cyclic-gmp and mirabegron

Overstimulation of the orthosympathetic system leads to cardiovascular cell and tissue damage through prolonged activation of β-1-2 adrenergic receptors (BARs). The more recent identification of the third isotype of BAR (B3AR) in cardiac myocytes and endothelial cells with a distinctive coupling and effect on cardiac function and remodelling introduced a new facet to this paradigm. In particular, B3AR is up-regulated in cardiac disease and less prone to homologous desensitization, which may reinforce its influence on the diseased myocardium. Mice with transgenic cardiac-specific expression of the human B3AR are protected from cardiac hypertrophy and fibrosis in response to neurohormonal stimulation. B3AR has also been implicated in cardiac protection after ischaemia-reperfusion and the benefits of exercise on the heart. Many of these salvage mechanisms are mediated by B3AR coupling to nitric oxide synthase (eNOS and nNOS) and downstream cGMP/protein kinase G signalling. Notably, B3AR exerts antioxidant protective effects on these and other signalling elements, which may subserve its protective properties in the setting of chronic heart failure. Additional vasorelaxing properties and paracrine NO-mediated signalling by B3AR in endothelium, together with systemic metabolic effects on beige/brown fat complete the pleiotropic protective properties of this new therapeutic target.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Endothelial Cells; Heart Diseases; Humans; Myocardial Contraction; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Receptors, Adrenergic, beta-3; Signal Transduction; Thiazoles; Ventricular Remodeling

Mirabegron is the first β3-adrenoceptor agonist approved on the market and may offer beneficial pharmacological action in patients with overactive bladder and erectile dysfunction. Here, we further investigate the mechanisms by which mirabegron induces rat corpus cavernosum (CC) relaxation. Adult male Wistar rats were used. The CC were isolated for in vitro functional assays and β-adrenoceptors subtypes mRNA expression evaluation. Animals were treated orally with mirabegron (30 mg/kg, 3 h), tadalafil (10 mg/kg, 3 h) or both for intracavernous pressure (ICP). Intracellular levels of cAMP and cGMP were also determined. The β

Topics: Acetanilides; Animals; Arterial Pressure; Cyclic AMP; Cyclic GMP; Gene Expression Regulation; Intracellular Space; Male; Muscle Contraction; Muscle Relaxation; Penile Erection; Penis; Rats; Rats, Wistar; Receptors, Adrenergic, beta; RNA, Messenger; Thiazoles