Kenia Pedrosa Nunes

Beneficial effect of the Soluble Guanylyl Cyclase stimulator BAY 41-2272 on impaired penile erection in db/db-/- Type II Diabetic and obese Mice

Type 2 diabetes mellitus (DM2) and obesity are major risk factors for erectile dysfunction (ED). In diabetes, increased oxidative stress leads to decreased nitric oxide (NO) bioavailability, and diabetic patients appear to be less responsive to conventional therapy with phosphodiesterase type 5 inhibitors. We investigated whether the soluble guanylyl cyclase stimulator BAY 41-2272 (5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4ylamine) is effective in improving impaired corpus cavernosum (CC) relaxation in obese DM2 mice by reducing oxidative stress. Adult db/db−/− mice or their lean db/+ littermates were used to assess vascular function, cGMP levels, antioxidant status, NADPH oxidase expression, and superoxide formation in the absence or presence of BAY 41-2272. Results showed that BAY 41-2272 (10−8 to 10−5 M) potently relaxed CC from db/+ or db/db−/− mice in a similar manner. BAY 41-2272 significantly enhanced both endothelium-dependent and nitrergic relaxation induced by electrical field stimulation (EFS), and improved the impaired relaxation to acetylcholine and EFS in the diabetic animals in a concentration-dependent manner (10−8 to 10−7 M). BAY 41-2272 increased cGMP levels and potentiated relaxation responses to exogenous NO in CC. Total antioxidant status was reduced in plasma and urine whereas expression of vascular NADPH oxidase subunits (gp91phox, p22phox, and p47phox) was increased in the CC of db/db−/− mice, suggesting a state of oxidative stress. These effects were prevented by BAY 41-2272 in a concentration-dependent manner. These results suggest that BAY 41-2272 improves CC relaxation in db/db−/− mice by increasing cGMP and augmenting antioxidant status, making this drug is a potential novel candidate to treat ED.

Current Perspectives on Pharmacotherapy Treatments for Erectile Dysfunction

Erectile dysfunction (ED) is the most common sexual problem in men [1]. ED is defined as a difficulty in initiating or maintaining penile erection adequate for sexual activity. ED has a weighty effect on intimate relationships, quality of life, and overall self-esteem for men. In addition, ED may also be an early indication of undetected cardiovascular disease [2]. One of the largest current studies of ED, the Massachusetts Male Aging Study, established that the prevalence of ED increases with age as it affects up to half of the male population between 40 and 70 years old [3]. Thus, as the world’s older population increases, it is estimated that the prevalence of ED will double from 152 million men in 1995 to 322 million men in 2025, indicating a dire need to reevaluate current ED therapeutic strategies [4]. In most documented cases, ED may also present with comorbidities of hypertension, diabetes mellitus, obesity, and atherosclerosis [3].

Gene and Stem Cell Therapy in Erectile Dysfunction

Erectile dysfunction (ED) is a complex, multifactorial issue commonly affecting men of all ages. ED is currently defined as “the inability to achieve and/or maintain penile erection sufficient to permit satisfactory sexual intercourse”, and has been associated with such risk factors as hypertension, diabetes, alcoholism, smoking, and pelvic surgery [1]. This condition has seriously impacted the men’s quality of life. Even though nowadays there are a large number of options to treat ED, a considerable number of patients do not answer adequately the conventional therapies available. Penile erection is achieved through a neurovascular response exhibiting an increase in arterial inflow, relaxation of corporal smooth muscle, and restriction of the venous outflow. Relatively recent pharmacological advances, namely oral phosphodiesterase-5 (PDE5) inhibitors, have become the first line of treatment in ED. PDE5 inhibitors allow the patient to achieve a penile erection via the effects on the nitric oxide (NO) signaling pathway, which is the principal mediator of corporal smooth muscle relaxation. The inhibition of the degradative actions of PDE5 on 3’,5’-cyclic guanosine monophosphate (cGMP), the second messenger molecule of NO signaling, lead to an increased bioavailability of NO in the corporal smooth muscle thus promoting vasodilation and penile erection. However, despite the widespread efficacy of these medications, there are still men for which oral PDE5 inhibitors are ineffective. ED in men with diabetes, for example, is typically more severe, exhibiting a less effective response to PDE5 inhibitors when compared to non-diabetic patients. The vascular injuries that accompanies diabetes is often too damaging to endothelial physiology to allow adequate penile erections [4] and thus complicates use of the oral medications as treatment for ED. Due to the vast array of potential causes of ED ranging from neurogenic and vasculogenic to hormonal issues, there exists a continuing need to address these deficiencies in patient management of ED and pursue new treatments. Two avenues showing a great deal of promise in ED treatment are gene therapy and stem cell therapy, both of which could possibly provide methods to prevent or even cure ED. This chapter will focus on recent studies in both gene and stem cell therapies in ED research, with the objective to establish that continued scientific exploration into these fields will yield clinically applicable approaches to combat this condition.

The Innate Immune System via Toll-Like Receptors (TLRs) in Type 1 Diabetes - Mechanistic Insights

Type 1 diabetes (T1D) is a form of diabetes mellitus resulting from the lack of insu‐ lin secretion by the pancreatic beta cells and which accounts for approximately 5% of the total number of patients with diabetes worldwide. T1D is one of the most common endocrine disorders of children, and its incidence is steadily increasing. T1D is largely considered an autoimmune disorder resulting from the specific de‐ struction of the pancreatic beta-cells that produce insulin. However, T1D patho‐ physiology is still not completely understood, and although insulin and other therapies ameliorate the manifestations of the disease, no cure is currently available. Traditionally, T1D has been thought of as a condition of cellular adaptive immuni‐ ty, but evidence exists that components of the innate immune system, such as Tolllike receptors (TLRs), play a critical role in T1D development. TLRs have a central role in sensing microbial infections as well as endogenous alarm signals and trigger the release of inflammatory cytokines. The involvement of these receptors in the pathophysiology of several chronic diseases has become a major research interest, and in the last two decades, many studies have suggested the involvement of the innate immune system in the mechanism triggering T1D. Furthermore, microvascu‐ lar complications in diabetic patients result in considerable morbidity, particularly diabetic nephropathy, retinopathy, and atherosclerosis. A hallmark of diabetic vas‐ cular pathology is inflammation and endothelial dysfunction. Recent literature sug‐ gests that TLR signaling is involved in vascular inflammation and endothelial dysfunction and that TLR activation may play a crucial role in diabetic microangi‐ opathy. However, the mechanisms by which TLRs and their ligands contribute to T1D are not yet clear, and further investigation is needed. The goal of the present chapter is to address the contribution of TLRs to the mechanisms leading to the de‐ velopment and progression of T1D and to review current possibilities of targeting TLRs to forestall diabetic complications.

The Role Erectile Dysfunction Plays in Cardiovascular Diseases

Erectile dysfunction (ED) is defined as the persistent inability to maintain or achieve a penile erection sufficient for satisfactory sexual performance (1-2). ED is a very common condition in middle-aged men (3). According to the National Institute of Health (NIH) this physiological disorder affects 30 million men in the United States (US) (2). The outlook for 2025 is scary because this number is expected to grow to approximately 322 million (4). Although ED is directly associated with aging (5), its etiology is considered multifactorial. Both conditions, ED and aging, share a variety of risk factors such as atherosclerosis, sedentary lifestyle, abnormal lipids, diabetes, smoking, metabolic syndrome and hypertension (2, 6-7). In addition, ED is considered an important marker of cardiovascular disease (CVD) (8). Studies over the last decade suggest vascular changes as a common factor between ED and CVD (1, 7, 9). Also, the most important vascular alteration mentioned in these pathologies cited above is endothelial dysfunction. According to several authors, endothelial and smooth muscle dysfunction are crucial factors involved in systemic and peripheral vascular diseases, especially ED (10). In this chapter we will discuss the association between the main CVD and ED.