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From the Departments of Urology and Pharmacology, Pulmonary and Critical Care Medicine, Tulane Health Sciences Center, New Orleans, Louisiana.
| Correspondence to: Dr Wayne J. G. Hellstrom, Professor of Urology, Chief, Section of Andrology, Tulane University, Health Sciences Center, Department of Urology, 1430 Tulane Ave, SL-42, New Orleans, LA 70112 (e-mail: whellst{at}tulane.edu). |
| Received for publication August 27, 2008; accepted for publication January 21, 2009. |
The aim of this study was to evaluate erectile function in monocrotaline
(MCT)–treated rats with pulmonary hypertension (PH). Forty rats were
divided into control (n = 20) and MCT-treated (n = 20) groups. Rats were
treated with MCT (60 mg/kg subcutaneously) for 3 weeks to induce PH. Mean
pulmonary arterial pressure (mPAP), medial hypertrophy index (percentage of
wall thickness of pulmonary artery), and right ventricular hypertrophy (ratio
of right ventricle [RV] to left ventricle + septum weight) were evaluated. In
vivo erectile responses were assessed by measurement of intracavernosal
pressure (ICP)/mean arterial pressure and total ICP (area under the curve). In
vitro organ bath studies with corpus cavernosum smooth muscle strips were
performed under both normoxic (95% O2/5% CO2) and
hypoxic (by changing gas mixture to 95% N2/5% CO2)
conditions. Erectile tissue was processed for immunohistochemistry. The
MCT-treated group was associated with an increase in mPAP, medial hypertrophy
index, and RV hypertrophy. MCT-induced PH rats had significantly reduced
erectile responses compared with controls. Nitrergic, endothelium-dependent
relaxations, as well as
-adrenergic contractile responses were
significantly reduced in the corpus cavernosum of MCT rats. The functional
responses during prolonged periods of hypoxia were similar to those observed
in MCT-treated tissues. PH rats showed enhanced inducible nitric oxide
synthase (NOS) protein localization, but endothelial NOS and neuronal NOS were
unchanged. These results suggest changes in cavernosal physiology are caused
by MCT acting on the penile tissues and the systemic vasculature.
Key words: Pulmonary hypertension, erectile dysfunction, electrical stimulation, hypoxia
PH is a fatal disease characterized by increased pulmonary arterial pressure, right ventricular failure, pulmonary vascular remodeling, and death (Fishman, 1976; Hinderliter et al, 1997; Nishimura et al, 2001). Currently, there is no evidence showing a relationship between ED and PH. Moreover, mild to moderate PH is a common complication of chronic obstructive pulmonary disease (COPD; Chaouat et al, 2008). COPD is a respiratory disorder resulting in many extrapulmonary consequences and has been associated with sexual dysfunction and ED. Progression of chronic respiratory failure results in further sexual insufficiency (Ibanez et al, 2001). In a national survey of France, the prevalence of sexual dysfunction was approximately 40% in patients with chronic respiratory disorders (Alexandre et al, 2004). Furthermore, sildenafil is a selective inhibitor of the phosphodiesterase type-5 (PDE-5) enzyme that has been approved for treatment of PH. PDE-5 inhibition with sildenafil improves by balancing pulmonary and systemic vasodilation. Numerous studies have affirmed the relationship between ED and cardiovascular disease. The monocrotaline (MCT)–induced model with PH, cardiac hypertrophy, right ventricular failure, and endothelial dysfunction may also be associated with ED.
MCT is a plant-derived toxin that causes PH, endothelial cell injury and, subsequently, a mononuclear infiltration into the perivascular regions of arterioles and muscular arteries (Seyfarth et al, 2000; Hessel et al, 2006). The ventricles of MCT-treated rats exhibit severe pressure overload–induced hypertrophy, with some animals developing heart failure (Seyfarth et al, 2000). However, the effect of MCT treatment on penile corpus cavernosum smooth muscle (CCSM) function has not been established.
Elevation of pulmonary arterial pressure and right ventricle (RV) hypertrophy confirmed that our animals had PH. Additionally, the PAP/RV data suggest that MCT affects the right heart. Right heart catherization measurements are the gold standard for a diagnosis of PH (Baber et al, 2007). The aim of the present study was to determine the effects of MCT treatment on erectile function in the rat. It is our hypothesis that MCT-induced endothelial dysfunction is associated with impaired erectile responses.
Materials and Methods
Development of MCT-Induced PH Rat Model
Forty male Sprague-Dawley rats weighing 250 to 300 g were divided into
control (n = 20) and MCT-treated (n = 20) rats. MCT was dissolved in 1 N HCl,
neutralized with 0.5 N NaOH, and diluted with phosphate-buffered saline (PBS).
MCT solution was administered as a single subcutaneous injection in a dose of
60 mg/kg (Dupuis et al,
2000).
Hemodynamic Measurements
The American Physiological Society's principles for animal research were
followed. Rats were anesthetized with thiopentobarbital (50 mg/kg
intraperitoneally) and placed on a thermoregulated surgical table. The trachea
was cannulated (PE-40 tubing) to maintain a patent airway, and the animals
breathed room air enriched with 95% O2/5% CO2. A femoral
artery was cannulated (PE-50 tubing) for the measurement of systemic arterial
pressure.
Technique for Measuring Pulmonary Arterial Pressure
The anesthetized rats were strapped in a supine position to a fluoroscopic
table. A specially designed 3F single-lumen catheter was passed into the main
pulmonary artery from the right jugular vein under fluoroscopic guidance.
Pressure in the main pulmonary artery was measured with a pressure transducer
(Schneider/Namic, Glenn Falls, New York), and mean pulmonary arterial pressure
(mPAP) was derived electronically and recorded on a Grass Model 7 Polygraph
(Grass Instrument Co, Quincy, Massachusetts). For the determination of
pulmonary arterial wedge pressure, the catheter was advanced to the left or
right pulmonary artery and wedged with continuous measurement of the pressure
waveform (Baber et al,
2007).
Gravimetric Measurement
For assessment of RV hypertrophy, hearts were removed and dissected into 2
parts: RV free wall, and left ventricle (LV) with interventricular septum (S).
Each was weighed separately; the RV/(LV + S) weight ratio was calculated as
the gravimetric index of right ventricular hypertrophy. After death, the heart
was immediately dissected, and the RV and the LV plus S were weighed.
Percentage of wall thickness (% WT) of pulmonary artery was calculated
(Spees et al, 2008).
Morphometric Measurement of Pulmonary Artery
Elastin-trichrome–stained sections from control and MCT rats were
masked and analyzed by observers blinded to the treatments rendered. Pulmonary
artery diameter was measured using an Olympus microscope (Olympus Corp, Tokyo,
Japan) with a digital camera interfacing with a PC (Dell, Round Rock, Texas)
using ImagePro software (Image Pro, Bethesda, Maryland). Ten arteries with an
external diameter (D) of 50 to 200 µm per animal were selected for
measurement. The WT and D of selected pulmonary arteries were measured and
then calculated as % WT by the formula % WT = [2WT]/D x 100. The
resulting average measurements from individual animals were pooled with all
other animals in the same group to provide the mean % WT as an index of medial
hypertrophy.
In Vivo Evaluation of Erectile Function
For intracavernosal pressure (ICP) monitoring, the rats were anesthetized
with sodium pentobarbital (50 mg/kg intraperitoneally), the trachea was
exposed and cannulated (PE-240 tubing) to maintain the airway, and the carotid
artery was cannulated (PE-50 tubing) to measure mean arterial pressure (MAP)
via a transducer (Statham, Oxnard, California) attached to a data acquisition
system (MP 100 System; Biopac, Santa Barbara, CA; Bivalacqua et al,
2000,
2001). A 25-G needle filled
with 250 U/mL heparin and connected to polyethylene tubing was inserted into
the right crura of the penis and connected to a pressure transducer for
continuous measurement of ICP.
The rat bladder, prostate, and perivesical space were initially exposed through a midline abdominal incision. Using cotton swabs, we dissected and identified the major pelvic ganglion and cavernous nerves. The internal pudendal artery, the distal branch to the prostate, bladder neck, and cavernosal bodies were all identified. The cavernosal nerve lies on the posterolateral surface of the prostate with the cavernosal artery. In published data, the major pelvic ganglion and cavernous nerve are identified posterolateral to the prostate, whereupon a stainless steel bipolar hook electrode was placed around the cavernosal nerve. The MAP (mm Hg) and ICP (mm Hg) were continuously measured with pressure transducers. The total ICP was determined by the area under the curve (AUC; mm Hg/s). The cavernosal nerve was stimulated (2.5, 5, and 7.5 V; 15 Hz; 30-second pulse width) with a square wave stimulator (Grass Instruments, Quincy, Massachusetts).
Measurement of Isometric Tensions
After anesthesia, the penis was removed and placed in a Petri dish
containing Krebs-bicarbonate solution (containing [in mM]: NaCl 118.1, KCl
4.7, KH2PO4 1.0, MgSO4 1.0, NaHCO3
25.0, CaCl2 2.5, and glucose 11.1) and oxygenated with 95%
O2 and 5% CO2. The cavernosal tissue (1x1x 9
mm) was dissected and mounted under 1xg of resting tension in a
20-mL organ bath chamber (Radnoti; Radnoti Glass Technology Inc, Monrovia,
California), with one end attached to an electrode holder and the other to a
wire connected to a force transducer. Tissues were allowed to equilibrate for
60 minutes at 37°C (Gur and Ozturk,
2000).
In the first series of experiments, electrical field stimulation (EFS) was delivered as a train of square-wave pulses (pulse width, 0.5 ms; intensity, 20 V) at frequencies of 1 to 20 Hz across paired platinum electrodes placed on either side of the tissue strips. The strips were preincubated for 30 minutes with both guanethidine (5 µM), to eliminate noradrenergic effects, and atropine (1 µM), to prevent cholinergic responses. After phenylephrine (Phe) precontraction under these conditions, EFS was used to demonstrate tissue relaxation mediated by nonadrenergic, noncholinergic (NANC) fibers.
In the second series of experiments, dose-response curves for relaxations induced by acetylcholine (ACh; 10–8 to 10–3 M) and sodium nitroprusside (SNP; 10–8 to 10–3 M) were evaluated after precontraction with Phe (10 µM). In addition, cumulative dose-response curves with Phe (10–8 to 10–3 M) were obtained.
In the third series of experiments, corpus cavernosum (CC) rings were preconstricted with Phe, and the gas was switched to a hypoxic mixture (5% CO2 and 95% N2) for 50 minutes from normoxia (a mixture of 95% O2 and 5% CO2). All functional experiments were repeated under hypoxic conditions. At the end of experiments, tissues were wiped of excess solution and weighed.
Immunohistochemical Localization of NOS Proteins
Three weeks after MCT treatment, the cavernosal tissue was divided in two,
fixed in 10% formalin, and stored until processing for paraffin embedding.
CCSM cross-sections (8 µM) were cut and adhered to glass slides. Sections
were deparaffinized in xylene and hydrated through graded alcohol. Endogenous
peroxidases were quenched with 3% H2O2, and nonspecific
binding of immunoglobulin G was blocked using normal horse serum (1:50) in PBS
containing 0.1% bovine serum albumin. Slides were treated with 0.1% Triton
X-100 for 20 minutes and washed in PBS for 5 minutes before being incubated
with rabbit primary polyclonal antibodies (neuronal NOS [nNOS], endothelial
NOS [eNOS], and inducible NOS [iNOS]; BD Transduction Laboratories, San Diego,
California) at a dilution of 1:100 for 1 hour at room temperature. Samples
were then washed and incubated for an additional 30 minutes with biotinylated
secondary antibody (DAKO, Carpinteria, California), followed by a further
30-minute incubation with an avidin-biotin–conjugated horseradish
peroxidase (DAKO) and then a substrate (diaminobenzidine; Vecstatin; Vector
Laboratories, Peterborough, United Kingdom) for 5 minutes. Harris hematoxylin
was used as a counterstain, whereas negative control slides were stained with
only secondary antibody. The images were visualized under light microscopy
(Leica DM4000B and DFC 280 color digital camera system; Leica Microsystems,
Wetzlar, Germany). The nNOS-, eNOS-, and iNOS-positive cells appeared as dark
brown staining (Gur et al,
2008).
Semiquantitative Immunohistochemistry for CC Staining
From each of the 5 penile tissues, 6 to 8 sections were employed for
semiquantitative analysis of eNOS, nNOS, and iNOS staining. Staining intensity
of the immunohistochemical reaction was graded as negative (–), weak,
moderate (or positive), or intense.
Drugs
Phe, MCT, acetylcholine, guanethidine, atropine, and sodium nitroprusside
were purchased from Sigma Chemical Co (St Louis, Missouri).
Statistical Analysis
Values are expressed as means ± SE. Maximal effects of relaxant
agonists were expressed as percentage inhibition of Phe-stimulated
contractions (10 µm). The weight of each corporal strip was recorded, and
the responses to Phe were expressed as mean increase in gravity force per g
corporal muscle ± SE. Statistical analysis was performed with 1-way
analysis of variance using the Prism 4 statistical analysis package for
Windows (GraphPad Software, San Diego, California). A P value less
than .05 was considered significant. Comparisons were made versus control
values.
Results
Body and Corporal Weights
Body weight was not significantly different in control and MCT-treated
animals (Table). The weight of
corporal tissue strips increased slightly but did not differ significantly
between groups (Table).
|
Hemodynamic Experiments
The pulmonary hypertensive responses to MCT in the rats are summarized in
the Table. The mPAP in MCT rats
was increased (P < .05) when the animals were catheterized and
pulmonary arterial pressure measured 3 weeks after administration of the plant
alkaloid (Table;
Figure 1a). The WTs of
pulmonary arteries 50 to 200 µm in diameter were increased (P <
.001) 3 weeks after treatment with MCT compared with values in control animals
(Table;
Figure 1b). We selected these
muscularized arteries with an external diameter size ranging from 50 to 200
µm. The RV mass increased, and the PH was associated with an increase in RV
hypertrophy index (RV/[LV + S]; P < .001;
Table;
Figure 1c).
|
Erectile Responses
Stimulation of the nerves to the penis at 2.5, 5, and 7.5 V produced
stimulus-related increases in erectile parameters (ie, ICP/MAP). Three weeks
after MCT treatment, the increases in ICP/MAP
(Figure 2a) and total ICP
(Figure 2b) were significantly
reduced.
|
|
|
Under hypoxic conditions, the response to EFS (89% in control and 93% in MCT-treated rats; Figure 3a) and ACh-induced relaxations (70% in control and 73% in MCT-treated rats; Figure 3b) were decreased in a manner similar to the reductions observed in the MCT-treated groups compared with control normoxic conditions. Although endothelium-independent, SNP-induced relaxations were slightly diminished (30%) in MCT rats, hypoxia significantly diminished relaxations in response to SNP in control (63%) and in MCT-treated (61%) rats (Figure 3c). Hypoxia decreased the Phe-induced contractile response by 59% in control animals and by 70% in the MCT-treated groups (Figure 4). For the above drugs, we did not find any difference between control normoxia and MCT-normoxia groups (Figures 3 and 4).
Immunohistochemical Localization of NOS Enzymes
Three weeks after MCT treatment, there was no variability of staining
regarding expression of either eNOS or nNOS in the penile tissues. Both groups
displayed positive staining with similar intensities in the eNOS and nNOS
protein localization. There was a complete agreement on these findings between
all 4 independent observers (data not shown). However, after 3 weeks, iNOS
expression increased in MCT-treated rat penile tissue compared with control
(Figure 5). Although control
penile tissue slides for iNOS staining showed negative staining (–; no
reaction product detected; Figure
5a), penile tissues from the MCT group exhibited intense staining
regarding iNOS expression in the CCSM
(Figure 5b).
|
Discussion
The results of the present experiments in MCT-treated rats reveal a marked reduction in CCSM relaxation responses to EFS, ACh, and SNP, as well as in the contractile response to Phe. These data indicate that MCT causes dysfunction at both the endothelial and smooth muscle cell levels in the CC.
In this study, pulmonary arterial pressure, % WT of the pulmonary artery, and right ventricular mass increased significantly 3 weeks after exposure to MCT. RV hypertrophy was assessed by the weight ratio of RV to LV + S induced by MCT treatment. In previous studies, these alterations were established as an index of PH (Ghodsi and Will, 1981).
MCT treatment reduced the in vivo erectile response to cavernosal nerve stimulation and decreased the in vitro relaxant response of CCSM strips to NANC nerve stimulation. Previous studies have documented impaired erectile responses in hypertensive rat models (Zaloga et al, 1984; Chitaley et al, 2001; Wilkens et al, 2001; Ushiyama et al, 2004). Several factors can account for the observed reduction in NANC nerve–induced penile erection in MCT-treated rats. Reduced NOS expression or activity and substrate depletion in NANC nerves can reduce NO release. In the present study, nNOS was localized to cavernosal NANC nerve cells and was not altered by MCT treatment. Because nNOS expression was similar in the CCSMs from control and MCT-treated rats, the impaired relaxation observed in MCT-treated rats may not be attributed to decreased NO production by nNOS. In a study by Ushiyama et al (2004), nNOS gene expressions were similar in the CC of SHR and normotensive Wistar-Kyoto rats, whereas neurogenic relaxation in response to EFS in SHR was impaired. In addition, it has been reported that nNOS protein expression was not changed in mice with severe hypoxia-induced PH (Fagan et al, 2001). Similarly to what is observed with MCT treatment, hypoxia significantly decreased nerve-mediated relaxation in CCSM from MCT-treated rats. The effect of alterations in oxygen tension on NO production in rabbit CCSM has been reported previously (Kim et al, 1993). It is possible that depletion of the NO substrate, L-arginine, in the NANC nerves is responsible for this diminished CCSM response. There is evidence that supplementation with OH-arginine improves NO-mediated relaxation of rabbit CCSM and potentiates NO-mediated responses in hypoxic tissue (Angulo et al, 2003).
It has been observed that corporal tissue from MCT-treated rats exhibits markedly reduced responses to ACh when compared to controls; however, we observed a similar diminished response in control CCSM under hypoxic conditions. Previous studies have documented decreased vascular responses to ACh under hypoxic conditions (Thomas and Wanstall, 2003; Reboul et al, 2005), where penile tissues become similarly hyporesponsive (Moon et al, 1999; Vignozzi et al, 2006). In a similar manner, ACh-induced vasorelaxation is markedly attenuated in pulmonary arteries from pulmonary hypertensive rats (Goret et al, 2005). In contrast, we observed unaltered eNOS expression in penile tissues from MCT-treated rats. Although MCT treatment is known to increase eNOS mRNA (Nakazawa et al, 1999), levels of eNOS protein can increase (Resta et al, 1997), remain unchanged (Tyler et al, 1999; Jasmin et al, 2006), or decrease (Kanno et al, 2001; Hongo et al, 2005). Moreover, our results are similar to those of studies that show reduced NO formation in pulmonary arteries at early time points in the MCT model of PH (eg, 2 weeks after MCT), despite unchanged or even increased eNOS levels (Mathew et al, 2002). It has been reported that MCT, hypoxia, and senescence lead to sequestration of eNOS away from its functional caveolar location and provide a mechanism for a reduction in pulmonary arterial NO levels in experimental PH, despite sustained eNOS protein expression (Mukhopadhyay et al, 2007). Although it is recognized that MCT-induced PH is associated with a decrease in NO production in the pulmonary vasculature (Nakazawa et al, 1999), there have been conflicting reports about changes in levels of eNOS protein. In a recent study, the induction of cavernosal ischemia caused no significant change in expression of either eNOS or nNOS at 4 weeks (Azadzoi et al, 2004).
It is known that both constitutively expressed nNOS and eNOS isoforms mediate penile erection by producing NO from L-arginine. Neuronal NOS initiates CCSM and vascular relaxation, whereas eNOS facilitates blood flow into erectile tissue to maintain erection (Burnett, 2004). In our data, nNOS and eNOS expressions were not altered with MCT treatment, despite a diminished functional response. We hypothesize that mild chronic hypoxia during MCT treatment has an important role in the diminished functional response. It is interesting to note that we observed enhanced iNOS levels in MCT-treated tissues. Inducible NOS may play a physiologic role in MCT-induced ED.
Tissue bath experiments were conducted under hypoxic conditions. The
tissues in Krebs solution under normoxic conditions were gassed with 95%
O2 and 5% CO2. Gassing with such high oxygen levels
leads to hyperoxia (PO2 
500 mm Hg), whereas MCT treatment causes chronic
systemic hypoxia (Nagaoka et al,
2005), with arterial PO2 levels at approximately 70 mm Hg. CCSM
from hypoxic animals, when placed in hyperoxic conditions, likely produces
pathophysiologic changes. Tissues adapt to chronic hypoxia, and in such
circumstances hyperoxia may induce superoxide overproduction. Superoxide can
scavenge NO and reduce EFS- and ACh-induced CCSM relaxation. For this reason,
the hypoxic environment was maintained in our experiments to mimic a similar
MCT in vivo environment.
In this study, SNP-induced, endothelium-independent CCSM relaxation was decreased slightly in the MCT-treated group. In addition, CCSM from control and MCT-treated rats exposed to hypoxic conditions exhibited significantly diminished responses. These data suggest that MCT-induced hypoxia may change CCSM function similarly to the effect observed with hypoxia alone. In previous studies, there was a lack of consistency with regard to SNP-induced relaxation after hypoxic exposure. For example, the hypoxic penis showed increased sensitivity to the relaxant effect of the nitric oxide donor SNP (Vignozzi et al, 2006). In another study, it was reported that although neutrally evoked relaxation of the bovine retractor penis was impaired by hypoxia, responses to SNP or an inhibitory factor isolated from the bovine retractor penis were not affected (Bowman and McGrath, 1985). In a recent study, Lin et al (2008) reported that relaxation induced by SNP in CCSM was significantly diminished at both 2 and 8 weeks after partial bladder outlet obstruction, which induces hypoxia by vascular obstruction. Therefore, we infer that the severity of hypoxia can affect CCSM relaxation responses.
Contracted (flaccid penis) CCSM is mediated in large part by the release of
noradrenaline. In the present study, we investigated the contribution of the
adrenergic system to penile flaccidity. Our data demonstrate the contractile
response to Phe, an 1-adrenoceptor agonist, in isolated CCSM strips
from MCT-treated rats was reduced to approximately 61% of control. It is
unclear why the contractile response to Phe is markedly reduced in CCSM from
MCT-treated rats. In SHR rats, diminished erectile responses have been
attributed to impairment of -adrenergic mechanisms (Behr-Roussel et al,
2003). A recent study showed that hypoxia diminished the contractile response
to Phe (Muneer et al, 2005).
In our study, exposure to hypoxia decreased Phe responses in both control and
MCT-treated rats. Chronic hypoxia has been demonstrated previously to
attenuate the systemic vasoconstrictor response to a variety of agents
(Doyle and Walker, 1991;
Hu et al, 1996;
Caudill et al, 1998). The
inability of -stimulation to induce a tonic contraction of CCSM under
in vitro hypoxic conditions may be the reason for failure of intracorporal
injection of -adrenergic agonists to induce detumescence in patients
with hypoxic/ischemic priapism.
In published data, RV dysfunction is associated with increased reactive oxygen species (ROS) produced by NADPH oxidase and mitochondria (Redout et al, 2007). In the present study, we used an established model of RV dysfunction induced by MCT PH (Buermans et al, 2005). However, oxidative stress seen in the failing RV and mild hypoxia favor ROS production. Mitochondrial ROS production may be particularly important in directly affecting contraction and Ca2+ handling in ED, because mitochondria are in close proximity to the contractile apparatus and sarcoplasmic reticulum in penile tissue. Penile hypoxia in MCT-induced PH has been hypothesized to occur as a consequence of the mismatch between oxygen demand and supply CC and can result in altered NO bioavailability and ED.
In conclusion, MCT treatment impairs erectile function in the rat. This
diminished erectile response in the rat was mediated by both
endothelium-dependent and endothelium-independent mechanisms. The contractile
response of CCSM to -agonists is impaired by hypoxia. Future studies
are needed to explore the underlying mechanisms by which MCT and decreased
oxygen tension affect CCSM function.
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