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Figure S1. TRV027 hemodynamic effects are more pronounced in dogs with elevated PRA than dogs with normal PRA. (A) MAP, and (B) pulmonary capillary wedge pressure (PCWP) effects of TRV027 at similar doses in normal dogs (blue circles, 1.0 µg/kg/min), tachypaced heart failure dogs (orange squares, 1.0 µg/kg/min), and tachypaced heart failure dogs receiving furosemide (black squares, 1.5 µg/kg/min). Data for each dog was retrospectively sorted into “normal PRA” (less than or equal to 5.8 ng/mL/h, the upper limit of the laboratory reference range for salt depleted humans per SOP M8060.1, Mayo Clinic, Rochester, MN) and “high PRA” (higher than 5.8 ng/mL/h) populations. Hemodynamic and PRA data from references 19 and 20. As expected, heart failure dogs are overrepresented in the “high PRA” group, and TRV027 effects on MAP and PCWP are more pronounced in this group.

Figure S2. TRV027 is rapidly cleared in rats and dogs. TRV027 infused at 10 µg/kg/min for 2 hours to rats (A) or dogs (B) rapidly reaches steady-state plasma concentration after a continuous infusion, and is rapidly cleared after the infusion is terminated. Data are mean ± SEM of three animals per study.

Figure S3. TRV027 has no effect on heart rate in healthy volunteers with either normal or elevelated PRA. Data are mean ± SEM of six subject-periods for high-PRA TRV027-treated subjects, 58 subject-periods and 18 placebo-treated subjects.

Table S1. Number of Subjects with Treatment Emergent Adverse Events

Table S2. Pharmacokinetic Properties of TRV734.

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