ExcelMale
Menu
Home
What's new
Latest activity
Forums
New posts
Search forums
What's new
New posts
Latest activity
Videos
Lab Tests
Doctor Finder
Buy Books
About Us
Men’s Health Coaching
Log in
Register
What's new
Search
Search
Search titles only
By:
New posts
Search forums
Menu
Log in
Register
Navigation
Install the app
Install
More options
Contact us
Close Menu
Forums
Testosterone Replacement, Low T, HCG, & Beyond
When Testosterone Is Not Enough
does PDE5 inhibitors downregulate NO production?
JavaScript is disabled. For a better experience, please enable JavaScript in your browser before proceeding.
You are using an out of date browser. It may not display this or other websites correctly.
You should upgrade or use an
alternative browser
.
Reply to thread
Message
<blockquote data-quote="madman" data-source="post: 191936" data-attributes="member: 13851"><p>PDE5i enhances the effectiveness of NO.</p><p></p><p></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/beyond-ed-emerging-indications-of-sildenafil.22317/[/URL]</p><p></p><p><em><span style="color: rgb(184, 49, 47)">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]. <strong><u>Indeed, sildenafil collaborates with NO to preserve the high level of intracellular cGMP</u>.</strong> <strong>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. </strong>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].</span></em> </p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/pharmacology-and-perspectives-in-erectile-dysfunction-in-man.20458/[/URL]</p><p></p><p><strong>2.2.1.1 Nitric Oxide </strong></p><p></p><p><span style="color: rgb(184, 49, 47)"><strong>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. <u>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</u>. </strong>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). </span></p><p></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/the-science-and-practice-of-erection-physiology-story-of-a-revolutionary-gaseous-molecule.19597/[/URL]</p><p></p><p>[ATTACH=full]11974[/ATTACH]</p><p><strong><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735973/figure/F1/" target="_blank">Fig. 1.</a> <span style="color: rgb(44, 130, 201)">Schematic diagram of the nitric oxide signaling pathway in the penis for mediating the erection response.</span></strong> <strong>The diagram shows the molecular basis for erection physiology that may transition between flaccidity <span style="color: rgb(184, 49, 47)">(erectile tissue contraction)</span> and erection <span style="color: rgb(184, 49, 47)">(erectile tissue relaxation)</span> depending upon the extent of sexual stimulation.</strong> <strong>Nitric oxide is generated constitutively from L-arginine by catalysis of neuronal nitric oxide synthase<span style="color: rgb(184, 49, 47)"> (NOS) </span>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 <span style="color: rgb(184, 49, 47)">(GTP)</span> to 3′, 5′-cyclic guanosine monophosphate <span style="color: rgb(184, 49, 47)">(cGMP)</span>. This cyclic nucleotide then exerts downstream effects resulting in penile erection. <span style="color: rgb(184, 49, 47)">Phosphodiesterase type 5 (PDE5) degrades cGMP to its inactive form, 5′-GMP, which is subsequently reformed into GTP. <u>A PDE5 inhibitor blocks PDE5 activity, thereby potentiating effector actions of cGMP</u>.</span></strong> </p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/pharmacodynamics-of-the-agents-used-for-the-treatment-of-erectile-dysfunction.17254/[/URL]</p><p></p><p><strong>2.2. Mechanism </strong></p><p></p><p><span style="color: rgb(184, 49, 47)"><strong>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]. <u>It is primarily mediated by the neurotransmitter nitric oxide (NO) through the cyclic guanosine monophosphate (cGMP) pathway [9]</u>. (Figure 1) </strong></span></p><p></p><p><strong><span style="color: rgb(184, 49, 47)">Sexual stimulation leads to the synthesis and release of NO from nerve endings and vascular endothelial cells in the penis. <u>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)</u> 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]. </span></strong></p><p></p><p><span style="color: rgb(184, 49, 47)"><strong><u>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</u>.</strong></span><span style="color: rgb(26, 188, 156)"> <strong><u>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]</u>. </strong></span></p><p></p><p></p><p><span style="color: rgb(184, 49, 47)"></span></p><p><span style="color: rgb(184, 49, 47)"></span></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/tadalafil-15-years-journey-in-male-erectile-dysfunction-and-beyond.17167/[/URL]</p><p></p><p><strong>4.1 | Tadalafil in MED </strong></p><p><strong></strong></p><p><strong><span style="color: rgb(184, 49, 47)">More than 100 million men worldwide suffer from ED whereby they fail to reach and maintain an adequate erection (Ayta, McKinlay, & Krane, 1999). <u>Sexual stimuli induce the release of NO in the corpus cavernosum, thus increasing the production of cGMP</u>. </span><span style="color: rgb(26, 188, 156)"><u>cGMP is hydrolyzed via PDE5, an action that is terminated by Tadalafil (2)</u>. <u>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</u>. 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).</span></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Figure 3 <span style="color: rgb(184, 49, 47)">Cellular mechanisms involved in penile erection.</span></strong></p><p>[ATTACH=full]11975[/ATTACH]</p></blockquote><p></p>
[QUOTE="madman, post: 191936, member: 13851"] PDE5i enhances the effectiveness of NO. [URL unfurl="true"]https://www.excelmale.com/forum/threads/beyond-ed-emerging-indications-of-sildenafil.22317/[/URL] [I][COLOR=rgb(184, 49, 47)]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]. [B][U]Indeed, sildenafil collaborates with NO to preserve the high level of intracellular cGMP[/U].[/B] [B]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. [/B]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].[/COLOR][/I][COLOR=rgb(184, 49, 47)] [/COLOR] [URL unfurl="true"]https://www.excelmale.com/forum/threads/pharmacology-and-perspectives-in-erectile-dysfunction-in-man.20458/[/URL] [B]2.2.1.1 Nitric Oxide [/B] [COLOR=rgb(184, 49, 47)][B]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. [U]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[/U]. [/B]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). [/COLOR] [URL unfurl="true"]https://www.excelmale.com/forum/threads/the-science-and-practice-of-erection-physiology-story-of-a-revolutionary-gaseous-molecule.19597/[/URL] [ATTACH type="full"]11974[/ATTACH] [B][URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735973/figure/F1/']Fig. 1.[/URL] [COLOR=rgb(44, 130, 201)]Schematic diagram of the nitric oxide signaling pathway in the penis for mediating the erection response.[/COLOR][/B][COLOR=rgb(44, 130, 201)] [/COLOR][B]The diagram shows the molecular basis for erection physiology that may transition between flaccidity [COLOR=rgb(184, 49, 47)](erectile tissue contraction)[/COLOR] and erection [COLOR=rgb(184, 49, 47)](erectile tissue relaxation)[/COLOR] depending upon the extent of sexual stimulation.[/B] [B]Nitric oxide is generated constitutively from L-arginine by catalysis of neuronal nitric oxide synthase[COLOR=rgb(184, 49, 47)] (NOS) [/COLOR]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 [COLOR=rgb(184, 49, 47)](GTP)[/COLOR] to 3′, 5′-cyclic guanosine monophosphate [COLOR=rgb(184, 49, 47)](cGMP)[/COLOR]. This cyclic nucleotide then exerts downstream effects resulting in penile erection. [COLOR=rgb(184, 49, 47)]Phosphodiesterase type 5 (PDE5) degrades cGMP to its inactive form, 5′-GMP, which is subsequently reformed into GTP. [U]A PDE5 inhibitor blocks PDE5 activity, thereby potentiating effector actions of cGMP[/U].[/COLOR][/B][COLOR=rgb(184, 49, 47)] [/COLOR] [URL unfurl="true"]https://www.excelmale.com/forum/threads/pharmacodynamics-of-the-agents-used-for-the-treatment-of-erectile-dysfunction.17254/[/URL] [B]2.2. Mechanism [/B] [COLOR=rgb(184, 49, 47)][B]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]. [U]It is primarily mediated by the neurotransmitter nitric oxide (NO) through the cyclic guanosine monophosphate (cGMP) pathway [9][/U]. (Figure 1) [/B][/COLOR] [B][COLOR=rgb(184, 49, 47)]Sexual stimulation leads to the synthesis and release of NO from nerve endings and vascular endothelial cells in the penis. [U]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)[/U] 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]. [/COLOR][/B] [COLOR=rgb(184, 49, 47)][B][U]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[/U].[/B][/COLOR][COLOR=rgb(26, 188, 156)] [B][U]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][/U]. [/B][/COLOR] [COLOR=rgb(184, 49, 47)] [/COLOR] [URL unfurl="true"]https://www.excelmale.com/forum/threads/tadalafil-15-years-journey-in-male-erectile-dysfunction-and-beyond.17167/[/URL] [B]4.1 | Tadalafil in MED [COLOR=rgb(184, 49, 47)]More than 100 million men worldwide suffer from ED whereby they fail to reach and maintain an adequate erection (Ayta, McKinlay, & Krane, 1999). [U]Sexual stimuli induce the release of NO in the corpus cavernosum, thus increasing the production of cGMP[/U]. [/COLOR][COLOR=rgb(26, 188, 156)][U]cGMP is hydrolyzed via PDE5, an action that is terminated by Tadalafil (2)[/U]. [U]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[/U]. 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).[/COLOR] Figure 3 [COLOR=rgb(184, 49, 47)]Cellular mechanisms involved in penile erection.[/COLOR][/B] [ATTACH type="full"]11975[/ATTACH] [/QUOTE]
Insert quotes…
Verification
Post reply
Share this page
Facebook
Twitter
Reddit
Pinterest
Tumblr
WhatsApp
Email
Share
Link
Sponsors
Forums
Testosterone Replacement, Low T, HCG, & Beyond
When Testosterone Is Not Enough
does PDE5 inhibitors downregulate NO production?
This site uses cookies to help personalise content, tailor your experience and to keep you logged in if you register.
By continuing to use this site, you are consenting to our use of cookies.
Accept
Learn more…
Top