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ARTICLES |
Departments of Urology (A.M.T., K.P., V.D., N.N.K., R.B.M., I.G.) and Biochemistry (A.M.T.), Boston University School of Medicine, Boston, Massachusetts 02118
Address all correspondence and requests for reprints to: Abdulmaged M. Traish, Ph.D., Professor of Biochemistry & Urology, Department of Urology, Center for Advanced Biomedical Research, Boston University School of Medicine, 700 Albany Street, Room W607, Boston, Massachusetts 02118. E-mail: atraish{at}bu.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-1 adrenergic receptor protein expression; 3) neural
NO synthase protein expression and activity; 4) phosphodiesterase type
5 activity; and 5) trabecular smooth muscle/connective tissue balance.
One week after bilateral orchiectomy, animals were treated for 7 days
with vehicle alone, testosterone, or estradiol. Intact control animals
received vehicle only. Systemic arterial blood and intracavernosal
pressures (ICP) were measured in each animal before and after
electrical stimulation of the cavernosal nerve.
1-adrenergic receptor protein expression was determined
by ligand binding studies. NO synthase expression and activity were
determined by Western blot analyses and conversion of
L-arginine to citrulline, respectively. Phosphodiesterase
type 5 activity was determined by hydrolysis of guanosine 3',5'-cyclic
monophosphate (cGMP) in tissue extracts in the absence or presence of
100 nM sildenafil. Smooth muscle content was assessed by
Masson’s trichrome staining and computer-assisted histomorphometry.
Castration significantly reduced ICP, but it did not alter systemic
arterial blood pressure during stimulation of the cavernosal nerve.
Testosterone, but not estradiol, treatment prevented the effects of
castration and restored ICP to values similar to those obtained in
intact animals. Castration reduced expression of
1-adrenergic receptor, and this reduction was prevented
or reversed by testosterone replacement. Neural NO synthase protein
expression and total activity were not altered significantly by
castration or after testosterone replacement. However,
phosphodiesterase type 5 activity increased in castrated animals
treated with testosterone. Castration significantly reduced trabecular
smooth muscle content, and this reduction was restored by testosterone
(but not estradiol) treatment. The results of this study demonstrate
that androgen deprivation alters the functional responses and structure
of erectile tissue. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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During erection, the penis acts as a capacitor, accumulating blood under pressure (7, 8, 9). Dilation of the resistance arterial bed of the penis provides flow and pressure to the corpora, and relaxation of the trabecular smooth muscle allows expansion of the lacunar spaces and trapping of blood by compression of the draining venules (7, 8, 9). When corpus cavernosum smooth muscle is fully relaxed, the intracavernosal pressure (ICP) is dependent on the cavernosal arterial pressure. Trabecular smooth muscle is an important structure in the penis, which contributes to control of detumescence and erection (7). Neurotransmitters and vasoactive substances, such as NO, mediate the local control of trabecular smooth muscle tone. Erectile function is, therefore, dependent on the integrity of corpus cavernosum structure and the integration and regulation of functional interplay between neuroeffectors and vasoactive agents and their receptors (7, 8). Any imbalance in smooth muscle connective tissue ratio (10) or the integration of signal transduction caused by changes in receptor expression or function or down-stream events may result in erectile dysfunction (7, 8). Androgen deprivation may alter trabecular smooth muscle content or neurotransmitters and their receptors, resulting in altered function.
In the rat model, erection is androgen dependent (1, 11, 12). In
castrated rats, ICP was reduced in response to electrical field
stimulation of the cavernosal nerve. Testosterone treatment of
castrated rats restored this response, suggesting androgen dependence
of erectile function (11). The primary action of androgens in erectile
function in the rat is postulated to be via stimulation of NO synthesis
(11, 12, 13, 14, 15, 16). Neural NO synthase (NOS) messenger RNA and protein expression
were reduced in castrated rats (13, 17); however, other studies
demonstrated that neural NO synthase protein expression was not reduced
but NOS activity was diminished (18, 19). Castration also
reduced NOS containing nerve fibers, innervating corpus cavernosum
tissue, and enhanced nonadrenergic noncholinergic (NANC) nerve-mediated
relaxation in isolated corpus cavernosum strips and increased the
reactivity to -adrenergic stimulation (11). In addition, castration
induced programmed smooth muscle cell death in the rat penis,
suggesting that androgens may have an important role in maintaining
smooth muscle growth and functional integrity (3). In the rabbit model,
corpus cavernosum strips from castrated animals exhibited greater
relaxation to electrical field stimulation than cavernosal strips from
intact animals (20). However, the relaxation to exogenous NO donors was
similar in cavernosal strips from castrated and intact animals (20).
Tissue strips from intact rabbits showed a greater degree of
contraction than tissue from castrated animals, suggesting changes in
the adrenergic pathway in response to androgen deprivation (21). Though
it was reported in the rat model that NANC nerve fibers are reduced by
castration (16), these fibers were thought to be increased in the
castrated rabbit model (20), suggesting differences in the response to
androgens among species.
Most of the studies on the role of androgens on erectile function have focused on the effects of androgens on altering the expression or activity of NO synthase in the rat. Although the NO/cGMP pathway is an important regulator of smooth muscle contractility, penile erectile function is dependent on the balance and integration of multiple physiological functional control systems, including neurotransmitters, vasoactive agents, endocrine factors, and tissue fibroelastic properties. Thus, although the effects of androgens on NO synthase have been investigated in the rat, the effects of androgens on the smooth muscle/connective tissue balance and possible alteration of corporal veno-occlusive mechanisms have yet to be investigated.
The goal of this study was to investigate the effects of androgen
depletion and androgen replacement in a rabbit model on: 1) the
hemodynamics of erectile tissue in vivo; 2) the expression
of 1 adrenergic receptors; 3) neural NO synthase; 4)
phosphodiesterase type 5 activity; and 5) smooth muscle content of
corpus cavernosum.
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Materials and Methods |
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2000 Ci/mmol),
L-[14C]arginine (300 µCi/mmol), and
8-[3H]cGMP (7.64 Ci/mmol) were obtained from New
England Nuclear, Boston, MA. Unlabeled prazosin, phenylmethylsulfonyl
fluoride, aprotinin, and pepstatin A were obtained from Sigma Chemical Co. (St. Louis, MO). All other chemicals were reagent
grade and were obtained from commercial sources. Enhanced
chemoluminescence (ECL) Western blot detection kits were obtained from
Pierce Chemical Co. (Rockland, IL).
Animal castration and androgen replacement
The Animal Care Committee of the Boston University School of
Medicine approved this study. New Zealand white male rabbits (3–3.5
kg) were divided into four groups (nine animals per group). One group
was kept intact (controls). The remaining groups of animals were
bilaterally castrated through 3-cm scrotal incisions, under anesthesia.
One week post orchiectomy, the animals were either injected with
vehicle (benzoylbenzoate: castor oil, 1:4) daily for 7 days
(vehicle) or injected sc daily with testosterone (14 mg/day) or
estradiol (14 mg/day) dissolved in vehicle.
Measurements of systemic arterial blood and ICPs
Animals were anesthetized with im injections of ketamine (35
mg/kg) and xylazine (5 mg/kg). Anesthesia was maintained with 0.2 ml iv
bolus injection of pentobarbital (25 mg/ml), as needed. A 20-gauge
angiocatheter was placed into the carotid artery for measurement of
systemic arterial blood pressure. A 21-gauge minicatheter was placed
intracavernosally for measurement of ICP. A midline abdominal incision
was made to expose the perivesical space. The internal pudendal artery
was identified; and the distal branch to the prostate, bladder neck,
and cavernosal bodies was localized. The cavernosal nerve bears
relation to the cavernosal artery on the posterolateral surface of the
prostate. Using platinum wire electrodes, we electrically stimulated
the cavernosal nerve at varying frequencies (1–25 Hz) with a train of
square waves at 10 V and a pulse width of 8 msec for a total duration
of 30–60 sec.
Measurements of 1-adrenergic receptors in
corpus cavernosum membranes
Rabbit corpus cavernosum membranes were prepared as previously
reported (22). Alpha adrenergic receptor binding studies were carried
out using [125I]HEAT as a ligand, and nonradioactive
prazosin as unlabeled competitor, as described previously (22, 23).
Protein-bound radioactivity was determined by filtration assay, and the
specific binding was determined by subtraction of nonspecific binding
and was normalized, per milligram DNA, to correct for possible loss of
DNA caused by programmed cell death that may take place
subsequent to castration (3).
Determination of neural NO synthase expression by Western blot
analyses
Neural NO synthase protein expression in corpus cavernosum was
carried out by Western blot analyses using isoform-specific monoclonal
antibodies (Transduction Research, Paducah, KY). Rabbit corpus
cavernosum tissue was homogenized, and the homogenates were centrifuged
at 800 x g for 30 min at 4 C, to obtain crude
cytosolic extracts. Aliquots of each extract were assayed for protein
concentration by the method of Lowry. Identical amounts of protein (100
µg total protein/lane) from each extract were electrophoresed on
7.5% SDS polyacrylamide gels. After transfer to nitrocellulose
membranes, samples were incubated with mouse antirat neural NOS
monoclonal antibody. Membranes were washed and incubated with
horseradish peroxidase-linked goat antimouse IgG (secondary antibody,
Pierce Chemical Co.). Membranes were developed with an ECL
kit and exposed to autoradiography film (Hyperfilm; Amersham Corp., Arlington Heights, IL) to obtain visible bands at 160
kDa. Rat pituitary lysate was used as positive control (10 µg/lane;
rat neural NO synthase). The bands were scanned by densitometry, and
the values obtained were normalized, per milligram protein, or mg
DNA.
Determination of NO synthase activity
NO synthase activity in the total tissue extract was determined
by conversion of L-[14C]arginine to
[14C]citrulline and NO, as described by Kim et
al. (24). Briefly, aliquots of the tissue extract were incubated
with tetrahydrobiopterin (3 µM), calmodulin (30 U/ml),
L-arginine (50 µM), [14C]
L-arginine (2µCi/ml), NADPH (20 mM), and
calcium chloride (1 mM) at 37 C for 45 min. Parallel
samples were incubated at 2 C. Citrulline was separated from arginine
by ion exchange columns (1 ml) of AG50W-X8 resin (Bio-Rad Laboratories, Inc., La Jolla, CA) and quantified by
scintillation counting of radioactivity. Enzymatic activity was
expressed as µM of citrulline per mg protein or ug DNA
per 45 min.
Assay of phosphodiesterase type 5 activity
Phosphodiesterase activity assays were carried out as described
previously (25, 26). Briefly, aliquots (50 µl, in triplicates) of
cytosol were incubated at 30 C for 30 min in the presence of unlabeled
cGMP (1 µM) and [3H]cGMP (50
nM), in 40 mM 4-morpholine propane sulfonic
acid buffer, 0.8 mM EGTA, 5 mM Mg acetate, 0.2
mg/ml BSA (pH 7.0), with or without 100 nM sildenafil
(phosphodiesterase type 5 selective inhibitor), in a final vol of 250
µl. Parallel incubations were made, in the absence of cytosol, to
serve as control (blank). The reactions were terminated by incubation,
at 100 C for 1 min, to inactivate the enzyme. The reaction mixtures
were incubated with 2.5 µl of 10 mg/ml Crotalus atrox
venom, to hydrolyze GMP to guanine, for 10 min at 30 C (25, 26).
Deionized water (0.5 ml) was added to each sample, and the total
incubation mixture was chromatographed on an ion exchange resin (DEAE
Sephadex A-25), preequilibrated with 20 mM Tris-HCl, pH
7.5. Hydrolyzed guanine was eluted with 3 ml of 20 mM
Tris-HCl buffer directly into scintillation vials, and the column
retained the unhydrolyzed GMP and cGMP. Liquiscint (10 ml) was added to
each vial, and the radioactivity was counted. The radioactivity
representing spontaneous cGMP hydrolysis, determined from the control
(blank) incubation, was considered background activity and was
subtracted from radioactivity determined in each sample. The
concentration of cGMP hydrolyzed by phosphodiesterase type 5 was
determined for each sample, normalized for isotope dilution protein and
DNA concentrations.
Determination of smooth muscle/connective tissue ratio by
histomorphometry
We carried out, in a blinded fashion to the animal treatment,
histomorphometric analyses to determine the relative content of smooth
muscle vs. connective tissue in corpus cavernosum, as
described previously (27, 28). Briefly, after ICP measurements in
response to nerve stimulation, the penis was removed en
bloc, and the corpus cavernosum tissue was dissected. Tissues were
fixed, paraffin-embedded, sectioned, and stained with Masson’s
trichrome (27, 28). We used computer-assisted color histomorphometry to
assess the mean percentage of the trabecular smooth muscle to total
erectile tissue (smooth muscle plus connective tissue). Sections from
proximal, distal, and medial region of the penis of each animal were
examined. For each tissue section, 10–15 fields (400 x
magnification) were examined; and the smooth muscle content was
assessed using image analysis software to quantitate areas stained red
(smooth muscle) and areas stained blue (connective tissue).
Statistical analyses
Where applicable, data were analyzed by ANOVA, followed by
two-tailed Student’s t test, for comparison between two
groups with appropriate Bonferroni corrections. Data were considered
statistically significant when P values were less than 0.02.
However, for any given set of experiments, we reported lower
P values to indicate actual levels of significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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demonstrates that androgen
deprivation resulted in no changes in systemic systolic and diastolic
blood pressure in all animal treatment groups. ICP in the flaccid state
remained unchanged for all groups. ICP, after electrical stimulation of
the pelvic nerve, however, was significantly reduced in the castrated
animal groups treated with vehicle only (Fig. 1, lower
panel, V) and in castrated animals treated with estradiol
(Fig. 1, lower panel, E). Testosterone treatment of
castrated animals (Fig. 1, lower panel, T) reversed
the effects of castration and restored it to control levels (Fig. 1, lower panel, C).
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1-adrenergic receptors in rabbit corpus
cavernosum1-adrenergic agonist than tissue strips from castrated
animals (1). We investigated the effects of androgen deprivation and
androgen replacement on the expression of 1-adrenergic
receptor. As shown in Fig. 2, the
concentration of 1-adrenergic receptor functional
protein (fmol/mg DNA) was reduced significantly in corpus cavernosum of
castrated animals and was restored to control levels in castrated
animals treated with testosterone.
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). When the band densities were
normalized on a DNA basis, a similar increase in neural NO synthase
protein expression was noted in castrated animals and castrated
estrogen-treated animals (Fig. 4).
However, these differences were not significantly different from
control (P > 0.02).
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). Although a marked
increase in NOS activity was observed in castrated animals treated with
estradiol, these changes were not statistically significant
(P > 0.02). These observations suggest that, in
contrast to the rat model, androgen deprivation does not significantly
alter neural NO synthase protein expression or activity in the rabbit
corpus cavernosum.
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).
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, panel V), when compared with controls
(panel C). Androgen replacement (panel T) prevented smooth muscle loss
and maintained the smooth muscle staining, comparable to that observed
in control animals (panel C). Estradiol (panel E) did not prevent the
effects of castration. These changes were assessed quantitatively by
computer-assisted histomorphometric analyses of corpus cavernosum
tissue sections from control (C), castrated rabbits, treated with
vehicle only (V), castrated rabbits treated with testosterone (T), and
castrated rabbits treated with estradiol (E). The data in Fig. 8 confirmed the qualitative histologic
observations.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The effect of androgens on erectile function is complex, and androgens may influence not only the central nervous system but also affect the peripheral nervous system and penile erectile tissue (1). Several studies have pointed to androgen regulation of neurotransmitters in erectile function. Androgens were reported to regulate NO synthase in neurons of the major pelvic ganglion in the rat (17). Androgen receptors also colocalize with NO synthase and vasoactive intestinal polypeptide in the major pelvic ganglion of the rat penis (33). Androgens modulate programmed trabecular smooth muscle cell death (apoptosis) in rat penile tissue (3), suggesting a direct effect of androgens on cavernosal smooth muscle and trabecular tissue structure. Thus, androgens may affect erectile function by acting at different sites. The exact mode of androgen action in regulation of erectile function remains unknown.
In this study, we have investigated the effects of androgen depletion and replacement on the functional responses of erectile corpus cavernosum, by assessment of hemodynamic changes produced in response to electrical field stimulation of the cavernosal nerve and biochemical and histological parameters. Androgen deprivation did not affect the systemic arterial blood pressure in castrated animals or in castrated animals treated with testosterone or estradiol. However, ICP, which is indicative of erectile function, was significantly reduced by androgen deprivation and was restored to control levels by testosterone (but not by estradiol) treatment. The results suggested that androgens had altered either the synthesis or release of neurotransmitters, receptor function, or tissue structure, and therefore altered the reactivity of the corpus cavernosum. In the castrated rabbits, stimulation of the cavernosal nerve resulted in attenuated erection, suggesting that androgens are critical for maintaining the neural/smooth muscle functional and metabolic integrity.
Androgens may affect neurotransmitter synthesis, release, or
neurotransmitter receptor density or distribution on the trabecular
smooth muscle, thus altering tissue responsiveness (11). In this
study, we focused mainly on effects of castration and androgen
replacement on expression of functional 1-adrenergic
receptors but made no attempts to examine the changes in
neurotransmitter synthesis or release. We observed that castration
reduced the density of functional 1-adrenergic receptor
in the corpus cavernosum smooth muscle. Androgen replacement restored
1-adrenergic receptor levels to those of control
animals. Because 1- adrenergic receptors mediate the
contractile response, one would expect the decrease in the density of
1-adrenergic receptors, subsequent to castration, to
attenuate smooth muscle contraction and enhance nerve-stimulated penile
erection. However, we observed attenuation of nerve-stimulated penile
erection in the castrated animals. This observation suggests that
androgens affect the trabecular smooth muscle function via other
mechanisms, which may include structural changes, and reduced
synthesis, and release of vasoactive factors.
Alternatively, androgens may influence the activity of the NANC neurotransmitter or down-stream signal transduction pathways, and/or the reactivity of the trabecular smooth muscle, to neurotransmitters (13, 14, 15, 16, 17, 18). In the rabbit corpus cavernosum, castration did not reduce neural NO synthase protein expression or activity when normalized on protein or DNA basis. This finding is in contrast to previous reports in the rat penis (14) in which castration resulted in reduced neural NO synthase messenger RNA and protein expression.
Upon cavernosal nerve stimulation, NO released from the nonadrenergic, noncholinergic nerves activate guanylyl cyclase and increase intracellular cGMP synthesis. This increase in intracellular cGMP modulates intracellular calcium, which, in turn, regulates smooth muscle contractility and erectile function (34). Phosphodiesterase type 5 plays an important physiological role by regulating the intracellular levels of cGMP and smooth muscle relaxation (25, 34). Castration did not significantly reduce phosphodiesterase type 5 activity in erectile tissue of the rabbit; however, androgen replacement produced a significant increase in phosphodiesterase type 5 activity, when normalized on DNA basis. Though the implication of this observation in not clear, at present, it may relate to the complex regulation of neural NO synthase and phosphodiesterase type 5 by androgens in this tissue.
Penile erection depends on a functional veno-occlusive mechanism (9, 10, 27, 28), which requires a critical balance between trabecular smooth muscle and connective tissue (10, 27, 28). If androgen deprivation results in programmed trabecular smooth muscle cell death and an imbalance in this critical ratio, one would expect failure of the veno-occlusive mechanism and impairment of erectile function. In this study, we determined the effects of castration and androgen replacement on the balance between smooth muscle and connective tissue content. We noted a significant decrease in the content of trabecular smooth muscle in castrated rabbits and in castrated animals treated with estradiol. Treatment of castrated animals with testosterone restored smooth muscle content to those of control animals. Because the data obtained with castrated animals treated with vehicle only were similar to those obtained with castrated animals treated with estradiol, we suggest that administration of estradiol did not prevent the loss of trabecular smooth muscle; nor did it result in its restoration, suggesting androgen specificity of this process. However, a role for estrogens in maintaining smooth muscle growth or function cannot be ruled out at this time (see below). These observations are consistent with the marked decreases in the ICPs (loss of erectile function), after cavernosal nerve stimulation in castrated animals treated with vehicle only or with estradiol.
To relate the observed effects of androgens on erectile tissues, we used estradiol, a nonandrogen steroid, which cannot be converted back to androgens in vivo. For this reason, this study did not attempt to address specifically the role of estrogen in erectile function. Nevertheless, several studies suggest that estradiol may have different effects in different animal species. In one study, no significant differences in behavior of animals treated with vehicle and estradiol were reported (35), suggesting that estradiol had no effect on maintaining sexual activity. In another study, estrogen failed to return penile responsiveness after castration in rats (36). Estradiol, however, was shown to be sufficient to activate copulatory behavior in male rats (37) and further restored sexual behavior in castrated male rats (38). Whether estrogens play a role in erectile function in the rabbit remains unknown.
The results of this study suggest that androgen deprivation results in
marked reduction of ICP, -adrenergic receptors, and smooth muscle
content. Androgen replacement restored these changes to control levels.
Androgen deprivation may contribute to impairment of the functional
veno-occlusive mechanism and reduced erectile function.
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Acknowledgments |
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Footnotes |
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Received September 1, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1-adrenergic receptor subtypes in human corpus
cavernosum tissue and in cultured trabecular smooth muscle cells.
Receptors 5:145–157
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