Journal Article

Nitric Oxide-Independent Soluble Guanylate Cyclase Activation Improves Vascular Function and Cardiac Remodeling in Sickle Cell Disease

Straub, Adam C, Potoka, Karin P, Wood, Katherine C, Bueno, Marta, Sun, Bin, Schrott, Valerie, Osei-Hwedieh, David O, Sandner, Peter, Gladwin, Mark T, Wittwer, Matthias, Mallampalli, Grace M, Truebel, Hubert, Baust, Jeffrey J, Vanderpool, Rebecca R, Mathar, Ilka, Becker-Pelster, Eva-Maria, Stampfuss, Jan, Mora, Ana L, Bachman, Tim, Stasch, Johannes-Peter, Hahn, Scott A, Bullock, Grant C

2018

Overview

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 soluble guanylate cyclase (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 (17 mg/kg/d), sGC stimulator, BAY 41-8543, sildenafil, and placebo for 4-12 weeks in the Berkeley transgenic mouse model of SCD (BERK-SCD) and their hemizygous (Hemi) littermate controls (BERK-Hemi). Right ventricular (RV) maximum systolic pressure (RVmaxSP) was measured using micro right-heart catheterization. RV hypertrophy (RVH) was determined using Fulton's index and RV 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 with the sGC activator more effectively lowered RVmaxSP and RVH, with 90-day treatment delivering superior results, when compared with other treatments and placebo groups. In myography experiments, acetylcholine-induced (endothelium-dependent) and sodium-nitroprusside-induced (endothelium-independent NO donor) relaxation of the pulmonary artery harvested from placebo-treated BERK-SCD was impaired relative to BERK-Hemi but improved after therapy with sGC activator. By contrast, no significant effect for sGC stimulator or sildenafil was observed in BERK-SCD. These findings suggest that sGC is oxidized in the pulmonary arteries of transgenic SCD mice, leading to blunted responses to NO, and that the sGC activator, BAY 54-6544, may represent a novel therapy for SCD-associated pulmonary arterial hypertension and cardiac remodeling.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Acetylcholine / Anemia / Anemia, Sickle Cell - complications / Anemia, Sickle Cell - genetics / Animals / Arterial Pressure - drug effects / Bioavailability / Blood pressure / Catheterization / Cyclic GMP / Disease Models, Animal / Endothelium / Enzyme Activation / Enzyme Activators - pharmacokinetics / Enzyme Activators - pharmacology / Enzymes / FDA approval / Guanylate cyclase / Heart diseases / Heart failure / Heart Ventricles - drug effects / Heart Ventricles - enzymology / Heart Ventricles - physiopathology / Heme / Homeostasis / Hypertension, Pulmonary - drug therapy / Hypertension, Pulmonary - enzymology / Hypertension, Pulmonary - genetics / Hypertension, Pulmonary - physiopathology / Hypertrophy / Hypertrophy, Left Ventricular - enzymology / Hypertrophy, Left Ventricular - genetics / Hypertrophy, Left Ventricular - physiopathology / Hypertrophy, Left Ventricular - prevention & control / Intubation / Kinases / Mice, Transgenic / Morpholines - pharmacology / Nitric oxide / Nitric Oxide - metabolism / Original Research / Pulmonary arteries / Pulmonary artery / Pulmonary Artery - drug effects / Pulmonary Artery - enzymology / Pulmonary Artery - physiopathology / Pulmonary hypertension / Pyrimidines - pharmacology / Rodents / Sickle cell disease / Sildenafil / Sildenafil Citrate - pharmacology / Smooth muscle / Sodium / Soluble Guanylyl Cyclase - metabolism / Studies / Tibia / Transgenic mice / Vasodilation - drug effects / Veins & arteries / Ventricle / Ventricular Dysfunction, Right - drug therapy / Ventricular Dysfunction, Right - enzymology / Ventricular Dysfunction, Right - genetics / Ventricular Dysfunction, Right - physiopathology / Ventricular Function, Right - drug effects / Ventricular Pressure - drug effects / Ventricular Remodeling - drug effects