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Have you read ? Best of the Best: Basic Research
to excessive presence of reactive oxygen species
(ROS) outstands.
In this study, Nunes and collaborators evalu-
ate the effects of the soluble guanylyl cyclase
(sGC) stimulator, BAY-41-2272 on cavernosal
function and oxidative stress in corpus caver-
nosum in mice with type 2 diabetes and obesity.
The mouse model used consisted of animals
(db/db) that lack leptin receptor which results
in the development of type 2 diabetes and obe-
sity after 1 – 2 months of age. They determined
in 14 – 16 weeks old diabetic db/db and their
lean, non-diabetic (db/+) littermates functional
responses of corpora cavernosa, systemic meta-
bolic parameters and antioxidative status as well
as cGMP content, superoxide generation and
NADPH expression in corpus cavernosum.
This murine model of type 2 diabetes and obesity
is associated with an impairment of endothelium-
dependent and neurogenic relaxations in corpus
cavernosum, a profile of cavernosal alteration
consistently observed in diabetic models and
humans. In contrast, relaxation induced by an
NO-donor or the sGC stimulator in corpus cav-
ernosum of db/db-/-mice is not altered. Treat-
ment with mid-high nanomolar concentrations of
BAY 41-2272 improves endothelium-dependent
relaxation to acetylcholine and neurogenic relaxa-
tion induced by electrical field stimulation (EFS)
in corpus cavernosum from diabetic/obese mice.
In fact, the sGC stimulator increases duration of
relaxant response to EFS in corpus cavernosum
from both diabetic/obese and non-diabetic/lean
animals. In addition to increase cGMP content in
corpus cavernosum, treatment with BAY 41-2272
potentiates the cGMP accumulation induced by
EFS and the NO-donor, sodium nitroprusside,
Positive effects on NO/cGMP pathway by BAY
41-2272 are related to the down-regulation of
the expression of the NADPH oxidase subunits
gp91
phox
, p22
phox
and p47
phox
which are all up-reg-
ulated in corpus cavernosum from db/db-/-mice.
Furthermore, consistently with NADPH oxidase
down-regulation, BAY 41-2272 effectively coun-
teracts the increase in superoxide generation
produced in corpus cavernosum from diabetic/
obese mice.
The profound reduction of NO bioavailability
seems to be the key factor in cavernosal dysfunc-
tion in diabetes. The results by Nunes and col-
laborators support this idea and provide evidence
of the positive effects of
acting downstream of
NO activity
. This is because of the preservation
of diabetic cavernosal smooth muscle to relax
when exogenous NO is provided to activate sGC
or when sGC is directly stimulated.
Acting at
this step of the pathway the defective NO
availability could be overcome
. Additionally,
the potentiating effects in cGMP accumulation
caused by co-administration of BAY 41-2272
and the NO-donor or the NO derived from EFS
suggest that BAY 41-2272 would
interact with
NO to produce a robust stimulation of sGC
.
This would account for the beneficial effects of
the sGC stimulator on functional responses driven
by physiological/pharmacological NO genera-
tion in corpus cavernosum from diabetic mice.
However, potentiation of NO-mediated relaxation
could be contributed by an additional mechanism
suggested in this study. It is well established the
pathophysiological role of reactive oxugen spe-
cies (ROS) and, specifically, superoxide anion in
the defective bioavailability of NO found in caver-
nosal tissue from diabetic animals and humans.
In this sense, BAY 41-2272 is able to
antagonize
the elevation of superoxide caused by dia-
betes/obesity
in cavernosal tissue, probably by
down-regulating the expression of NADPH oxi-
dase, an enzyme with outstanding participation in
the generation of superoxide in cavernosal tissue
and other vascular territories. The present work
does not clarify if
this additional mechanism
is specific for BAY 41-2272 or attributable
to any sGC stimulator through the increased
production of cGMP
.
Other open question would be related to the pos-
sible therapeutic advantage of combining PDE-5
inhibition with sGC stimulation in this model and
the impact on systemic hemodynamics. Finally,
the interpretation of the present results should
consider the fact that this is not a type 2 dia-
betes model but a type 2 diabetes and obesity
model. Although obesity and type 2 diabetes are
closely related conditions and both impact erec-
tile function, the specific contribution of obesity
to cavernosal dysfunction could influence the
application of the results to type 2 diabetes in
the absence of obesity.
Diabetic ED – Hypoxic preconditioning for
cell therapy
Hypoxia precondition promotes adipose-de-
rived mesenchymal stem cells based repair
of diabetic erectile dysfunction via augment-
ing angiogenesis and neuroprotection.
Wang XY, Liu CL, Li SD, Xu Y, Chen P, Liu Y, Ding
G, Wahafu W, Hong BF, Yang MH.
PLoS One 2015, 10: e0118951.
Along last 10 years, a large number of studies
have provided evidences supporting the ability
of stem cells to recover erectile function in dif-
ferent animal models of ED. From embryonic to
adult stem cells from different tissue sources,
the implantation of these cells has shown certain
degree of recovery/preservation of erectile func-
tion. Although neurogenic ED after cavernous
nerve injury has been the main focus for cell
therapy, other ED models involving different aeti-
ologies such as diabetes have shown therapeutic
response to cell implantation. However, further
research to enhance the efficacy of cell therapy
is being afforded.
Wang and co-workers have evaluated the hypoxic
preconditioning as a way to enhance the efficacy
of adipose-derived mesenchymal stem cells
(ADSC) in reversing ED in diabetic rats. They have
chosen the very well know model of type 1
diabetes induced in rats by a single injection of
streptozotocin. The treatments were started
8 weeks afterwards, a time known to be enough
to produce vascular alterations and ED. However,