Akin to combination therapy with sildenafil and riociguat, shown to excessively potentiate the NO pathway leading to significant systemic hypotension without additional benefits in PAH (Galie et al., 2015), combining β3 AR agonists upstream of sGC‐PDE5 with agents targeting these downstream molecules may cause excessive potentiation of NO signaling, and should be avoided. This evidence concerns the gene SGCB and pulmonary arterial hypertension.