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Preserving vascular function is crucial for preventing multiorgan failure and death in ischemic and low-pressure states such as trauma/hemorrhagic shock (T/HS). It has recently been reported that inhibiting circulating proteases released from the bowel to the circulation during T/HS may preserve vascular function and improve outcomes following T/HS. This study aimed to evaluate the role of the serine protease inhibitor gabexate mesilate (GM) in preserving vascular function during T/HS when given enterally. We studied the vascular reactivity of mesenteric arteries from male Wistar rats treated with enteral GM (10 mg/kg) (GM-treated, n = 6) or control (Shock-control, n = 6) following (T/HS) using pressure myography. Concentration-response curves of endothelial-dependent and endothelial-independent agonists (e.g., acetylcholine, sodium nitroprusside) ranging from 10-10 to 10-5 M were performed. In a second set of experiments, ex-vivo arteries from healthy rats were perfused with plasma from shocked animals from both groups and vascular performance was similarly measured. Arteries from the GM-treated group demonstrated a preserved concentration-response curve to the α1 adrenergic agonist phenylephrine compared to arteries from Shock-control animals (- logEC50: - 5.73 ± 0.25 vs. - 6.48 ± 0.2, Shock-control vs. GM-treated, p = 0.04). When perfused with plasma from GM-treated rats, healthy arteries exhibited an even greater constriction and sensitivity to phenylephrine (- logEC50: - 6.62 ± 0.21 vs. - 7.13 ± 0.21, Shock-control vs. GM-treated, p = 0.02). Enteral GM also preserved the endothelium-dependent vascular response to agonists following T/HS and limited syndecan-1 shedding as a marker of glycocalyx compromise (41.84 ± 9 vs. 17.63 ± 3.97 ng/mL, Shock-control vs. GM-treated, p = 0.02). Syndecan-1 cleavage was correlated with plasma trypsin-like activity (r2 = 0.9611). Enteral gabexate mesilate was able to maintain vascular function in experimental T/HS, which was reflected by improved hemodynamics (mean arterial pressure 50.39 ± 7.91 vs. 64.95 ± 3.43 mmHg, Shock-control vs. GM treated, p = 0.0001). Enteral serine protease inhibition may be a potential therapeutic intervention in the treatment of T/HS.

Introduction: Infection by SARS-CoV-2 and subsequent COVID-19 can cause viral sepsis. We investigated plasma protease activity patterns in COVID-19-induced sepsis with bacterial superinfection, as well as plasma proteomics and peptidomics in order to assess the possible implications of enhanced proteolysis on major protein systems (e.g., coagulation). Methods: Patients (=4) admitted to the intensive care units (ICUs) at the University of California, San Diego (UCSD) Medical Center with confirmed positive test for COVID-19 by real-time reverse transcription polymerase chain reaction (RT-PCR) were enrolled in a study approved by the UCSD Institutional Review Board (IRB# 190699, Protocol #20-0006). Informed consent was obtained for the collection of blood samples and de-identified use of the data. Blood samples were collected at multiple time points and analyzed to quantify a) the circulating proteome and peptidome by mass spectrometry; b) the aminopeptidase activity in plasma; and c) the endopeptidase activity in plasma using fluorogenic substrates that are cleaved by trypsin-like endopeptidases, specific clotting factors and plasmin. The one patient who died was diagnosed with bacterial superinfection on day 7 after beginning of the study. Results: Spikes in protease activity (factor VII, trypsin-like activity), and corresponding increases in the intensity of peptides derived by hydrolysis of plasma proteins, especially of fibrinogen degradation products and downregulation of endogenous protease inhibitors were detected on day 7 for the patient who died. The activity of the analyzed proteases was stable in survivors. Discussion: The combination of multiomics and enzymatic activity quantification enabled to i) hypothesize that elevated proteolysis occurs in COVID-19-induced septic shock with bacterial superinfection, and ii) provide additional insight into malfunctioning protease-mediated systems, such as hemostasis.

It is well known that cardiometabolic dysfunction gradually increases after menopause, and the sedentary lifestyle can aggravate this condition. Therefore, we compared the effects of aerobic exercise training during the premenopausal period and after ovariectomy (OVX) on metabolic, hemodynamic, and autonomic parameters in an experimental rat model of menopause. The female rats were divided into four groups: control (C), sedentary OVX (SO), trained OVX (TO), and previously trained OVX (PTO). The PTO group was trained for 4 weeks prior to+8 weeks after OVX, and the TO group trained only after OVX on a motor treadmill. Autonomic modulation was evaluated, white adipose tissue (WAT) was removed and weighed, and lipolysis was assessed. The citrate synthase activity in the soleus muscle was analyzed. The trained groups prevented the impairment of baroreceptor reflex sensitivity in relation to SO; however, only PTO reduced the low-frequency band of the pulse interval compared to SO. PTO reduced the weight of WAT compared to the other groups; lipolysis in PTO was similar to that in C. PTO preserved muscle metabolic injury in all types of fibers analyzed. In conclusion, this study suggests that exercise training should be recommended in a premenopausal model to prevent cardiometabolic and autonomic menopause-induced deleterious effects. [ABSTRACT FROM AUTHOR]

Angiotensin-(1-7) counterbalances angiotensin II cardiovascular effects. However, it has yet to be determined how cardiovascular autonomic modulation may be affected by chronic and acute elevation of Ang-(1-7). Hemodynamics and cardiovascular autonomic profile were evaluated in male Sprague-Dawley (SD) rats and transgenic rats (TGR) overexpressing Ang-(1-7) [TGR(A1-7)3292]. Blood pressure (BP) was directly measured while cardiovascular autonomic modulation was evaluated by spectral analysis. TGR received A-779 or vehicle and SD rats received Ang-(1-7) or vehicle and were monitored for 5 h after i.v. administration. In another set of experiments with TGR, A-779 was infused for 7 days using osmotic mini pumps. Although at baseline no differences were observed, acute administration of A-779 in TGR produced a marked long-lasting increase in BP accompanied by increased BP variability (BPV) and sympathetic modulation to the vessels. Likewise, chronic administration of A-779 with osmotic mini pumps in TGR increased heart rate, sympathovagal balance, BPV, and sympathetic modulation to the vessels. Administration of Ang-(1-7) to SD rats increased heart rate variability values in 88% accompanied by 8% of vagal modulation increase and 18% of mean BP reduction. These results show that both acute and chronic alteration in the Ang-(1-7)Mas receptor axis may lead to important changes in the autonomic control of circulation, impacting either sympathetic and (or) parasympathetic systems. Key words: renin-angiotensin system, angiotensin-(1-7), A-779, blood pressure, autonomic nervous system, heart rate variability, spectral analysis. L'angiotensine (1-7) compense les effets cardiovasculaires de l'angiotensine II. Cependant, il reste a determiner comment la modulation autonome du systeme cardiovasculaire pourrait etre affectee par la hausse chronique et aigue d'angiotensine (1-7). Nous avons evalue l'hemodynamie et le profil autonome du systeme cardiovasculaire chez des rats males Sprague-Dawley (SD) et transgeniques (TG) surexprimant l'angiotensine (1-7) [TGR(A1-7)3292]. Nous avons mesure directement la tension arterielle (TA) tout en evaluant la modulation autonome du systeme cardiovasculaire a l'aide de l'analyse spectrale. Nous avons administre par voie i.v. de l'A-779 ou le vehicule au rats TG et de l'angiotensine (1-7) ou le vehicule aux rats SD, puis effectue une surveillance de 5 heures. Dans une autre serie d'experiences avec les rats TG, nous avons perfuse de l'A-779 pendant 7 jours a l'aide de mini pompes osmotiques. Bien que nous n'ayons observe aucune difference au debut de l'etude, l'administration aigue d'A-779 a entraine chez les rats TG une augmentation marquee et de longue duree de la TA, laquelle etait accompagnee d'une augmentation de la variabilite de la TA (VTA) ainsi que d'une modulation sympathique des vaisseaux. De la meme maniere, l'administration chronique d'A-779 a l'aide de mini pompes osmotiques chez les rats TG a entraine une augmentation de la frequence cardiaque, de l'equilibre sympathovagal, de la VTA et de la modulation sympathique des vaisseaux. L'administration d'angiotensine (1-7) chez les rats SD a entraine une augmentation des valeurs de variabilite de la frequence cardiaque de 88 %, accompagnee d'une augmentation de la modulation vagale de 8 % ainsi que d'une diminution de la TA moyenne de l'ordre de 18 %. Ces resultats montrent que la modification aigue comme chronique de l'axe angiotensine (1-7)-Mas pourrait entrainer des variations marquees de la regulation autonome de la circulation, avec une incidence sur le systeme sympathique et (ou) le systeme parasympathique. [Traduit par la Redaction] Mots-cles: systeme renine-angiotensine, angiotensine (1-7), A-779, tension arterielle, systeme nerveux autonome, variabilite de la frequence cardiaque, analyse spectrale., Introduction The renin-angiotensin system (RAS) is a key regulatory mechanism of the renal, cardiovascular, and autonomic nervous systems (Baltatu et al. 2011). The discovery and characterization of Ang-(1-7) and its [...]