bay-58-2667 and Inflammation

The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic 3',5'-guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular regulation by promoting vasodilation and inhibiting vascular smooth muscle cell growth, platelet aggregation, and leukocyte adhesion. In pathophysiological states with endothelial dysfunction this signaling pathway is impaired. Activation of sGC has traditionally been achieved with nitrovasodilators; however, these drugs are associated with the development of tolerance and potentially deleterious cGMP-independent actions. In this review the actions of BAY 41-2272, the prototype of a new class of NO-independent sGC stimulators, in cardiovascular disease models is discussed. BAY 41-2272 binds to a regulatory site on the alpha-subunit of sGC and stimulates the enzyme synergistically with NO. BAY 41-2272 had antihypertensive actions and attenuated remodeling in models of systemic arterial hypertension. It also unloaded the heart in experimental congestive heart failure. BAY 41-2272 reduced pulmonary vascular resistance in acute and chronic experimental pulmonary arterial hypertension. Furthermore, BAY 41-2272 inhibited platelet aggregation in vitro and leukocyte adhesion in vivo. These findings make direct sGC stimulation with BAY 41-2272 a promising new therapeutic strategy for cardiovascular diseases and warrant further studies. Finally, the significance of the novel NO- and heme-independent sGC activator BAY 58-2667, which activates two forms of NO-insensitive sGC, is briefly discussed.

Topics: Animals; Antihypertensive Agents; Benzoates; Cardiovascular Diseases; Cell Adhesion; Cyclic GMP; Disease Models, Animal; Endothelium, Vascular; Enzyme Activation; Enzyme Activators; Guanylate Cyclase; Heart Failure; Heme; Humans; Hypertension; Hypertension, Pulmonary; Inflammation; Leukocytes; Nitric Oxide; Platelet Aggregation; Pyrazoles; Pyridines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Vasodilator Agents