Modest Contribution of Bradykinin to Blood Pressure Reduction by Sacubitril/Valsartan in Chronic Heart Failure

BACKGROUND: Symptomatic hypotension can limit sacubitril/valsartan therapy. Neprilysin inhibition may augment vasodilators, such as bradykinin. We hypothesized that bradykinin contributes to blood pressure (BP) lowering with sacubitril/valsartan in stable ambulatory patients with heart failure and reduced ejection fraction <50%. METHODS: In a randomized, double-blind crossover trial, participants received intravenous infusion of the bradykinin B2 receptor inhibitor icatibant and a matching placebo for 6 hours following sacubitril/valsartan dosing at acute initiation (n=36) and after 8 weeks of chronic therapy (n=30). The primary end point was maximal change in mean arterial pressure (MAP). Plasma natriuretic peptides, urine cyclic GMP, urine volume, sodium excretion, renal plasma flow, and renovascular resistance were measured. RESULTS: =0.013). Icatibant also decreased renal plasma flow and increased renal vascular resistance after chronic dosing, without affecting heart rate, urine volume, urine sodium, cGMP/creatinine, or natriuretic peptides. CONCLUSIONS: BP lowering with sacubitril/valsartan occurs with both acute and chronic dosing. ANP (1-28) appears to mediate the initial BP reduction, whereas bradykinin contributes to BP lowering after dosing during chronic therapy. Clarifying these mechanisms may inform clinical management to optimize the benefit of this important heart failure and reduced ejection fraction therapy. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04113109.