The goal of this study was to develop an in vivo awake mouse model for extracellular bladder sensory nerve recording. A bipolar 125-μm silver electrode was positioned under a single postganglionic bladder nerve. Efferent nerve signals were eliminated by tying off the postganglionic bladder nerve between the major pelvic ganglion and the recording electrode. Sensory nerve activity was measured in the conscious animals 48 h after surgery during continuous intravesical infusion of 0.9% saline/0.5% acetic acid followed by 0.5% acetic acid with capsazepine (10 μM) at a rate of 0.75 ml/h. Continuous infusion of 0.9% NaCl led to a gradual increase in the frequency of sensory nerve firing that peaked upon reaching threshold pressure. Non-micturition contractions were observed in some animals during filling and other animals exhibited only minimal pressure fluctuations; both types of events were associated with a rise in sensory nerve activity. Intravesical infusion of 0.5% acetic acid reduced the intermicturition interval. This was associated with a 2.1-fold increase in bladder pressure during filling and a two-fold increase at both threshold and micturition pressures. Concurrent with these changes, sensory activity increased 2.8-fold during filling and 2.4-fold at threshold pressure. Subsequent intravesical infusion of capsazepine in 0.5% acetic acid reduced filling and threshold pressures by 21 and 31.2%, respectively, and produced corresponding decreases of 36 and 23.4% in sensory nerve activity. The current study shows that multifiber sensory nerve recordings can be reproducibly obtained from conscious mice.

ImportancePreclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology.ObjectiveTo evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor–biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II.Design, Setting, and ParticipantsTwo randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022.InterventionsA 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo.Main Outcomes and MeasuresThe primary outcome was oxygen-free days, an ordinal outcome that classifies a patient’s status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension.ResultsBoth trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, −2.3 [95% CrI, −4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, −2.4 [95% CrI, −5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo.Conclusions and RelevanceIn adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19.Trial RegistrationClinicalTrials.gov Identifier: NCT04924660

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