medical Psychology, Faculty of Psychology, University of Bergen, Bergen, Norway; 6Unicare Rehabilitation, Oslo, NorwayCorrespondence: Jonathan P WisorWashington State University, 412 E. Spokane Falls Blvd, Spokane, WA, 99202, USATel +1 509358-7577Email Jonathan.Wisor@wsu.eduPurpose: Poor sleep quality in chronic obstructive pulmonary disease (COPD) is a result of oxygen desaturation secondary to compromised lung function. Nitrate supplementation with dietary beetroot juice is known to elevate plasma nitrate and to increase the efficiency of oxygen utilization in non-COPD individuals; whether it is of therapeutic benefit for sleep quality in COPD has not been reported.Patients and Methods: In a counterbalanced within-subjects design involving 15 COPD patients as subjects, the subjects consumed either beetroot juice containing nitrate (BJ; ∼ 6.2 mmol NO 3–) or placebo (NO 3– -depleted juice) immediately before a night of polysomnographic monitoring. Nitrate was measured in plasma collected immediately after waking.Results: While BJ consumption had no effect on the amount of time spent in any sleep stages, wake-to-N2 transitions and direct wake-to-rapid eye movement sleep (REMS) transitions, hallmarks of disordered sleep, were less frequent on the BJ night than on the placebo night. In the last two hours of the BJ night, percent time in REMS increased and delta power during deep (N3) non-REMS decreased, relative to the placebo night. Collectively, the reduced frequency of atypical transitions and the normalization of non-REMS/REMS dynamics after BJ are indicative of an improvement of sleep quality. BJ also resulted in sustained elevation of peripheral oxygen saturation (SpO 2), during episodes of wake after sleep onset. Plasma nitrate was elevated nearly tenfold on the morning after BJ relative to placebo.Conclusion: BJ has a normalizing effect on disordered sleep in COPD, which may be related to improved oxygen delivery.Clinical Trial Registration: The activities of the Regional Committees for Medical and Health Research Ethics (REC) are founded on the Norwegian law on research ethics and medical research. This study was approved by NTNU/REK midt, Det medisinske fakultet, Postboks 8905, 7491 Trondheim (REK midt 2016/1360).Keywords: polysomnography, oxygen saturation, beetroot juice, hypoxia

Dmitry Grishenkov,1–3 Adrian Gonon,3,4 Eddie Weitzberg,5 Jon O Lundberg,5 Johan Harmark,6 Barbara Cerroni,7 Gaio Paradossi,7 Birgitta Janerot-Sjoberg1–3 1Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden; 2Department of Medical Engineering, KTH, Royal Institute of Technology, School of Technology and Health, Stockholm, Sweden; 3Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden; 4Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; 6Department of Biosciences and Nutrition, Karolinska Institutet, KTH, Royal Institute of Technology, School of Technology and Health, Stockholm, Sweden; 7Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Rome, Italy Abstract: The current study describes novel multifunctional polymer-shelled microbubbles (MBs) loaded with nitric oxide (NO) for integrated therapeutic and diagnostic applications (ie, theranostics) of myocardial ischemia. We used gas-filled MBs with an average diameter of 4 µm stabilized by a biocompatible shell of polyvinyl alcohol. In vitro acoustic tests showed sufficient enhancement of the backscattered power (20 dB) acquired from the MBs’ suspension. The values of attenuation coefficient (0.8 dB/cm MHz) and phase velocities (1,517 m/s) were comparable with those reported for the soft tissue. Moreover, polymer MBs demonstrate increased stability compared with clinically approved contrast agents with a fracture threshold of about 900 kPa. In vitro chemiluminescence measurements demonstrated that dry powder of NO-loaded MBs releases its gas content in about 2 hours following an exponential decay profile with an exponential time constant equal to 36 minutes. The application of high-power ultrasound pulse (mechanical index =1.2) on the MBs resuspended in saline decreases the exponential time constant from 55 to 4 minutes in air-saturated solution and from 17 to 10 minutes in degassed solution. Thus, ultrasound-triggered release of NO is achieved. Cytotoxicity tests indicate that phagocytosis of the MBs by macrophages starts within 6–8 hours. This is a suitable time for initial diagnostics, treatment, and monitoring of the therapeutic effect using a single injection of the proposed multifunctional MBs. Keywords: microbubbles, contrast agent, ultrasound, nitric oxide, myocardial ischemia

Myocardial depression in sepsis is frequently encountered clinically and contributes to morbidity and mortality. Increased plasma levels of endothelin-1 (ET-1) have been described in septic shock, and previous reports have shown beneficial effects on cardiovascular performance and survival in septic models using ET receptor antagonists. The aim of the current study was to investigate specific cardiac effects of ET receptor antagonism in endotoxicosis. Sixteen domestic pigs were anesthetized and subjected to endotoxin for 5 h. Eight of these pigs were given tezosentan (dual ET receptor antagonist) after 3 h. Cardiac effects were evaluated using the left ventricular (LV) pressure-volume relationship. Endotoxin was not associated with any effects on parameters of LV contractile function [end-systolic elastance (Ees), preload recruitable stroke work (PRSW), [power.sub.max]/end-diastolic volume (PW[R.sub.max]/EDV) and dP/[dt.sub.max]/end-diastolic volume (dP/[dt.sub.max]/EDV)] but with impairments in isovolumic relaxation (time constant for pressure decay, tau) and mechanical efficiency. Tezosentan administration decreased Ees, PW[R.sub.max]/EDV, and dP/[dt.sub.max]/EDV, while improving tau and LV stiffness. Thus, dual ET receptor antagonism was associated with a decline in contractile function but, in contrast, improved diastolic function. Positive hemodynamic effects from ET receptor antagonism in acute endotoxemia may be due to changes in cardiac load and enhanced diastolic function rather than improved contractile function. sepsis; endotoxin; inotropy; end-systolic elastance; diastolic

Positive inotropic and negative lusitropic effects of endothelin receptor agonism in vivo. Am J Physiol Heart Circ Physiol 289: H1702-H1709, 2005. First published June 10, 2005; doi: 10.1152/ajpheart.00892.2004.--The endothelin (ET) system is involved in the regulation of myocardial function in health as well as in several diseases, such as congestive heart failure, myocardial infarction, and septic myocardial depression. Conflicting results have been reported regarding the acute contractile properties of ET-1. We therefore investigated the effects of intracoronary infusions of ET-1 and of the selective [ET.sub.B] receptor-selective agonist sarafotoxin 6c with increasing doses in anesthetized pigs. Myocardial effects were measured through analysis of the left ventricular pressure-volume relationship. ET-1 elicited increases in the myocardial contractile status (end-systolic elastance value of 0.94 [+ or -] 0.11 to 1.48 [+ or -] 0.23 and preload recruitable stroke work value of 68.7 [+ or -] 4.7 to 83.4 [+ or -] 7.2) that appear to be mediated through [ET.sub.A] receptors, whereas impairment in left ventricular isovolumic relaxation ([tau] = 41.5 [+ or -] 1.4 to 58.1 [+ or -] 5.0 and [t.sub.1/2] = 23.0 [+ or -] 0.7 to 30.9 [+ or -] 2.6, where [tau] is the time constant for pressure decay and [t.sub.1/2] is the haft-time for pressure decay) was [ET.sub.B] receptor dependent. In addition, intravenous administration of ET-1 impaired ventricular relaxation but had no effect on contractility. Intracoronary sarafotoxin 6c administration caused impairments in left ventricular relaxation ([tau] from 43.3 [+ or -] 1.8 to 54.4 [+ or -] 3.4) as well as coronary vasoconstriction. In conclusion, ET-1 elicits positive inotropic and negative lusitropic myocardial effects in a pig model, possibly resulting from [ET.sub.A] and [ET.sub.B] receptor activation, respectively. cardiac; inotropy; end-systolic elastance; diastolic; porcine; sarafotoxin