Androgenic Maintenance Of The Rat Erectile Response Via A Non-nitric-oxide-dependent Pathway

[High_Prob]

Androgenic maintenance of the rat erectile response via a non-nitric-oxide-dependent pathway. - PubMed - NCBI

Androgenic maintenance of the rat erectile response via a non-nitric-oxide-dependent pathway.
Reilly CM1, Lewis RW, Stopper VS, Mills TM.
Author information

Abstract
Prior studies have demonstrated that the erectile response in the rat penis is androgen dependent and is mediated by nitric oxide (NO), the neurotransmitter synthesized by the enzyme nitric oxide synthase (NOS). The present studies used L-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, to determine if androgens also regulate alternative pathways leading to the erectile response but not mediated by NO. Castrated rats that were treated with L-NAME (L-NAME CASTRATE) exhibited little or no increase in intracavernosal pressure in response to stimulation of the major pelvic ganglion. This ganglion controls blood flow into the penis and, when stimulated, normally leads to erection. However, when castrated animals were treated with testosterone along with L-NAME (L-NAME TESTO), the animals responded to the ganglionic stimulation with increased intracavernosal pressure. This finding suggests that there are other androgen-dependent pathways that lead to penile erection but are not mediated by NO. Erection occurred in both L-NAME CASTRATE and L-NAME TESTO rats in response to intracavernosal injection of sodium nitroprusside (an NO donor drug), proving that the NO responsive mechanisms were unaffected by the inhibition of NOS activity. To investigate further the nature of this NO independent pathway, L-NAME CASTRATE and L-NAME TESTO rats were treated with either zaprinast (a specific phosphodiesterase 5 inhibitor), which would block the breakdown of cGMP to 5'GMP, or methylene blue (an inhibitor of guanylate cyclase) to prevent the synthesis of cGMP. Zaprinast treatment led to increased erectile response in L-NAME TESTO rats but not in L-NAME CASTRATE rats, demonstrating that androgen-sensitive alternative pathways increased guanylate cyclase activity. Methylene blue inhibited the erectile response in all treatment groups, showing that cyclic GMP is critical to the NO-independent pathway as well as the NO-dependent pathway. Taken together, these results support the hypothesis that androgens maintain the erectile response by alternate pathways, including one that is independent of NO but involves the synthesis of cyclic GMP.

 

[Aleeri]

Stumbled upon this post in google search while reading up on cAMP/cGMP and PDE involvement in androgens. Will probably make another post about it soon.

Either way, this is interesting, talking about a NO-independent pathway involving cGMP for erectile response.




Have you noticed how a PDE-5 inhibitor here: Zaprinast - is used to preserve cGMP and improve erections independent from NO? Same happens with Viagra and Cialis: https://www.physiology.org/doi/full/10.1152/ajpendo.00337.2010

Methylene Blue is considered beneficial on this forum but clearly, it blocks cGMP which is bad for erectile function and androgens.




The Opposing Roles of Nitric Oxide and cGMP in the Age-Associated Decline in Rat Testicular Steroidogenesis

The molecular mechanism of the aging-associated dysfunction of Leydig cells (LCs) is complex and poorly understood. In this study, we analyzed the contribution of nitric oxide (NO) and cGMP signaling to the age-dependent decline in LC function. Significant (>50%) decreases in serum, intratesticular, and LC androgens in aging rats (15–24 months) were accompanied by a proportional increase in NO production, an up-regulation of cGMP levels, and the expression of soluble guanylyl cyclase-1B and protein kinase G1 in LCs. In contrast, LC cAMP levels decreased with age, most likely reflecting the up-regulation of cAMP-specific phosphodiesterase expression. Moreover, the expression of genes encoding enzymes responsible for cholesterol transport and its conversion to T were reduced. Exposing LCs from aged animals to NO further increased cGMP levels and decreased cAMP and androgen production, whereas the addition of cell-permeable 8-bromoguanosine-cGMP alone had the opposite effect. In vivo inhibition of cGMP-specific phosphodiesterase-5 for 3 and 6 months in aged rats led to a partial restoration of androgens, NO, and cyclic nucleotide levels, as well as the expression of steroidogenic and NO/cGMP signaling genes. These results indicate that a progressive increase in NO production contributes to the age-dependent decrease in steroidogenesis in a cGMP-independent manner, whereas the sustained elevation in cGMP levels significantly slows the decline in LC function.

This whole post by @haidut talks about caffeine having androgenic effects on the testes by boosting cAMP, this is actually the same thing as Viagra does also. Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue. - PubMed - NCBI



I am confused about Cialis and Viagra, many of their effects on cGMP and cAMP seem very beneficial and not mediated by NO.

It's actually the same effect as many popular herbs for testosterone and erectile function has.

Erectogenic and Aphrodisiac Effects of Butea frondosa Koenig ex Roxb. in Rats: Involvement of Enzyme Inhibition

Collagen-III level (visible as green mesh under polarized microscope when stained with picrosirius red) also increased in the penile tissue of aged rats and might be responsible for decreased erectile function. In young rats, MEBF treatment increased smooth muscle percentage in rat CCSM. We also observed that the increase in collagen-III level of aged rats decreased after treatment with MEBF and sildenafil. An earlier study reported that chronic treatment with sildenafil, a cGMP specific PDE inhibitor, ameliorated corporal smooth muscle cell loss and fibrosis in 20-month-old rat [20]. In our study, MEBF and sildenafil treatment increased sexual function of all the young rats. Treatment with MEBF and sildenafil also increased sexual function significantly in 50% of the aged rats that had decreased sexual function. The data from 3 aged rats was included for calculation of statistical significance.

Lastly, antifibrotic properties of MEBF could be due to PDE inhibition and subsequent increase in the level of cGMP, known to have antifibrotic property. In addition, NO has been reported to have antifibrotic property [41], and androgen-induced NO production might be in part responsible for antifibrotic property of MEBF (Figure 5).

The question I have is this, what about androgen-induced NO production?

When I look at PDE inhibitor research I keep seeing positive things, such as involvement in cAMP/cGMP.

From rapalogs to anti-aging formula
Long-term inhibition of PDE5 ameliorates aging-induced changes in rat testis - ScienceDirect

Inhibition of PDE5 increases levels of cGMP and hydrogen sulfate. These signaling molecules increase life span in C elegans [214, 215].

Long-term inhibition of PDE5 ameliorates aging-induced changes in rat testis - ScienceDirect

Long-term in vivo PDE5 inhibition reduces aging-related NO increment & testosterone drop in blood.

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Long-term in vivo PDE5 inhibition reduces aging-increased expression of Leydig cells antiapoptotic & survival kinases

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Long-term in vivo PDE5 inhibition slow down aging-associated regressive changes in testicular structure.

NO-cGMP signaling pathway has been implicated in reduction of testicular steroidogenesis during aging. Here we analyzed the effect of PDE5 inhibition on old testicular phenotype formation. The old phenotype exhibited low testosterone and increased nitrite levels in circulation, increased cGMP accumulation in testicular interstitial fluid (TIF), progressive atrophy of testicular seminiferous tubules and enlargement of interstitial area followed by rise in blood vessel density and slight increase in the number of Leydig cellsand macrophages. Leydig cells have reduced steroidogenic capacity, increased MAP kinases expression (MEK, ERK1/2, JNK) and antiapoptotic PRKG1 and AKT, suggesting increased proliferation/survival and accumulation of senescent Leydig cells in testis. In 12 month-old rats, a long-term treatment with sildenafil (PDE5 inhibitor) normalized testosterone/nitrite levels in circulation and cGMP accumulation in TIF; improved Leydig cell steroidogenic capacity; decreased MEK, ERK1/2 and PRKG1 expression; prevented an increase in the Leydig cells number and atrophy of seminiferous tubules leading to histological appearance of young rat testes. In 18 month-old rats, long-term PDE5 inhibition partially recovered testosterone and nitrite levels in serum; normalized PRKG1 expression without effect on MEK and ERK1/2; and slowed down Leydig cell and macrophage accumulation and regressive tubular changes. Culturing of primary Leydig cells from aged rats in presence of PDE5-inhibitor stimulated steroidogenic and MAPK gene expression. Taking together, results indicate that cGMP targeting alter both steroidogenesis and signaling pathways associated with cell proliferation/survival. The long-term PDE5 inhibition improves testicular steroidogenesis and slows-down regressive changes in testes during aging.