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PDE5i enhances the effectiveness of NO.
Beyond ED: Emerging indications of sildenafil
Sildenafil Beyond Erectile Dysfunction and Pulmonary Arterial Hypertension: Thinking About New Indications Moein Ala, Razieh Mohammad Jafari, Ahmad Reza Dehpour ABSTRACT Sildenafil, approved two decades ago, is the inhibitor of Phosphodiesterase 5 (PDE5). First of all, it was designated...
It acts through inhibition of PDE5. PDE5 is responsible for catabolizing cGMP (cyclic GMP) and converting it into GMP. cGMP itself is part of the NO signaling pathway and activates cGMP-dependent protein kinase (PKG). PKG phosphorylates other proteins and participates in muscle relaxation [3]. One of these proteins is a charybdotoxin-sensitive K+ channel. Activation of this type of k+ channel is critical for hyperpolarization and vasorelaxation of smooth muscle cells [4]. Indeed, sildenafil collaborates with NO to preserve the high level of intracellular cGMP. Sildenafil does not inhibit generally guanylate cyclase but only the soluble guanylate cyclase. NO activates soluble guanylate cyclase and this enzyme produces cGMP to induce the remaining signaling pathway of vasodilation. The NO/cGMP signaling pathway is not limited to vasorelaxation, and scientists have found that sildenafil is involved in regulating platelet function, and synaptic transmission [5, 6].
Pharmacology and perspectives in erectile dysfunction in man
Abstract Penile erection is a perfect example of microcirculation modulated by psychological factors and hormonal status. It is the result of a complex neurovascular process that involves the integrative synchronized action of vascular endothelium; smooth muscle; and psychological, neuronal...
2.2.1.1 Nitric Oxide
NO has a key role in the relaxation of HCC smooth muscle and vasculature, it is a well-consolidated concept (Burnett et al., 1993; Toda et al., 2005). NO is synthesized in the nerve terminals and in the endothelium by the action of the tissue-specific enzyme NOS, which catalyzes the production of NO and citrulline from oxygen and L-arginine. NO passively diffuses into cavernous smooth muscle cells, where it binds and activates the soluble guanylate cyclase (sGC), which catalyzes the breakdown of guanosine triphosphate into cGMP. In parallel, NANC, as reported above, plays an important role in erectile function, as they are involved in the relaxation of corpus cavernosum. Studies involving pharmacological modulation have indicated that NANC neurotransmission in the HCC muscle is nitrergic, i.e., involves NO as the major mediator (Kimura et al., 1993; Adaikan & Ng., 2000).
THE SCIENCE AND PRACTICE OF ERECTION PHYSIOLOGY: STORY OF A REVOLUTIONARY GASEOUS MOLECULE
THE SCIENCE AND PRACTICE OF ERECTION PHYSIOLOGY: STORY OF A REVOLUTIONARY GASEOUS MOLECULE Abstract The field of sexual medicine, in reference to the science of the sexual response and the clinical management of sexual dysfunctions, has evolved remarkably in the last 25 years. Erection...
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Fig. 1. Schematic diagram of the nitric oxide signaling pathway in the penis for mediating the erection response. The diagram shows the molecular basis for erection physiology that may transition between flaccidity (erectile tissue contraction) and erection (erectile tissue relaxation) depending upon the extent of sexual stimulation. Nitric oxide is generated constitutively from L-arginine by catalysis of neuronal nitric oxide synthase (NOS) and endothelial NOS localized to neurons and endothelial cells, respectively. After its release from generator cells in the penis, nitric oxide diffuses locally to corporal smooth muscle cells whereby it activates guanylate cyclase to convert 5′-guanosine triphosphate (GTP) to 3′, 5′-cyclic guanosine monophosphate (cGMP). This cyclic nucleotide then exerts downstream effects resulting in penile erection. Phosphodiesterase type 5 (PDE5) degrades cGMP to its inactive form, 5′-GMP, which is subsequently reformed into GTP. A PDE5 inhibitor blocks PDE5 activity, thereby potentiating effector actions of cGMP.
Pharmacodynamics of the agents used for the treatment of erectile dysfunction
ABSTRACT Introduction: Erectile dysfunction (ED) is one of the most common complaints encountered by the practicing urologist, particularly when treating older men. The last 20 years have represented a pivotal time in the treatment of ED. Areas covered: Several pharmacologic agents have been...
2.2. Mechanism
Penile erection is a neurovascular phenomenon that requires dilation of the penile vasculature, relaxation of cavernosal smooth muscle, increased intracavernosal blood flow, and normal veno-occlusive function [9]. It is primarily mediated by the neurotransmitter nitric oxide (NO) through the cyclic guanosine monophosphate (cGMP) pathway [9]. (Figure 1)
Sexual stimulation leads to the synthesis and release of NO from nerve endings and vascular endothelial cells in the penis. NO rapidly diffuses in the corpora cavernosa and stimulates guanylyl cyclase, an enzyme that catalyzes the conversion of guanosine triphosphate to cGMP. Elevated cGMP stimulates the relaxation of penile smooth muscle and a several-fold increase in arterial inflow augmented by a decrease in the venous outflow. This process is terminated by the degradation of cGMP by PDE5, an enzyme that breaks the phosphodiester bond in biological molecules, returning the penis to the flaccid state [10], (Figure 1) Notably, phosphodiesterase (PDE) is present throughout the body (Table 1) and is categorized into at least 11 different isoenzymes and 53 isoforms, with PDE5 being the most important for the penile erection process [11,12]. PDE5, which was identified by Francis et al. in 1980, contains two identical subunits and each has catalytic and regulatory domains [13].
PDE5 inhibitors, which are similar to cGMP in structure, can bind to PDE5 competitively and inhibit the degradation of cGMP. Therefore, cGMP levels remain high and facilitate the maintenance of a penile erection. It is important to recognize that PDE5 inhibitors are not erectogenic drugs. They require the release of NO from penile nerve endings and vascular endothelium under the influence of sexual stimulation in order to produce an erection [14].
Tadalafil: 15 years' journey in male erectile dysfunction and beyond
Abstract Tadalafil, Cialis, Eli Lilly & Co./ICOS, (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12ahexahydropyrazino[10,20:1,6] pyrido[3,4-b]indole-1,4-dione, was first discovered in 2003. It was reported to have high diastereospecificity for phosphodiesterase 5 (PDE5) inhibitions...
4.1 | Tadalafil in MED
More than 100 million men worldwide suffer from ED whereby they fail to reach and maintain an adequate erection (Ayta, McKinlay, & Krane, 1999). Sexual stimuli induce the release of NO in the corpus cavernosum, thus increasing the production of cGMP. cGMP is hydrolyzed via PDE5, an action that is terminated by Tadalafil (2). Tadalafil allows an increase in the concentration of cGMP to allow relaxation of erectile tissues and dilatation of the corpora cavernosa arteries in patients with MED. The higher blood flow causes the engorgement of the corpora cavernosa. This engorgement diminishes penile venous outflow and causes higher penile blood pressure, resulting in a physiological erection (Figure 3) (Lincoln & Cornwell, 1991).
Figure 3 Cellular mechanisms involved in penile erection.
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