NO-independent sGC Activation Improves Vascular Function and Cardiac Remodeling in Sickle Cell Disease.

NO-independent sGC Activation Improves Vascular Function and Cardiac Remodeling in Sickle Cell Disease. Am J Respir Cell Mol Biol. 2017 Dec 21;: Authors: Potoka KP, Wood KC, Baust JJ, Bueno M, Hahn SA, Vanderpool RR, Bachman T, Mallampalli GM, Osei-Hwedieh DO, Schrott V, Sun B, Bullock GC, Becker-Pelster EM, Wittwer M, Stampfuss J, Mathar I, Stasch JP, Truebel H, Sandner P, Mora AL, Straub AC, Gladwin MT Abstract Sickle cell disease (SCD) is associated with intravascular hemolysis and oxidative inhibition of nitric oxide (NO) signaling. BAY 54-6544 is a small molecule activator of oxidized sGC; which unlike endogenous NO and the sGC stimulator BAY 41-8543; preferentially binds and activates heme-free, NO-insensitive sGC to restore enzymatic cGMP production. We tested orally delivered sGC activator BAY 54-6544, sGC stimulator BAY 41-8543, sildenafil, or placebo for 4-12 weeks in a transgenic mouse model of SCD (BERK-SCD) and their hemizygous littermate controls (BERK-Hemi). Right ventricular maximum systolic pressure (RVmaxSP) was measured using micro right heart catheterization. Right ventricle hypertrophy (RVH) was determined using Fulton's Index and right ventricle corrected weight (ratio of RV to tibia). Pulmonary artery vasoreactivity was tested for endothelium-dependent and -independent vessel relaxation. Right heart catheterization revealed higher RVmaxSP and RVH in BERK-SCD versus BERK-Hemi, which worsened with age. Treatment ...
Source: Am J Respir Cell Mol... - Category: Respiratory Medicine Authors: Tags: Am J Respir Cell Mol Biol Source Type: research