bay-58-2667 and Hypertension

Lower urinary tract symptoms (LUTS), comprising storage (such as urinary incontinence and urinary frequency), voiding, and postmicturition symptoms, are highly prevalent conditions that affect millions of people worldwide. LUTS have a profound effect on quality of life and are a considerable cost to health care systems. In men specifically, BPH commonly leads to LUTS. Clinical studies also show an association of LUTS with erectile dysfunction (ED). Nitric oxide (NO) has long been recognized as an important nonadrenergic, noncholinergic (NANC) transmitter in bladder, urethra, prostate, and corpus cavernosum smooth muscle. Data from clinical and basic research show that oxidation and degradation of soluble guanylate cyclase (sGC; also known as GCS) and reduced cyclic GMP (cGMP) levels are involved in the physiopathology of genitourinary diseases. The NO-sGC-cGMP signalling pathway has a role in disease pathophysiology of the bladder, urethra, prostate, and corpus cavernosum in animal models and humans. Advances in targeting sGC directly to enhance cGMP production independently of endogenous NO have been made using NO-independent stimulators and activators of sGC. These molecules are potential therapeutics in the treatment of LUTS and ED.

Topics: Aging; Animals; Benzoates; Diabetes Complications; Enzyme Activators; Humans; Hypertension; Indazoles; Lower Urinary Tract Symptoms; Nitric Oxide; Obesity; Phosphodiesterase 5 Inhibitors; Pyrazoles; Pyridines; Reactive Oxygen Species; Risk Factors; Soluble Guanylyl Cyclase; Urinary Tract

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

A major problem with using nitrates in the treatment of ischemic heart disease is that tolerance develops to their vasodilatory actions. YC-1 was used as the lead compound to synthesize further nitric oxide-independent soluble guanylate cyclase activators, including BAY-41-2272 and BAY-41-8543. A nitric oxide and heme-independent activator of soluble guanylate cyclase, BAY-58-2667, was subsequently discovered by high-throughput screening. Tolerance to the vasodilatory actions of BAY-41-8543 and BAY-58-2667 does not develop. Results from animal studies have suggested that these compounds may have potential in the treatment of ischemic heart disease, essential and pulmonary hypertension, congestive heart failure, glomerulonephritis and erectile dysfunction.

Topics: Animals; Benzoates; Enzyme Activators; Glomerulonephritis; Guanylate Cyclase; Heart Failure; Humans; Hypertension; Morpholines; Myocardial Ischemia; Nitric Oxide; Pyrimidines

Nitric oxide regulates BP by binding the reduced heme iron (Fe2+) in soluble guanylyl cyclase (sGC) and relaxing vascular smooth muscle cells (SMCs). We previously showed that sGC heme iron reduction (Fe3+ → Fe2+) is modulated by cytochrome b5 reductase 3 (CYB5R3). However, the in vivo role of SMC CYB5R3 in BP regulation remains elusive. Here, we generated conditional smooth muscle cell-specific Cyb5r3 KO mice (SMC CYB5R3-KO) to test if SMC CYB5R3 loss affects systemic BP in normotension and hypertension via regulation of the sGC redox state. SMC CYB5R3-KO mice exhibited a 5.84-mmHg increase in BP and impaired acetylcholine-induced vasodilation in mesenteric arteries compared with controls. To drive sGC oxidation and elevate BP, we infused mice with angiotensin II. We found that SMC CYB5R3-KO mice exhibited a 14.75-mmHg BP increase, and mesenteric arteries had diminished nitric oxide-dependent vasodilation but increased responsiveness to sGC heme-independent activator BAY 58-2667 over controls. Furthermore, acute injection of BAY 58-2667 in angiotensin II-treated SMC CYB5R3-KO mice showed greater BP reduction compared with controls. Together, these data provide the first in vivo evidence to our knowledge that SMC CYB5R3 is an sGC heme reductase in resistance arteries and provides resilience against systemic hypertension development.

Topics: Angiotensin II; Animals; Benzoates; Blood Pressure; Cytochrome-B(5) Reductase; Genotype; Heme; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Nitric Oxide; Oxidation-Reduction; Soluble Guanylyl Cyclase; Transcriptome; Vasodilation

Oxidative stress, a central mediator of cardiovascular disease, results in loss of the prosthetic haem group of soluble guanylate cyclase (sGC), preventing its activation by nitric oxide (NO). Here we introduce Apo-sGC mice expressing haem-free sGC. Apo-sGC mice are viable and develop hypertension. The haemodynamic effects of NO are abolished, but those of the sGC activator cinaciguat are enhanced in apo-sGC mice, suggesting that the effects of NO on smooth muscle relaxation, blood pressure regulation and inhibition of platelet aggregation require sGC activation by NO. Tumour necrosis factor (TNF)-induced hypotension and mortality are preserved in apo-sGC mice, indicating that pathways other than sGC signalling mediate the cardiovascular collapse in shock. Apo-sGC mice allow for differentiation between sGC-dependent and -independent NO effects and between haem-dependent and -independent sGC effects. Apo-sGC mice represent a unique experimental platform to study the in vivo consequences of sGC oxidation and the therapeutic potential of sGC activators.

Topics: Animals; Benzoates; Blood Pressure; Cardiovascular System; Gene Knock-In Techniques; Guanylate Cyclase; Heme; Hypertension; Hypotension; Mice; Mice, Transgenic; Muscle, Smooth, Vascular; Nitric Oxide; Oxidative Stress; Platelet Aggregation; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Tumor Necrosis Factor-alpha