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Department of Urology, University of California School of Medicine, Harbor-UCLA Medical Center, Torrance, California 90509
Address all correspondence and requests for reprints to: Nestor Gonzalez-Cadavid, Ph.D., Harbor-UCLA Medical Center, Division of Urology, Department of Surgery, Building F-6, 1000 West Carson Street, Torrance, California 90509.
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As penile erection is nitric oxide (NO) dependent (10, 11, 12, 13), it is not surprising that castration has been shown to decrease the activity of nitric oxide synthase (NOS), the enzyme that catalyzes the formation of NO during the conversion of L-arginine into L-citrulline, mainly in the penile cytosol. Only the neuronal isoform of the enzyme (nNOS) has been conclusively identified histochemically in the penis (at nerve terminals) (14, 15), although the endothelial isoform (eNOS) is expressed in the penile cytosol, as shown by Western blots (9, 16). In addition, the inducible isoform of the enzyme (iNOS) can be induced in rat penile smooth muscle cells in culture (17) and in penile corpora cavernosa (18). Recent studies have shown that the administration of flutamide to castrated rats decreases NOS activity, but not nNOS content, implying that the direct control of NOS enzyme activity may be responsible for the added diminutive effect of complete androgen ablation on erectile function (9).
As far as we are aware, there are only a few articles regarding the influence of adrenalectomy and adrenal replacement on mating behavior in laboratory animals (19, 20), and they seem to rule out the role of adrenal hormones in maintaining this behavior in male and female rats after castration. However, adrenalectomy affects a complex sexual pattern such as mammalian monogamy by inhibiting partner preference formation in male prairie voles and facilitating it the female animal. Glucocorticoids have differential effects on this process according to sex (21). In humans, there are some unpublished anecdotal reports on relatively potent men who had previously undergone castration as treatment for metastatic prostate cancer becoming completely impotent after bilateral adrenalectomies for advancing disease.
Regardless of the results, behavioral studies are not directly applicable to the mechanism of the penile erectile response, derived from the relaxation of the corpora cavernosal smooth muscle triggered by neural stimulation (22, 23). There are no reports on the role of adrenalectomy or of adrenal substances, such as dehydroepiandrosterone (DHEA), aldosterone, or hydrocortisone, on erectile response or NOS in the penis in animal models. It may be assumed that if the substance(s) responsible for the remainder of erectile function after castration is of adrenal origin, then removal of the adrenal gland in a castrate animal will ablate the erectile response. In addition, it is possible that this could occur through a NOS-mediated pathway, although no evidence has been reported on the corticosteroid or adrenal control of NOS in any organ other than the well known inhibition of iNOS expression by glucocorticoids (24, 25). However, iNOS does not seem to be involved in physiological erection (18). nNOS has been identified in the adrenal gland itself (26, 27), but no data are available regarding the role of corticoids on its expression or activity.
The purpose of this work was to determine whether the adrenal gland plays a role in erectile function and in the maintenance of penile NOS content and/or activity in the rat model. In addition, if the adrenal gland does participate in the maintenance of the NO-mediated erectile response in the rat, this study attempts to determine what adrenal compounds are the most important in these processes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animals
Adult 5-month-old male Fisher 344 rats were purchased from
Harlan Sprague-Dawley (San Diego, CA) and Charles River Laboratories
(Wilmington, MA). Animals were maintained under controlled lighting and
were treated according to NIH regulations. Adrenalectomy and castration
were performed under thiopental-ketamine anesthesia (50 and 35 mg/kg,
respectively, ip). Rats were divided into the following experimental
groups (n = 5–7): 1) intact controls, 2) castrated, 3)
adrenalectomized using bilateral dorsal lumbotomy incision, 4)
castrated/adrenalectomized, 5) castrated/adrenalectomized with daily sc
injections of aldosterone (1.25 mg/kg) and hydrocortisone (12 mg/kg) in
saline, 6) castrated/adrenalectomized with DHT (1.2-cm SILASTIC brand
tubing pellet), 7) castrated/adrenalectomized with DHEA (2-cm tubing),
8) castrated/adrenalectomized with aldosterone alone (1.25 mg/kg), and
9) castrated/adrenalectomized with hydrocortisone alone (12 mg/kg).
Preliminary experiments showed that daily sc injection of saline or
implantation of empty SILASTIC brand tubing did not affect the erectile
response or NOS content in the penis, and therefore, groups 1–4 were
left untreated. The implantation of SILASTIC brand tubing (od, 3.17 mm;
id, 1.57 mm) was carried out under anesthesia. All rats subjected to
adrenalectomy were given normal saline (0.9% NaCl) in their drinking
water (19). Treatments were terminated after 7 days of therapy, unless
specified. Some groups of rats were selected for performing NOS
determinations in the penile cytosol from rats not submitted to EFS. In
those cases (intact, castrated, adrenalectomized, and
castrated/adrenalectomized), six new rats per group were treated as
described above.
Measurement of the erectile response
Rats were anesthetized as described above, and the erectile
response was measured essentially as previously described (1, 2, 9, 16, 18). Preliminary experiments indicated that control rats from both
suppliers used in this study did not show any significant difference in
their erectile response, but whenever possible treated rats were
matched with their respective control animals from the same supplier.
Briefly, the cavernosal nerve was surgically exposed and stimulated
with a square pulse stimulator connected to a platinum bipolar
electrode positioned on the nerve. Using a 25-gauge butterfly needle
inserted into the corpora cavernosa, the intracavernosal pressure was
recorded with a pressure transducer integrated into a computerized data
acquisition system that was calibrated with a manometer to express the
response in millimeters of mercury. The animals were reinjected every
45 min with 35 mg/kg ketamine for the duration of the experiment
(
1–1.5 h).
Each rat was submitted to EFS at a frequency of 15 Hz for pulses of 30 sec, separated by no less than 5-min intervals, initially at 10 V and then at 2.5, 5, and 10 V, in this order, for the voltage response curve. The response at 10 volts was designated the maximal intracavernosal pressure (MIP). The mean arterial pressure (MAP) was measured during the experiment by intrafemoral artery cannulation and recorded as described above. The penises (including the bulb) and in some animals the cerebellum were surgically removed. The penile gland and skin were excised, and the organs were weighed and stored under liquid nitrogen for the Western blot studies.
Measurement of NOS activity
NOS activity in tissue homogenates was determined in the penis
from animals not subjected to EFS, as previously described (1, 2, 9, 16, 18). Briefly, rats were anesthetized with thiopental, and the
penile shaft and bulb (excluding skin and glans) were excised and
stored at -80 C. Each penis was weighed, and homogenates were prepared
in 6 vol cold medium containing 0.32 M sucrose, 20
mM HEPES (pH 7.2), 0.5 mM EDTA, 1
mM dithiothreitol, and protease inhibitors (3
µM leupeptin, 1 µM pepstatin A, and 1
mM phenylmethylsulfonylfluoride), using the Polytron
homogenizer (Brinkmann, Lucerne, Switzerland). The postmitochondrial
(cytosol) and particulate fractions were separated by centrifugation at
12,500 x g for 60 min. The cytosol fraction was passed
through Dowex AG50WX-8 (Na+) resin to remove endogenous
arginine, and 50-µl aliquots were incubated in triplicate for 45 min
at 37 C as indicated in the presence of 2 µCi/ml resin-purified
L-[3H]arginine, 2 mM NADPH, 0.45
mM Ca2+, and 100 µM
L-arginine, with or without L-NAME (2 mM).
After eliminating the residual L-[3H]arginine
through the resin, [3H]citrulline was counted in the
trichloroacetic acid ether-extracted supernatant. Determinations were
performed in triplicate. All values were corrected by the radioactivity
eluted in time zero incubations and expressed per mg soluble protein or
per g original tissue.
Measurement of NOS levels by Western blots
Equal amounts of protein (40–80 µg) of the penile cytosol
from rats submitted to EFS were run on 7.5% polyacrylamide-SDS gels,
and the proteins were transferred to a nitrocellulose membrane for
16 h at 30 V, followed by 1 h at 100 V (2, 9, 16, 28). The
transfer efficiency was controlled by gel staining with Coomassie blue.
Prestained protein markers (48–199 kDa) were always run in each gel.
Immunodetection on the Western blot was carried out with an affinity
chromatography-purified primary antibody consisting of the mouse
monoclonal antibody against a 22.3-kDa fragment of the carboxy-terminus
of human cerebellum nNOS (1 h, 1:500 dilution). The secondary antibody
was an antimouse IgG (rabbit) linked to horseradish peroxidase, and the
incubation (1:10,000 dilution) was carried out for 1 h. The
reactive bands were detected with a luminol-based kit. The cytosol from
rat cerebellum was always used as a positive control. In certain gels,
negative controls were also included, consisting of the cytosol from
rat penile smooth muscle cells that had been induced with bacterial
lypolysaccharide and interferon-
(17, 18), and a commercial human
endothelial cell lysate.
In the case of eNOS, the primary antibody consisted of a mouse monoclonal against a 20.4-kDa protein fragment containing amino acids 1030–1209 (carboxy-terminus) of human eNOS (1:500). The secondary antibody and the detection procedure (9, 16) were performed as described above for the monoclonal nNOS. The cytosol fraction was used for most of the analysis, and in certain cases, the particulate fraction was also submitted to Western blot. For that purpose, the 12,500 x g/60 min pellets were resuspended in a buffer consisting of 50 mM Tris-HCl (pH 7.2), 0.1 mM EDTA, 0.1 mM EGTA, 12 mM 2-mercaptoethanol, and 10% glycerol with the protease inhibitors described above. The suspensions were stored at -70 C, and when needed, they were thawed, the detergent CHAPS was added to 20 mM, and the mixtures were thoroughly resuspended. The extracts were centrifuged at 12,500 x g for 60 min, and the supernatant was collected and designated the particulate extract. Samples were run on PAGE as described above (50 µg protein) and submitted to Western blot analysis. A human endothelial lysate (4 µg protein) was used as a control.
The quantitative determination of band intensities was carried out by submitting each luminol-reacted membrane to several x-ray exposure times and selecting the one(s) falling within the film response range. The films were then scanned, and each band density was evaluated by densitometry with an adequate program.
Statistical analysis
Experimental values were expressed as the mean ±
SEM for the number of separate animals indicated in each
case. The normality distributions of the data were established using
the Wilk-Shapiro normality test. One-way ANOVA was used to determine
whether any differences were present between the various study groups.
As the specific goals of the study called for planned comparisons
between certain control groups and various study groups,
post-hoc testing between groups was performed using the
Fisher’s least significant difference test. The difference between two
groups was considered significant if it was greater than the least
significant difference statistics corresponding to an 
error of
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows the erectile response
to EFS (as measured by MIP; top panel) in adult rats
submitted to treatments intended to modify the function of the adrenal
axis. The adrenalectomized rats appeared alert, active, and in fairly
good health status throughout the course of the experiment, and no
significant changes in body weight were noticed compared with the
nonadrenalectomized control animals. The mean MIP in the intact control
group was 84 mm Hg. Castration alone decreased MIP by nearly 50%, as
expected. The residual erectile response in the castrated animals was
markedly sensitive to adrenalectomy, as adrenal ablation in
orchidectomized rats caused a significant reduction in the MIP (10 mm)
compared with those in both the intact and castrated groups.
Adrenalectomy was sufficient by itself to decrease the EFS-elicited
erection up to or below castrate levels.
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). Similar effects were obtained with each drug
given separately at the same doses and for identical period of time
(n = 5; not shown; see below). Testicular androgen replacement
therapy with DHT restored some, but not all, erectile function in these
animals. Administration of the adrenal androgen precursor, DHEA, had no
effect on the erectile response to EFS of the
adrenalectomized/castrated rats.
In all treatments only the MIP seemed to be affected, since no
significant variations were noticed in the amplitude and latency of the
response. Because some of the MIP changes could simply result from
alteration of the systemic blood pressure by the respective treatment,
MAP values were simultaneously determined. Figure 1 (middle
panel) shows that although adrenalectomy per se causes
only slight and nonsignificant hypotension, the combination of
adrenalectomy and castration leads to a rather severe hypotensive
effect. Therefore, the MIP/MAP ratios (Fig. 1, bottom) were
calculated to correct for the influence of systemic blood pressure on
the erectile response (4, 5).
The effects seen with the MIP appear not to be dependent on the drop in MAP, and the differences previously observed remain significant when the results are expressed as MIP/MAP ratios. This value in the adrenalectomized group (0.37), compared with that in the intact group (0.75), was reduced to values found in the castrated group (0.40). The most significant reduction in MIP/MAP was seen in the adrenalectomized/castrated group (0.16). The binary adrenal replacement therapy (aldosterone and hydrocortisone) partially reversed the impairment of the erectile response induced by adrenalectomy and castration (0.63). The same occurred with each corticosteroid given separately (not shown), where the mean ± SEM for the MIP/MAP values were 0.67 ± 0.06 for the animals receiving aldosterone and 0.56 ± 0.05 for rats treated with hydrocortisone.
Effects of manipulating the adrenal axis on the content and
activity of penile NOS
nNOS content was determined based on a quantitative densitometric
estimation of the 155- to 160-kDa band immunodetected by Western blot.
Figure 2, top panel, shows a
typical autoradiographic image of one series of penile cytosol
fractions immunoblotted with a monoclonal antibody against the human
cerebellum nNOS. An intense signal at the expected size plus a fainter
lower band is observed with the positive control, the soluble fraction
from the rat cerebellum. The lower band is considered to be either the
product of cross-reactivity with a homologous protein or most likely an
alternate splicing nNOS species (2, 9, 16, 28). The specific antibody
was characterized in those previous publications. Visual inspection of
the autoradiographies was based, therefore, on the top 155- to 160-kDa
band, which corresponds to the full-length nNOS variant expressed in
the penis that differs from the cerebellar nNOS and is designated PnNOS
(31).
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As eNOS is present in the penile corpora cavernosa, most likely in the
endothelium of sinusoids and blood vessels, it was important to
determine whether adrenalectomy affects its content in both the cytosol
and particulate fractions. The group experiencing a significant
reduction in nNOS content, adrenalectomized and castrated rats, was
chosen for analysis in comparison to intact and castrated animals and
to adrenalectomized and castrated rats receiving DHT. Figure 3 (top) presents the Western
blots immunoreacted with an antibody recognizing a single 140-kDa eNOS
band (Fig. 3, top). As in the case of the nNOS assay, the
specificity of the eNOS antibody has been characterized previously (2, 9, 16). The densitometric analysis (Fig. 3, bottom) shows
that the only significant change in comparison to intact rats was
observed in the penile cytosol from castrated rats, where eNOS
substantially increased. However, in the adrenalectomized/castrated
rats, eNOS levels remained normal compared with those in intact
animals, although in the soluble fraction they were decreased compared
to those in castrated rats.
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(left) shows that, as
expected (1, 2, 9), NOS activity in the castrated rats was reduced by
nearly 50%, and a similar situation occurred in the adrenalectomized
animals. The fraction of NOS activity that was sensitive to 2
mM L-NAME (Fig. 4, right) in the
adrenalectomized rats was similar to that in intact animals (80%),
thus indicating that the reduction truly involved penile NOS.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The decrease in MIP caused by adrenalectomy of castrated rats was not due to the reduction observed in MAP, because when this factor was corrected by expressing the erectile response in terms of the MIP/MAP ratio, this value was still significantly reduced in the adrenalectomized/castrated group compared with that in the castrated only rats. The same conclusion applies to adrenalectomy performed on noncastrated rats. The correction of MIP values by the corresponding MAP values does not rule out the possibility that a drastic decrease in MAP could drop below a certain threshold of blood pressure that hypothetically would be required to trigger penile erection. Although this alternative explanation has not been tested, the good general health status and normal activity of the adrenalectomized/castrated rats would suggest that at this level of hypotension the MIP/MAP ratio continues to be a fair indication of the integrity of the erectile mechanism.
Because of the complete blockade of erectile response induced by total androgen ablation (9), it is clear that there is no androgen-independent component in the erectile response of the rat. However, as adrenalectomy per se is sufficient to remove all circulating corticoids but still leaves about 40% of the erectile response to EFS, it may be concluded that the corticoid dependence of erection is only partial. Therefore, it is reasonable to assume that both testosterone and DHT, on one side, and the adrenal factors, on the other side, cooperate and are necessary to sustain the erectile mechanism, but androgens are indispensable, whereas corticosteroids are less important.
It is important to emphasize that the EFS of the cavernosal nerve measures the integrity of the main neural efferent pathway in penile erection that conveys the postganglionic neurons destined for the penis and provides the majority of autonomic inputs to this organ (22, 23, 32). This procedure recruits both sympathetic and parasympathetic fibers, and the results may not strictly mimic the physiological stimulation which, in addition, involves auxiliary nerve circuits, such as the sensory fibers of the dorsal nerve of the penis or the somatic pudendal nerve controlling the ischiocavernosus and bulbospongiosus muscles. However, the fact that reflexive erections conducted by the dorsal nerve may survive some types of spinal cord lesions does not invalidate the preponderant role of the cavernosal nerve in physiological erections and the clinical evidence showing that its surgical damage during radical prostatectomy results in impotence. A similar effect has been shown to occur in rats, where transection of the cavernosal nerve abolishes erections of penile body, even if erections of the penile glans (rich in dorsal nerve terminals) are not completely eliminated (33). Therefore, despite the caveats discussed above, our results based on the measurement of the erectile response to EFS of the cavernosal nerve evaluate the function of a fundamental part of the erectile mechanism that when impaired is likely to affect physiological erections in the rat.
Another feature of EFS determinations is that they are relatively context independent, although they measure the effects on the erectile mechanism of long term modifications of the hormonal milieu. This implies that the strong stimulation applied may obliterate hormonal influences that are transiently active during behavioral copulatory studies, spontaneous erections, and penile reflexes in nonanesthetized laboratory animals, mainly the rat (33). However, this is, in fact a requirement for studying the penile efferent nerve/smooth muscle response independent from libido and other central nervous system effects that operate in physiological erections. The cavernosal EFS procedure is particularly suitable for investigating the direct effects of hormonal deprivation or replacement on penile tissue, leading to changes that influence the erectile mechanism, with the important additional caveat that the complex integration of afferent and efferent neural circuits and hormonal control may vary between species and even between animal strains.
The nature of the adrenal substances that are involved in the maintenance of erection is unknown. The fact that both aldosterone and hydrocortisone, either in combination or alone, were able to prevent the further reduction of erectile response in castrated rats caused by adrenalectomy suggests that mineralocorticoid and glucocorticoid receptors may affect the same erection-related target. The slight stimulation of the erectile response above the castration level exerted by corticoids probably does not have a physiological meaning. The preventive effects on erection by either aldosterone or hydrocortisone given to adrenalectomized/castrated rats imply that androgens produced at the adrenal level are probably not major contributors to the maintenance of the erectile mechanism. However, they may partially substitute for gonadal androgens in animals submitted to castration only. In any case, whether the corticoid effects are directly at the corpora cavernosa or through a different type of mechanism operating at a central level remains to be determined. No corticosteroid receptors have been reported in the penis.
It is interesting that DHT prevents the erectile failure seen in adrenalectomized and castrated rats essentially to the same extent as corticosteroids, but does not normalize it completely. This agrees with the dual dependence of the rat erectile mechanism on both the adrenal and gonads. In contrast, the major androgen precursor produced by the adrenal cortex, DHEA (34, 35), does not have any restorative effect on the erectile response in adrenalectomized/castrated animals. This compound is only a weak androgen by itself but is putatively involved in conditions associated with aging, immune suppression, and major diseases (34, 35). In addition, some researchers have claimed that DHEA enhances the feeling of well-being, but not libido, in older men (34). The complete inactivity of DHEA on the maintenance of the erectile mechanism supports the view that corticoids are the adrenal substances involved in this process.
The fact that a mineralocorticoid, aldosterone, contributes to the erectile response suggests that at the corpora cavernosa level, this compound may act via its effect on K+ excretion involving K+ channels or on Ca2+ fluxes (36, 37, 38) in addition to any possible control of nNOS content (see below). nNOS and eNOS enzyme activities are regulated by Ca2+ (39). Aldosterone may conceivably act as a K+ channel opener, relaxing the corpora cavernosal tissue, similar to what has been described with several agents in this group (40, 41), or alternatively, it may modulate the levels of K+ channels. As such, or in a K+-independent route, aldosterone may then decrease intracellular Ca2+, promoting smooth muscle relaxation. In the case of hydrocortisone, its prevention of erectile failure may be related to the same mechanism, by mimicking the action of mineralocorticoids because of a high dose effect. Although angiotensin II and its receptor have recently been detected in the penis and assumed to play a role in the maintenance of the contractile tone of the cavernosal smooth muscle (42, 43), it is unlikely that corticosteroids act via an angiotensin II pathway. In fact, corticosteroids up-regulate angiotensin II levels and angiotensin II receptor, thus potentiating angiotensin II action in vascular tissue (44). If this process occurs in the penis, the expected effects would counteract the observed restoration of corpora cavernosal relaxation by corticoids.
The effects on penile NOS exerted by adrenalectomy in castrated rats coincide with those of castration alone in terms of the decrease in cytosolic NOS enzyme activity, which represents most of the penile NOS (10, 12), and in the fact that the penile eNOS content remains unaffected after 1 week. However, adrenalectomy combined with castration significantly reduced penile nNOS content, in contrast to what was found with castration or total ablation of androgen binding in the penis (2, 9), where NOS activity appears to be inhibited in the presence of constant NOS levels. As in previously documented cases in rat models, spontaneous diabetes, and chronic smoking, the cause of this reduction in penile nNOS content is unknown. It may be related to a loss of nerve terminals or a true NOS down-regulation (45, 46).
Regardless of the mechanism, as in previous cases, e.g. diabetes and complete androgen ablation, the moderate reduction of penile NOS activity in adrenalectomized/castrated rats does not conform to the observed virtual obliteration of erectile function. This discrepancy extends to the fact that adrenalectomy of castrated rats does not seem to reduce penile NOS any further despite the fact that it does potentiate the erectile failure compared with that in castrated only rats. Therefore, the role of corticoids in the maintenance of cavernosal relaxation may exceed a mere effect on penile NOS and may involve other types of effects, such as those discussed above on K+ efflux, and induce a further impairment of the erectile response.
It is difficult to assess the relevance of these findings to human penile erection. The first problem is obviously the lack of a clinical correlate for the complete ablation of adrenal hormones occurring in the rat upon adrenalectomy. In the rat, it is possible to maintain the animal alive for weeks or months, particularly in younger animals. Obviously, men undergoing bilateral adrenal removal require immediate replacement treatment with corticosteroids. There are no reports in the literature of Addison’s disease presenting with isolated erectile dysfunction. In the rare condition of adrenal myeloneuropathy (47), there is impotence associated with a number of other problems, including diffuse focal demyelination causing spasticity and reduced cerebral function. In these patients, however, impotence seems more likely to be due to peripheral neuropathy or hypothyroidism, although the associated Addison’s disease may play a role in the erectile dysfunction. There is a single case report of a man presenting with impotence associated with Cushing’s disease in congenital adrenal hyperplasia (48). It is assumed that the erectile dysfunction was caused by the increased levels of estrogens inducing a number of feminizing features in addition to sexual dysfunction of otherwise normal appearing genitalia. We have examined the effect of estradiol in rats and found it to have an inhibitory effect on the erectile response to EFS (9). In conclusion, our data in the rat model suggest that corticosteroids and possibly other substances of adrenal origin play a significant role in the maintenance of the erectile mechanism and penile nNOS, but the clinical significance of these results remains to be investigated.
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Footnotes |
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Received January 24, 1997.
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