Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 2

Treatment with LCZ696 is unblinded in this study. After the two acute study days, subjects will be provided LCZ696 50 mg bid for two weeks. At the end of those two weeks subjects will report to the Clinical Research Center (CRC) for a dose escalation visit. If their tolerance, blood pressure, potassium, and eGFR meet escalation criteria they will be given LCZ696 100 mg bid for three weeks. (If they do not meet escalation criteria they will be continued on LCZ696 50 mg bid.) After three weeks, they will return to the CRC for the next escalation visit. If they meet criteria for escalation they will be given LCZ 200 mg bid for ten days. (If they do not meet escalation criteria they will be continued on the highest tolerated dose).

Icatibant will be given intravenously at 100 µg/kg over one hour followed by 20 µg/kg/hr during each study day.

Placebo (vehicle) will be given at the same rate as icatibant.

Para-aminohippurate (PAH) will be given at a dose of 8 mg/kg loading dose followed by a 12 mg/min steady-state infusion during each study day.

Iohexol will be given as 5 mL of iohexol solution (3.235 g iohexol) intravenously on each study day.