Selective inhibitor of phosphodiesterase type PDE

Selective inhibitor of phosphodiesterase type 5 (PDE5I) is commonly used for ED treatment. PDE5I exhibits its vasodilatory effect by inhibiting the degradation of cyclic guanosine monophosphate (cGMP), which relaxes the smooth muscle and allows increased blood flow for penile tumescence. Udenafil (Dong-A, Seoul, Korea) is a newly introduced PDE5I and active researches are performed to confer its efficacy and safety. Previous studies have proven that the increased cGMP level, because of active PDE5I, induces angiogenesis by forming capillary-like tubes in the corpus cavernosum and increasing the synthesis of vascular endothelial growth factor (VEGF)., The efficacy of udenafil was proven by Lee et al, which showed that the chronic administration promoted improved erectile function in a rat model of BCNI. Udenafil was effective in ameliorating fibrosis and apoptosis induced by cavernous nerve crush injury. Moreover, udenafil improved penile reaction in diabetic and spinal cord-injured animals and in hypertensive patients without increasing the frequency or severity of adverse events., In most cases, udenafil did not induce myalgias or abnormalities in color vision, which are profound side effects of tadalafil and sildenafil, other widely used PDE5Is.,
Introduction Adipose tissues ever an important function in regulating insulin action and may be a potential pharmacological target for the treatment of metabolic diseases, such as type 2 diabetes, obesity, and cardiovascular diseases. Insulin resistance is believed considered to be the most important predisposing factor, although the degree of resistance varies in different tissues [1]. Obesity-induced insulin resistance is considered to be a direct cause of fat accumulation in the liver and muscles, in particular, intracellular fat accumulation as a more important factor [2]. Increased fat accumulation is thought to be due to decreasing intracellular fatty Chlorpromazine HCl oxidation (FAO). Furthermore, it has been reported that a reduction in FAO can inhibit the activity of glucose metabolic enzymes and induce changes in intracellular signal transduction substances, resulting in insulin resistance. FAO occurs mostly in the mitochondria. Since the 1990s, several studies have suggested that mitochondrial dysfunction plays an important role in insulin resistance [3], [4], [5], [6]. In one human study, approximately 40% reduction in the activity of the mitochondrial oxidative phosphorylation (OxPhos) system was observed in individuals with insulin resistance [5]. Mitochondria are the organelles that produce most of the adenosine triphosphate (ATP) in cells by coupling the tricarboxylic acid cycle (TCA) cycle with OxPhos [7]. As almost all cellular functions are maintained by the energy obtained from ATP, mitochondria play a central role in cellular processes and metabolism. Mitochondria dysfunction can result from a decrease in the content and activity of oxidative proteins, such as those in the complexes comprising the electron transport chain (ETC). According to some reports, cyclic guanosine monophosphate (cGMP) signaling was associated with the induction of mitochondrial biogenesis [8], [9]. Phosphodiesterase type 5 (PDE5) inhibitors are indicated for the treatment of erectile dysfunction (ED), and have also demonstrated efficacy in the treatment of pulmonary arterial hypertension (PAH) [10], [11]. The currently approved PDE5 inhibitors include sildenafil (Viagra®), tadalafil (Cialis®), vardenafil (Levitra®) and avanafil (Stendra®), udenafil (Zydena®), mirodenafil (Mvix®) and avanafil (Zepeed®). The mechanism of PDE5 inhibitors act by selectively blocking the cGMP hydrolyzing enzyme, ultimately increasing intracellular cGMP concentration and activating cGMP-dependent kinase in various types of tissues and cells. Several small clinical trials have reported that chronic PDE5 inhibition improved cardiac performance and hypertrophy, measures associated with cardiac failure [12], [13]. Some studies have proposed that PDE5 inhibitors could improve insulin sensitivity; however, the mechanism has not been clearly elucidated [14]. Using mice models, chronic treatment with sildenafil was found to increase arterial cGMP levels and improve insulin sensitivity [15]. Interestingly, PDE5 blockade stimulates insulin-mediated glucose uptake in 3T3-L1 preadipocytes [16]. However, the mechanism underlying the insulin sensitizing effect of PDE5 inhibitors remains largely unknown.