bay-58-2667 and Obesity

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

Intracellular levels of cyclic nucleotides can also be controlled by the action of multidrug resistance protein types 4 (MRP4) and 5 (MRP5). To date, no studies evaluated the role of their inhibition in an animal model of erectile dysfunction (ED).. To evaluate the effect of a 2-week treatment with MK571, an inhibitor of the efflux of cyclic nucleotides in the ED of obese mice.. Mice were divided in three groups: (i) lean, (ii) obese, and (iii) obese + MK571. The corpus cavernosum (CC) were isolated, and concentration-response curves to acetylcholine (ACh), sodium nitroprusside (SNP), and tadalafil in addition to electrical field stimulation (EFS) were carried out in phenylephrine pre-contracted tissues. Expression of ABCC4 and ABCC5, intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), the protein levels for pVASP. The MRPs inhibition by MK571 favored the accumulation of cGMP in the smooth muscle cells, thus improving the smooth muscle relaxation and the erectile function in obese mice.

Topics: Acetylcholine; Animals; ATP Binding Cassette Transporter, Subfamily B; Cyclic GMP; Erectile Dysfunction; Humans; Male; Mice; Mice, Obese; Nitroprusside; Obesity; Tadalafil