Evaluation of the phosphodiesterase inhibitor type-9 (PDE9) bay 73-6691 on the reactivity of cavernous smooth musculature in heart failure rats

Abstract

Erectile dysfunction (ED) is characterized as the inability to obtain or maintain a penile erection suitable for satisfactory sexual activity. Studies have demonstrated a strong association of heart failure (HF) with the development of ED. Epidemiological studies have shown that 85% of the patients with HF reported some episode of ED. Approximately 75% of these patients reported impaired libido and 30% had complete absence of sexual activity. ED and HF have common risk factors, such as hypertension, dyslipidemia and diabetes, which are associated with dysfunction of the autonomic nervous system, alterations of important signaling pathways that control smooth muscle cavernosal tone, oxidative stress and reduction of the availability of oxide Nitric acid (NO). In this way, the integrity of the nitrergic nerves and the endothelium are important for erectile responses due to the release of NO from these sources and consequent increase of intracellular cGMP in the smooth muscle of the cavernous body. The levels of cGMP are controlled by their synthesis from the soluble guanylyl cyclase and by their degradation by phosphodiesterases (PDEs). Alterations in the NO-cGMP signaling pathway result in erectile dysfunction, which is currently treated by the oral administration of the PDE5 inhibitors sildenafil, vardenafil and tadalafil. However, in certain cases of endothelial dysfunction or neuropathies that affect erectile function, the use of PDE5 inhibitors has only moderate beneficial effects, since a complete satisfactory response is not obtained in all patients. Thus, in the present project we decided to investigate the role of the PDE9 isoform in the regulation of smooth muscle tone of the corpus cavernosum and in the erectile function of rats with heart failure. Such effects will be assessed using the selective PDE9 inhibitor BAY 73-6691 (1- (2-chlorophenyl) -6 - [(2R) -3,3,3-trifluoro-2-methylpropyl] -1,5-dihydro -4H-pyrazolo [3,4-d] pyrimidin-4-one), which will be assayed in the cavernous body of rats with HF, using isolated tissue technique which allows studying the relaxing and contractile effects of this preparation, as well as As in in vivo experiments, in which erectile responses are obtained in anesthetized animals through stimulation of the cavernous nerve. In addition, the effects of BAY 73-6691 on the intracellular levels of cyclic nucleotides will be evaluated in segments of cavernous musculature of rats with heart failure. Thus, BAY 73-6691 may be a promising therapeutic target in the treatment of erectile dysfunction in subjects with heart failure. (AU)