Morphofunctional and molecular study of erectile function and lower urinary tract in rats with chronic heart failure: evaluation of the NO-sGC-cGMP signaling pathway

Abstract

Chronic heart failure (CHF) affects 6.4 million people in Brazil and has become a challenge to public health policies. Studies have shown a strong association of CHF with the development of erectile dysfunction (ED) and lower urinary tract symptoms (LUTS). Epidemiological studies have shown that 58-85% of CHF patients have reported an episode of ED, approximately 75% of these patients have reported impaired libido and 30% have no sexual activity. In addition, studies in patients with CHF showed that 32-34% of men and 41-62% of women have reported LUTS. Despite the high rates of ED and LUTS in patients with CHF, there are no experimental or human studies to evaluate the mechanisms responsible for urogenital dysfunctions. Evidence shows that CHF, ED and LUTS share similar risk factors, such as diabetes mellitus and cardiovascular disease. These risk factors are associated with autonomic nervous system dysfunction and changes in important signaling pathways such as the nitric oxide-soluble guanylyl cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) pathway. Synthetic drugs that mimic the effect of NO are subdivided into two groups: drugs with NO-dependent effect, inhibiting cGMP degradation, such as sildenafil, and drugs acting independently from NO, directly increasing levels of cGMP BAY 41-2272. Sildenafil has been used to treat disorders associated with CHF, such as pulmonary hypertension and ED, but no studies have evaluated the effect of PDE5 inhibitors in other urogenital dysfunctions in these patients. Studies have shown that sildenafil and BAY 41-2272 promote relaxation of the corpus cavernosum (CC) and the detrusor smooth muscle. Chronic treatment with BAY 41-2272 also improved CC relaxation and restored urinary bladder function in NO-deficient rats. Therefore, sildenafil and BAY 41-2272 are agents with therapeutic potential in diseases where the NO-sGC-cGMP signaling pathway is affected. Thus, this project aims to investigate the alterations in the erectile function and lower urinary tract due to chronic heart failure (CHF), by exploring morphofunctional, biochemical and molecular alterations, as well as investigating the relaxing and contractile responses of the erectile tissue of the urinary bladder and the measurement of intracavernous pressure and cystometry (in vivo), and elucidating the contribution of chronic treatment with agents that act dependently and independently from NO (sildenafil and BAY 41-2272, respectively), restoring the function of the NO-sGC-cGMP signaling pathway. (AU)