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From the * Department of Urology, St Joseph's
Health Care, Lawson Health Research Institute, and the
Department of Medical Biophysics, The
University of Western Ontario, London, Canada.
| Correspondence to: Dr Gerald Brock, Department of Urology, St Joseph's Health Care, London, Canada N6A 4V2 (e-mail: gebrock{at}sympatico.ca). |
| Received for publication February 4, 2004; accepted for publication April 21, 2004. |
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionConclusionReferences |
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-actin, nitrotyrosine, and endothelial cell
integrity. Urine nitrite and nitrate (NOx) concentration was
quantified, and electrolytes were tested by a serum biochemistry panel. A
significant decrease in ICP was recorded in the diabetic animals, with
improvement measured in the animals receiving PDE5 inhibitors either with or
without vitamin E; the controls had a pressure of 54.8 ± 5.3 cm
H2O, the vitamin E group had a pressure of 73.5 ± 6.6 cm
H2O, the sildenafil group had a pressure of 78.4 ± 10.77 cm
H2O, and the vitamin E plus sildenafil group had a pressure of 87.9
± 5.5 cm H2O (P < .05), compared with the normal cohorts
at 103.0 ± 4.8 cm H2O. Histoexaminations showed improved
nNOS, endothelial cell, and smooth muscle cell staining in the vitamin E plus
sildenafil group compared to the control animals. Urine NOx
increased significantly in all the diabetic groups but was blunted in the
vitamin E and vitamin E plus sildenafil groups. A significant increase in
positive staining for nitrotyrosine was observed in the vitamin E plus
sildenafil group. Vitamin E enhanced the therapeutic effect of the PDE5
inhibitor in this study, supporting the potential use of oxygen free radical
scavengers in salvaging erectile function in diabetic patients.
Key words: Impotence, vitamin E, sildenafil, nitric oxide, phosphodiesterase type 5
Nitric oxide (NO), derived from vascular endothelial and neural sources, plays an essential role in the early steps of the normal cascade of relaxation of the penile vasculature and cavernous smooth muscle, and its action is mediated through the cyclic guanosine monophosphate system (Burnett et al, 1992; Andersson and Wagner, 1995; Moreland et al, 2001). The presence of oxygen free radicals inactivates NO and reduces its physiologic impact. NO is a free radical and can react with other radicals, such as superoxide anions, to produce peroxynitrite and contributes to numerous pathological conditions such as atherosclerosis, ischemia, and generalized reperfusion injury (Cooke and Tsao, 1993; Beckman and Koppenol, 1996). Impaired NO activity and endothelial dysfunction have been described in diabetic animal models as well as in human volunteers (Saenz et al, 1989; Escrig et al, 2002). Additionally, increased auto-oxidation of glucose and oxidation of low-density lipoproteins have been described in diabetes, which may result in the overproduction of free radical species, leading to smooth muscle dysfunction (Tesfamariam and Cohen, 1992; Baynes and Thorpe, 1999). Direct inactivation of NO, largely by superoxide anions, which is believed to be present in higherthan-normal concentrations in diabetes, may also play a role in producing impaired cavernosal relaxation (Katusic, 1996).
Vitamin E (-tocopherol) is a lipid-soluble antioxidant and oxygen
free radical scavenger (Burton,
1994). It has been shown to enhance endothelial cell function,
trap oxygen free radicals (Willson,
1983), and inhibit monocyteendothelial adhesion and cytokine
release (Islam et al, 1998).
Additionally, some reports describe the inhibition of platelet adhesion and
aggregation by a protein kinase C–dependent mechanism
(Mabile et al, 1999; Saldeen et al, 1999). In vivo
as well as in vitro evidence demonstrates that vitamin E treatment can reverse
protein kinase C activation, which is believed to be responsible for a
component of glucose-induced vascular dysfunction in diabetes
(Kinlay et al, 1999;
Park et al, 1999). Vitamin E
has also been reported to improve NO-mediated arterial relaxation and to
maintain cell membrane integrity and protein stability
(Keegan et al, 1995; Karasu et al, 1997).
The potential positive clinical impact of combining vitamin E and sildenafil to treat diabetes-induced ED (ED-DM) has been demonstrated by our group (De Young et al, 2003) and others previously. This animal study was designed to gain insight into the role of oxidative stress and the effect of antioxidant therapy on treating ED. We selected a group of animals shortly after the induction of diabetes through faulty control of sugar levels, believing they had the greatest likelihood of reversibility (Soriano et al, 2001).
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionConclusionReferences |
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-tocopherol. The dose of 20 IU per animal per day of vitamin E was
selected following a literature review that demonstrated a therapeutic range
of 2–120 IU. Treatments were administered by using daily oral gavage for
3 weeks. All supplements were stopped at least 20 hours before evaluation of
erectile function. The final dose of sildenafil was administered 20 hours
preceding the electrostimulation experiments. Given that, at this time point,
greater than 5 half-lives of sildenafil expire in this animal model, changes
in blood pressure attributable to the vasoactive effects of sildenafil are not
expected; therefore, blood pressure was not measured.
Evaluation of Erectile Function
The lateral-prostatic space was dissected using a lower abdominal midline
incision. The major pelvic ganglion and cavernous nerve were identified,
isolated, and hooked with a stainless steel bipolar electrode. Through a
sagittal perineal incision, the penile crus was exposed. A 23-gauge needle
filled with heparin (250 IU/mL) and connected to Tygon tubing was inserted
into the penile crus. The microsurgery procedure was facilitated by the use of
a Zeiss SR operating stereomicroscope. Intracavernosal pressure (ICP) was
evoked with 0.2-millisecond pulses of 2 mA at 20 Hz for a 40-second duration
and recorded using LabVIEW 2 software (National Instruments, Austin, Tex).
Three electrostimulations were replicated at intervals of 10 minutes. The
animals were sacrificed using pentobarbital (200 mg/kg IP), after which penile
tissue was harvested for analysis. The animal experimental protocol was
approved by the University Council on Animal Care Animal Use Subcommittee,
University of Western Ontario, London, Canada.
Immunohistologic Analysis
Penile tissue was fixed in cold fresh 2% formaldehyde in 0.1 M phosphate
buffer (pH 7.4) for 4 hours; cryoprotected in 15% sucrose for 20 hours at
4°C; and then embedded in optical cutting compound (OCT) (Tissue-Tek,
Sakura, Torrance, Calif) and stored at -70°C. The OCT-embedded tissues
were cut into 5-µM sections and adhered to superfrost plus slides (Fisher
Scientific, Nepean, Canada). Immunostaining for nerves positive for neuronal
NO synthase (nNOS), endothelial cell marker, smooth muscle -actin, and
nitrotyrosine was performed. The sections were air dried for 10 minutes,
hydrated in phosphate-buffered saline (PBS) buffer, and then treated with 0.3%
hydrogen peroxide in methanol. After 2 rinses with water and PBS buffer, the
sections were blocked with 3% goat serum in PBS buffer for 3 hours at room
temperature. The sections were then incubated in blocking buffer at 4°C
overnight with primary mouse anti-nNOS, anti-CD31 (Transduction Lab BD
PharMingen, Mississauga, Canada), mouse anti–-actin (Roche
Diagnostics, Quebec, Canada), and rabbit anti-nitrotyrosine (Upstate New York,
NY) with dilutions of 1:100, 1:500, 1:300, and 1:50, respectively. The
sections were washed 3 times with PBS buffer and incubated with the secondary
antibody biotin conjugated goat anti-mouse immunoglobulin G (IgG; Sigma
Chemical Co, St Louis, Mo) at a dilution of 1:250 in PBS with 1% bovine serum
albumin for 2 hours at room temperature; for anti-nitrotyrosine, the sections
were incubated in a 1:100 dilution of a biotin conjugated goat anti-rabbit IgG
(Vector Laboratories, Burlingame, Calif). After 3 washings in PBS buffer, the
sections were incubated with an anti-biotin clone BN-34 peroxidase conjugate
IgG fraction (Sigma) for 2 hours. The antigen localization was visualized
using a diaminobenzidine peroxidase substrate (Sigma). The sections were
counterstained (except for nitrotyrosine-staining slides) with hematoxylin,
dehydrated through graded alcohols to xylene, and coverslipped.
Urine Nitrite and Nitrate Measurement
Urine samples were collected from rats before surgery and stored at
-20°C for nitrite and nitrate
,
or 
,
analysis. was analyzed
using an optimized NO chemiluminescence system
(Bateman et al, 2002), which
reduced to NO and detected
released NO by a chemiluminescent reaction with ozone using an NO analyzer
(NOA; Sievers, Boulder, Colo). In brief, thawed 10-µL urine samples were
injected into a purge vessel containing 0.05 M vanadium chloride in 1 M HCl
(Sigma) at 90°C. Liberated NO was transported to the NOA by helium carrier
gas. The system was calibrated against known concentrations of
NO3.
Serum Biochemistry Panel
The blood glucose level was measured by tail vein sampling at the time of
the erectile function assessment. Blood samples were collected after surgery,
and serum was separated and kept at -70°C until analyzed. All the tests
were performed by standard procedures used in our clinical biochemistry
laboratory.
Statistical Analysis
Values are expressed as the mean ± standard error of 5 experiments
for each group. Data were compared by 2-tailed t tests, =
.05.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionConclusionReferences |
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The peak ICP (PICP) during electrostimulation of the cavernous nerves is shown in Figure 1. It rose significantly in all treatment groups compared with the diabetic controls but did not reach the level measured among the normal animals. The group receiving vitamin E combined with sildenafil showed the greatest increase in PICP with the smallest intragroup variation among the 3 active treatment arms. The sildenafil-treated group showed a wide intragroup variation in PICP that is consistent with clinical experience among diabetic men with ED, in whom the efficacy of sildenafil is 50%–60%. The responder animals did not display improved sugar control or other evident biochemical parameters distinct from the nonresponders.
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The histologic examination was performed using a Zeiss microscope with a
computerized imaging system (Northern Eclipse, Empix, Canada). The reviewer
was blinded to the groups, and the counts were repeated for consistency. As
shown in Table 2, the sum of
NOS nerve fibers that stained positive was calculated as the total from the
dorsal nerve, an area adjacent to the dorsal vein, and 2 regions from the
right and left posterior corpus cavernosum in the field of view, at 400x
magnification. All treatment groups showed a significantly higher degree of
positive staining for nNOS than did the untreated diabetic animals (control).
The greatest increase relative to the diabetic control was observed among the
animals receiving a combination of vitamin E and sildenafil. The vitamin E,
sildenafil, and vitamin E plus sildenafil groups showed a degree of staining
that was 36%, 44%, and 110% higher than that of the diabetic controls. Penile
cavernosum sinusoidal endothelial cell staining was altered in all groups to
varying degrees compared with normal animals. The proportion of endothelial
cell marker CD31 staining was greatest in the normal group, and the treatment
groups were ordered as follows: vitamin E plus sildenafil > vitamin E >
sildenafil > diabetic control, measured as 53%, 38%, 32%, and 25%,
respectively, of normal levels, indicating impaired endothelial function
(Table 2). A significant
recovery in the positive staining for penile smooth muscle -actin was
measured in the vitamin E plus sildenafil group compared with the controls and
the vitamin E group (Table 2).
A significant increase in positive staining for nitrotyrosine was measured in
the controls (P < .001), the vitamin E group (P <
.05), and the sildenafil group (P < .001) when compared to that of
the normal animals (Table
2).
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Figure 2 presents representative cross sections of penile tissue showing immunologic staining with the endothelial cell marker CD31 (upper panel) and nitrotyrosine (lower panel). The sinusoidal endothelial cell staining of the vitamin E plus sildenafil group demonstrated an increase in the number and intensity of endothelial cells staining for CD31 and a decrease in the intensity of staining for nitrotyrosine relative to diabetic-positive controls.
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The measured concentrations of urine nitrite and nitrate (NOx) (Figure 3) are 24.8 ± 3.8 µM in the normal group and show a 3.3-, 2.4-, 3.1-, and 2-fold increase in the control, vitamin E, sildenafil, and vitamin E plus sildenafil groups, respectively. This represented a significant increase in all the diabetic groups. The animals receiving vitamin E and vitamin E plus sildenafil demonstrated smaller rises.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionConclusionReferences |
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-actin, and nitrotyrosine among
animals receiving the combined regime.
The protocol used in this study, in which the treatment was started just 2
days after diabetes was induced and then continued for 3 weeks, is clearly
artificial and may not lend itself to direct human comparison, where diabetes
is often detected and treated months or years after onset. We chose this early
time point and faulty level of diabetic control to evaluate penile function
without extensive end organ damage, believing these animals would be the most
likely to show a reversible effect of therapy
(Soriano et al, 2001). There
is supporting evidence from the literature concerning the beneficial role of
vitamin E in the aorta, lung, and other organs
(Pathania et al, 1998; Lang et al, 2000). Vitamin E
appears to be the first line of defense against the peroxidation of
polyunsaturated fatty acids that are contained in cellular and subcellular
membrane phospholipids, because it binds to peroxyl free radicals and forms
stable molecules (Mayes, 2000;
van Haaften et al, 2003).
Also, vitamin E binds to a variety of active oxidant species such as singlet
oxygen and superoxide free radicals
(Mayes, 2000). NO can react
with superoxide anions 
,
forming the toxic oxidizing agent peroxynitrite (ONOO-).
Peroxynitrite induces nitration of tyrosine residues, leading to changes in
protein structure and function and alterations in signaling pathways
(Ceriello et al, 2001). In
this study, we measured an increase in the urine levels of NOx
metabolites (nitrite and nitrate), which indicate the production of NO
(Tanaka et al, 1997). An
increased peroxynitrite formation and an elevated presence of nitrotyrosine in
protein have previously been reported in diabetic patients
(Ceriello et al, 2001;
Hoeldtke et al, 2003). Positive tissue staining of nitrotyrosine has been used as an indirect
indicator of oxidant stress (Ceriello et
al, 2002; Fries et al,
2003). In this study, the diabetic animals demonstrated increased
levels of urine NOx concentration as well as increased amounts of
nitrotyrosine staining in the penile tissue when compared with the normal
animals. This supports the belief that oxidative stress is an important factor
contributing to the pathological changes seen in diabetic-associated ED.
Furthermore, it provides supporting experimental evidence for our findings,
indicating that antioxidant treatment in association with PDE5 inhibition is a
useful salvage treatment approach.
This report supports the theory that ED-DM is a multifaceted condition affecting neural, muscular, vascular, and metabolic functions. The vitamin E–treated group showed improved endothelial cell staining, with the vitamin E plus sildenafil group most closely resembling the normal animals.
In summary, vitamin E was shown to protect penile tissue from injury and to preserve nerve and endothelial function, as demonstrated by nNOS and endothelial cell staining patterns and a measured rise in intracorporal pressure. There is support in the literature for the potential neurotrophic role of vitamin E in ischemic animal models (Gonzalez-Perez et al, 2002). Additionally, vitamin E has been shown to reduce oxidative stress in congestive heart failure (Shite et al, 2001); the mechanism is not yet known but may have contributed, in part, to the improved intracorporal pressure measured in this report. Finally, recent evidence strongly supports the potential benefit of vitamin E within the diabetic population. As described by Evans et al (2002), hyperglycemia within the diabetic population may lead to the activation of kinases and stress-activated protein kinases responsible for many of the pathological changes observed in this population.
As such, the utility of antioxidants should be considered an alternative new strategy for treatment. The addition of a PDE5 inhibitor to the vitamin E cocktail may further enhance endothelial function. Recent evidence demonstrating a protective role for PDE inhibitors in patients with endothelial dysfunction has been published (Halcox et al, 2002).
To our knowledge, this report is the first to record the potential interaction of oxygen free radical scavenger therapy with daily PDE5 inhibitors in an animal model of diabetes. Future work defining the dose, timing, and optimal parameter of these agents may provide an enhanced erectile response for this challenging-to-treat population.
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