Physiopathological alterations of urogenital tract in metabolic syndrome: experimental study

Abstract

Metabolic syndrome is one of the leading public health problems in the present century. Metabolic syndrome is a collection of three or more clinical abnormalities, including obesity, arterial hypertension, dyslipidemia, glucose intolerance and insulin resistance and, therefore, can vary significantly in its profile. Recent clinical studies show a strong correlation between metabolic syndrome and the so-called lower urinary tract symptoms (LUTS), a condition where overactive bladder resulting in urinary incontinence presents a key role. Metabolic syndrome also progress to erectile dysfunction, possibly as a consequence of cardiovascular alterations associated with endothelial dysfunction and enhancement of oxidative stress. Epidemiogical studies have shown that LUTS in turn can potentially lead to male impotence. Both LUTS and erectile dysfunction are highy prevalent in men. Prevalence of sexual dysfunction is usually higher in men with LUTS, and diagnostic of LUTS normally precedes that of sexual dysfunction. Therefore, studies that attempt to explore the understanding of urogenital tract disorders (LUTS and male impotence) and their relationships with metabolic syndrome are of great interest because help to elucidate the underlying physiopathological mechanisms involved in such disorders, as well as to improve disease treatment and prevention. The present project aims to understand the morphofunctional alterations of the urogenital tract (overactive bladder and erectile dysfunction) caused by metalolic syndrome using an experimental model. To achieve this, C57/BL6 male mice fed with a hyperlipidemic diet for 10 weeks will be used. Preliminary data of our group show that mice fed with hyperlipidemic diet for 10 weeks develop aspects of metabolic syndrome such as increase of body weight, epididymal fat mass, serum levels of total cholesterol (and LDL), as well as impaired glucose tolerance. These animals also present overactive bladder and sexual dysfunction, as measured by in vitro and in vivo assays. Generally, we aim to carry out functional studies in control and hyperlipidemic mice examining the responses of smooth muscle detrusor and erectile tissue both in vitro (organ bath techniques) and in vivo (cystometry and measurement of intracavernous pressure in anaesthesized animals as an index of penile erection). In detrusor (and urethral smooth muscle), the contractile responses to electrical-field stimulation (EFS) and to muscarinic receptor activation, as well as the relaxant responses to b-adrenoceptor stimulation we be performed. The signaling pathways involved in the functional alterations will be explored by using pharmacological antagonists and/or inhibitors such as antimuscarinic agents, P2X channels blockers, Rho-kinase inhibitors, L-type Ca2+ channels blockers. Molecular biology and radioligand techniques for muscarinic M2 and M3 receptors, IP3, L-type Ca2+ channels and P2X receptors will be employed, if appropriate. In the erectile tissue, the main alterations involved in the release of NO will be investigated. Therefore, evaluation of the expressions / activity of neuronal and endothelial NO synthase (eNOS and nNOS), as well as of pro- and antioxidant enzymes (NADPH oxidase components and superoxide dismutase) is planned to be carried out. This project also aims to evaluate the effects of phosphodiesterase-5 (PDE5) inhibitors and NO-independent soluble guanylyl cyclase activators (such as BAY 41-2272) to prevent / restore the urogenital alterations in the hyperlipidemic-treated mice. (AU)