Soluble guanylate cyclase (sGC) is the primary cellular receptor for nitric oxide (NO). NO binds and activates a heme group in sGC, initiating the conversion of GTP to the second messenger cyclic GMP (cGMP). BAY-41-8543 is a heme-dependent stimulator of sGC, increasing the activity of recombinant sGC dose-dependently up to 92-fold. Surprisingly, NO donors synergize with BAY-41-8543 in stimulating recombinant sGC. BAY-41-8543 relaxes vessels and inhibits platelet aggregation in vitro at nM concentrations. In vivo, BAY-41-8543 decreases blood pressure dose-dependently, prolongs bleeding time, and reduces thrombosis. Inhalation of microparticles containing BAY-41-8543 increases pulmonary vasodilation without changing mean arterial pressure suggesting that agonists of sGC may be efficacious in treating pulmonary hypertension.
