All Top PDE-5 Inhibitors Explored and Resources

[Area 1255]

So there's a shortage of information on a lot of the lesser known ones as well so I have compiled some interesting information including on some more obscure PDE-5's such as Icariin and Xanthoparmelia.

Here is an article on the FULL pharmacodynamics/pharmacological profile of "Icariin" from horny goat weed.
Full Pharmacodynamics ; Mechanism of Icariin Explored

Summary

• Icariin is an AChE inhibitor (stops breakdown of acetylcholine)
• Icariin is a calcium channel blocker/modulator
• Icariin is inhibitory upon PDE-5 mRNA expression and Activity
• Icariin may sustain levels of monoamines in the Brain
• Icariin is a testosterone "mimetic"

Not much information on Xantho but I did a little more digging

(http://www.raysahelian.com/xanthoparmelia.html)
(http://www.mdidea.com/products/new/new03804.html)(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2104731/)
http://www.deepdyve.com/lp/elsevier/scabrosin-esters-and-derivatives-chemical-derivatization-studies-and-O0UzHCCdrw)
(http://pubs.rsc.org/En/content/articlelanding/2014/np/c3np70097f#!divAbstract )
and although there a couple anecdotal reports and studies from Asia - the main body of evidence suggests that Xantho's main effect comes from potent PDE-5 antagonism but is very selective and doesn't hit other PDE's.
It also seems to act as an Alpha-2-blocker (similar to Yohimbine)
Personally I like xantho better than Icariin short term but not long term.

More about ICARIIN now...

Icariin is a compound isolated from the plant "Epimedium" also known more commonly as "Horny Goat Weed" - it has been shown to have neuroprotective effects, anti-depressant effects and erectogenic effects. It may help treat Alzheimer's and other memory disorders and can effectively treat high blood pressure.

MECHANISM #1


PDE-5 Inhibition / cGMP Synthesis / nNOS Acitvator




OVERVIEW / SUMMARY


Icariin decreases the "expression" of PDE-5 enzymes over time, this means that there is a long-term decrease yielding permanent changes in genetic coding to this enzyme. As opposed to just temporarily blocking it, which it also does.


NOTE :: By this mechanism one could presume (though it has lower affinity than Say, Viagra) that it may give one more leverage over time as well as a permanent enhancing effect. Many people ask then, how long before Icariin supplements kick in or how long do they take to work?


ANSWER :: Based on the studies, it would seem plausible that minor effects would be felt in the first couple days (due to inhibition of PDE-5), but the peak effects would come after any where from 2-4 weeks of use(due to downregulation).

List of PDE-5 Inhibitors, Resources, Where to Get them and Information / Write-Ups as well as Uses

A couple other points are that there are conflicting reports about Tadalfil (Cialis) and that some reports are showing INCREASED aromatase activity whereas others are showing decreased estradiol.


Testosterone:estradiol ratio changes associated wi... [J Sex Med. 2006] - PubMed - NCBI

Quote:
J Sex Med. 2006 Jul;3(4):716-22.
Testosterone:estradiol ratio changes associated with long-term tadalafil administration: a pilot study.
Greco EA1, Pili M, Bruzziches R, Corona G, Spera G, Aversa A.
Author information
Abstract
INTRODUCTION:
It has been reported that lack of sexual activity due to erectile dysfunction (ED) may be associated with testosterone (T) decline.
AIM:
To investigate whether the known changes in sex hormones associated with resumption of sexual activity are sustained in the long term.
MAIN OUTCOME MEASURES:
Primary endpoints were variations from baseline of steroid hormones: total T, free T (f T), and estradiol (E). Secondary endpoints were variations of erectile function domain scores at International Index of Erectile Function-5 (IIEF-5).
METHODS:
In an open-label fashion, 20 patients (mean age 54.8 +/- 8.4 years) received tadalafil 10-20 mg on demand for 12 months. Exclusion criteria were those reported for phosphodiesterase inhibitors, including hypogonadism and hyperprolactinemia.
RESULTS:
Tadalafil assumption was safe and well tolerated (overall adverse effects in 15% of patients) and none discontinued medication. A significant decrease in E levels occurred at the end of the study (from 19.9 +/- 9.6 to 16.6 +/- 8.1 ng/dL, P = 0.042 vs. baseline), with parallel increase in the T:E ratio (26.3 +/- 15.3 to 32.6 +/- 17.7, P = 0.05), whereas no changes in T and f T serum levels were observed, respectively (411.4 +/- 131.4 to 434.2 +/- 177.1 ng/dL and 47.7 +/- 15.3 to 49.9 +/- 19.1 pmol/L, not significant). Interestingly, nonparametric subgroup analysis for related samples revealed that E decrease was detectable only in lean (N = 14) but not in obese (N = 6, body mass index > 27.5 kg/m2) subjects (17.8 +/- 10.1 vs. 13.5 +/- 6.8, P < 0.05). A net increase in IIEF-5 scores was observed at the endpoint (13.7 +/- 5.9 vs. 25.7 +/- 2.9, P < 0.0001).
CONCLUSIONS:
Sustained improvement in sexual function after 12 months of tadalafil administration is associated with increased T:E ratio mainly related to reduction of E levels. We hypothesize that androgen-estrogen cross-talk and possible inhibition of aromatase activity during chronic exposure to tadalafil might have a role in the regulation of erectile function.

Exposure to phosphodiesterase type 5 inhibitors st... [J Sex Med. 2011] - PubMed - NCBI

Quote:
Exposure to phosphodiesterase type 5 inhibitors stimulates aromatase expression in human adipocytes in vitro.
Aversa A1, Caprio M, Antelmi A, Armani A, Brama M, Greco EA, Francomano D, Calanchini M, Spera G, Di Luigi L, Rosano GM, Lenzi A, Migliaccio S, Fabbri A.
Author information
Abstract
INTRODUCTION:
Prolonged tadalafil administration in men with erectile dysfunction is associated with increased testosterone (T): estradiol (E(2)) ratio mainly related to reduction of E(2) levels.
AIM:
To investigate the presence of phosphodiesterase type 5 (PDE5) isoenzyme in primary human visceral adipocytes and whether different PDE5 inhibitors (PDE5i) could directly modulate aromatase (ARO) expression in differentiated human visceral adipocytes in culture.
MAIN OUTCOME MEASURES:
PDE5 mRNA and protein expression in primary human visceral adipocytes as well as mRNA and protein expression of ARO, with functional activity after selective PDE5 blockade by tadalafil and sildenafil.
METHODS:
Purified primary human visceral pre-adipocytes were differentiated ex vivo and were exposed to tadalafil or sildenafil (1 µM) for different intervals of time (6-12-24-96 hours). ARO mRNA content and expression were measured by Western Blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively. T and E(2) in supernatants were measured by ELISA also in the presence of letrozole.
RESULTS:
Differentiated adipocytes were found to express detectable levels of PDE5 transcripts. Acute exposure (6 hours) to both PDE5i tadalafil and sildenafil increased ARO mRNA expression by 4.7- and 2.8-fold, respectively (P < 0.001). ARO mRNA and protein levels were increased by the treatment with PDE5i in a time- and dose-dependent manner. Such effect was mimicked by 8-bromo-cGMP but was lost after 24 and 96 hours; differently, the PDE3B specific inhibitor milrinone (1 µM), displayed no effect. Accordingly, long-term exposure (24 and 96 hours) to PDE5i caused a significant increase in E(2) concentrations in the supernatant (1.7 and 2 fold, respectively; P < 0.001), with a parallel reduction of T (15% and 30%, respectively; P < 0.001). Such effect was reversed by the co-incubation with the specific ARO-inhibitor letrozole.
CONCLUSIONS:
Our results demonstrate that PDE5 is expressed in human visceral adipocytes and that acute exposure to PDE5i selectively stimulates ARO expression, which is related to a specific PDE5 blockade. We speculate that modulation of ARO activity by PDE5i could be one of the mechanisms responsible, at least in part, for the beneficial effects of PDE5i on endothelial and metabolic functions.

Feedback is welcomed as well as general thoughts on all of this.


Has anyone had bloodwork after and during the usage of PDE-5I's to determine effects on estradiol and do any of you think it is physiological or just purely Psychological???


It seems like aromatase is also positively affected or modulated by protein kinase c and thus alpha blockers would reduce aromatase?

J Neurochem. 1996 Nov;67(5):2087-95.
Neurotransmitter-mediated regulation of brain aromatase: protein kinase C- and G-dependent induction.

Abe-Dohmae S1, Takagi Y, Harada N.
Author information



Abstract

Aromatase in the diencephalic neurons, the level of which increases transiently during the prenatal to neonatal period, has been suggested to be involved in control of sexual behavior and differentiation of the CNS. Effects of neurotransmitters on levels of aromatase mRNA in cultured neurons were investigated to determine factors regulating the developmental increase that occurs in level of fetal brain aromatase. The expression of aromatase in diencephalic neurons of fetal mice at embryonic day 13, cultured in vitro, was significantly affected by alpha 1-adrenergic receptor ligands. Aromatase mRNA levels were higher in neurons treated with the alpha 1-agonist phenylephrine than in control neurons, whereas prazosin, an alpha 1-antagonist, suppressed this increase, and ligands for alpha 2- or beta-adrenergic receptors did not exert any influence. The profile of alpha 1-adrenergic receptor subtypes during actual development in vivo suggested that the alpha 1B subtype is in fact responsible for the signal transduction. Substance P, cholecystokinin, neurotensin, and brain natriuretic peptide also increased the level of expression along with phorbol 12-myristate 13-acetate and dibutyrylcyclic GMP, whereas forskolin and dibutyryl-cyclic AMP caused a decrease. These data indicate that stimulation via alpha 1 (possibly alpha 1B)-adrenergic receptors, as well as receptors of specific neuropeptides, controls the expression of aromatase in embryonic day 13 diencephalic neurons through activation of protein kinase C or G. beta-Adrenergic receptors would not appear to participate in the regulation, judging from their developmental profile, although cyclic AMP might be a suppressive second messenger.

http://www.ncbi.nlm.nih.gov/pubmed/8863518

Int J Fertil Menopausal Stud. 1993 Jan-Feb;38(1):50-6.
Gonadotropin-releasing hormone has a biphasic action on aromatase activity through protein kinase C in granulosa cells.

Imai A1, Iida K, Tamaya T.
Author information



Abstract

Gonadotropin-releasing hormone (GnRH) exerts direct effects on the ovary by binding to its specific receptor, and stimulates inositol phospholipid turnover in granulosa cells. This study was undertaken to determine the involvement of protein kinase C in the action of GnRH on follicle-stimulating hormone (FSH)-stimulated aromatase activity in rat granulosa cells. The aromatase activity was examined by conversion of exogenously supplied androstenedione to estrogen. FSH stimulated aromatase activity, with a low rate of estrogen production for the first 18 hours, followed by a high rate of production on further incubation. Addition of GnRH potentiated the aromatase response to FSH in the first 18 hours, but caused a dose-dependent inhibition of the FSH-stimulated aromatase activity from 20 to 45 hours of incubation. Half-maximal effects of GnRH occurred at 10 nM. Both of the biphasic actions of GnRH on aromatase response to FSH were mimicked by protein kinase C activators, phobol myristate acetate (PMA) and oleoylacetyl glycerol; maximal effects occurred at 1 to 10 ng/mL. When the cells were exposed first to FSH for 18 hours and then to PMA, the second phase of estrogen production was also suppressed. The second phase, producing quantitative estrogen, might result from induction of the enzyme, because cycloheximide (100 ng/mL) prevented the FSH-induced activation of aromatase from 20 hours of incubation. These results indicate that the biphasic actions of GnRH on FSH-stimulated aromatase activity are mediated by protein kinase C. The inhibitory action of GnRH on quantitative steroidogenesis caused by prolonged FSH stimulation might be expressed through the impaired induction of aromatase.

http://www.ncbi.nlm.nih.gov/pubmed/8485613​

 

[Area 1255]

Zhonghua Nan Ke Xue. 2004 Dec;10(12):890-3.[Effect of berberine on the mRNA expression of phosphodiesterase type 5 (PDE5) in rat corpus cavernosum].

[Article in Chinese]
Tan Y1, Tang Q, Hu B, Xiang J.
Author information



Abstract

OBJECTIVE:

<abstracttext label="OBJECTIVE" nlmcategory="OBJECTIVE">To further investigate the action mechanisms of berberine (Ber) and to assess the effects of Ber on the mRNA expression of phosphodiesterase type 5 (PDE5) in rat corpus cavernosum.</abstracttext>
METHODS:

<abstracttext label="METHODS" nlmcategory="METHODS">After incubating with Ber for 1 or 3 h respectively, we examined the levels of PDE5 mRNA by reverse transcription polymerase chain reaction (RT-PCR).</abstracttext>
RESULTS:

<abstracttext label="RESULTS" nlmcategory="RESULTS">There were PDE5A1 and PDE5A2 mRNA expressions in the rat corpus cavernosum with PDE5A2 as the dominant isoform. Ber could obviously inhibit the mRNA expression of the two isoforms in the rat penis and bring on a pronounced decrease in PDE5A2 (P < 0.01).</abstracttext>
CONCLUSION:

<abstracttext label="CONCLUSION" nlmcategory="CONCLUSIONS">The present study indicates that the inhibitory effect of Ber on PDE5 mRNA expression, especially on PDE5A2, might account for its molecular mechanism for treating ED.</abstracttext>


<dt style="font-size: 0.8465em; line-height: 1.4em; color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; white-space: nowrap; margin-left: 0px !important;">PMID:</dt><dd style="font-size: 0.8465em; line-height: 1.4em; color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; margin: 0px; display: inline; padding: 0px; white-space: nowrap;">15638014</dd><dd style="font-size: 0.8465em; line-height: 1.4em; color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; margin: 0px; display: inline; padding: 0px; white-space: nowrap;">[PubMed - indexed for MEDLINE]</dd>

Interesting how an herbal compound for diabetes can also have pro-erecile/pro-nitric oxide effects..very interesting..considering we are looking @ GENETIC EXPRESSION and not mere inhibition - therefore , berberine plus ICARIIN would semi-permanently or permanently eradicate PDE5 from the body.
Of course, it would take months or years to do enough downregulation for permanent enhancement!

 

[Area 1255]

Zhonghua Nan Ke Xue. 2004 Dec;10(12):890-3.[Effect of berberine on the mRNA expression of phosphodiesterase type 5 (PDE5) in rat corpus cavernosum].

[Article in Chinese]
Tan Y1, Tang Q, Hu B, Xiang J.
Author information



Abstract

OBJECTIVE:

<abstracttext label="OBJECTIVE" nlmcategory="OBJECTIVE">To further investigate the action mechanisms of berberine (Ber) and to assess the effects of Ber on the mRNA expression of phosphodiesterase type 5 (PDE5) in rat corpus cavernosum.</abstracttext>
METHODS:

<abstracttext label="METHODS" nlmcategory="METHODS">After incubating with Ber for 1 or 3 h respectively, we examined the levels of PDE5 mRNA by reverse transcription polymerase chain reaction (RT-PCR).</abstracttext>
RESULTS:

<abstracttext label="RESULTS" nlmcategory="RESULTS">There were PDE5A1 and PDE5A2 mRNA expressions in the rat corpus cavernosum with PDE5A2 as the dominant isoform. Ber could obviously inhibit the mRNA expression of the two isoforms in the rat penis and bring on a pronounced decrease in PDE5A2 (P < 0.01).</abstracttext>
CONCLUSION:

<abstracttext label="CONCLUSION" nlmcategory="CONCLUSIONS">The present study indicates that the inhibitory effect of Ber on PDE5 mRNA </abstracttext><abstracttext label="CONCLUSION" nlmcategory="CONCLUSIONS">expression</abstracttext><abstracttext label="CONCLUSION" nlmcategory="CONCLUSIONS"></abstracttext><abstracttext label="CONCLUSION" nlmcategory="CONCLUSIONS">, especially on PDE5A2, might account for its molecular mechanism for treating ED.</abstracttext>


<dt style="font-size: 0.8465em; line-height: 1.4em; color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; white-space: nowrap; margin-left: 0px !important;">PMID:</dt><dd style="font-size: 0.8465em; line-height: 1.4em; color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; margin: 0px; display: inline; padding: 0px; white-space: nowrap;">15638014</dd><dd style="font-size: 0.8465em; line-height: 1.4em; color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; margin: 0px; display: inline; padding: 0px; white-space: nowrap;">[PubMed - indexed for MEDLINE]</dd>

AND...

J Huazhong Univ Sci Technolog Med Sci. 2006;26(4):460-2.Effect of icariin on cyclic GMP levels and on the mRNA expression of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in penile cavernosum.

Jiang Z1, Hu B, Wang J, Tang Q, Tan Y, Xiang J, Liu J.
Author information



Abstract

<abstracttext>To further investigate the mechanisms of action of icariin (ICA), we assessed the effects of ICA on the in vitro formation of cGMP and cAMP in isolated rabbit corpus cavernosum. Isolated segments of rabbit corpus cavernosum were exposed to increasing concentrations of ICA and the dose-dependent accumulation of cGMP and cAMP was determined in the tissues samples by means of 125I radioimmunoassay. Responses of the isolated tissues preparations to ICA were compared with those obtained with the reference compounds sildenafil (Sild). Furthermore, the effects of ICA on the mRNA expression of specific cGMP-binding phosphodiesterase type V (PDE5) in rat penis were also observed. After incubation with ICA for 6 h or 14 h respectively, the levels of PDE5 mRNA were examined by reverse transcriptase polymerase chain reaction (RT-PCR). The results showed that ICA increased cGMP concentrations directly (P < 0.05), but there was no significant effect on cAMP concentrations (P > 0.05). In the presence of sodium nitroprusside (SNP), a stimulatory agent of cGMP, both ICA and Sild increased cGMP concentrations with increasing dose (P < 0.01). Their EC50 was 4.62 (ICA) and 0.42 (Sild) micromol/L respectively. Under the same condition, ICA and Sild unaltered cAMP level significantly (P > 0.05). There were PDE5A1 and PDE5A2 mRNA expressions in rat corpus cavernosum with PDE5A2 being the dominant isoform. ICA could obviously inhibit these two isoforms mRNA expression in rat penis, and decrease PDE5A1 more pronouncedly (P < 0.01). The present study indicated that the aphrodisiac mechanisms of icariin involved the NO-cGMP signal transduction pathway, with increasing cGMP levels in the corpus cavernosum smooth muscle. The </abstracttext><abstracttext>inhibitory effect of </abstracttext><abstracttext>I</abstracttext><abstracttext></abstracttext><abstracttext></abstracttext><abstracttext></abstracttext><abstracttext>cariin</abstracttext><abstracttext></abstracttext><abstracttext> on PDE5 mRNA expression, especially on </abstracttext><abstracttext></abstracttext><abstracttext></abstracttext><abstracttext>PDE5A1</abstracttext><abstracttext></abstracttext><abstracttext></abstracttext><abstracttext>,</abstracttext><abstracttext></abstracttext><abstracttext></abstracttext><abstracttext> might account for its molecular mechanisms for its long-term activity.</abstracttext>


<dl class="rprtid" style="margin-right: 15px; margin-left: 0px; font-size: 0.8465em; line-height: 1.4em; display: inline;"><dt style="display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px !important; white-space: nowrap;">PMID:</dt> <dd style="margin: 0px; display: inline; padding: 0px; white-space: nowrap;">17120748</dd> <dd style="margin: 0px; display: inline; padding: 0px; white-space: nowrap;">[PubMed - indexed for MEDLINE]</dd><dd style="margin: 0px; display: inline; padding: 0px; white-space: nowrap;"></dd></dl>


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