J Appl Physiol 99: 53–58, 2005.
First published March 24, 2005; doi:10.1152/japplphysiol.00154.2005.
Autonomic dysreflexia during sperm retrieval in spinal cord injury: influence
of lesion level and sildenafil citrate
A. William Sheel,1,2 Andrei V. Krassioukov,1,3,5 J. Timothy Inglis,1,2 and Stacy L. Elliott1,4
1
International Collaboration on Repair Discoveries, 2School of Human Kinetics, 3School of
Rehabilitation Sciences, 4Department of Psychiatry and Urology, 5Department of Physical Medicine
and Rehabilitation, The University of British Columbia, Vancouver, British Columbia, Canada
Submitted 7 February 2005; accepted in final form 17 March 2005
EJACULATORY DYSFUNCTION IS an uncommon cause of male
infertility in the general population (8). However, spinal cord
injury (SCI) commonly affects men in their reproductive years
during which many men experience fertility-related problems,
including erectile and ejaculatory dysfunction, impaired spermatogenesis, abnormal sperm (viability, motility, and morphology), genitourinary infection, and endocrine abnormalities
(26). The recent development and refinement of penile vibratory stimulation (PVS) and electroejaculation (EEJ) has enhanced the treatment of ejaculatory dysfunction in SCI (26).
The physiology of ejaculation is complex and is a highly
coordinated effort involving the brain, spinal cord, sympathetic
and parasympathetic nervous system, as well as efferent and
afferent components of the peripheral nervous system. In short,
the goal of PVS is to activate the ejaculatory reflex in the
thoracolumbar area of the spinal cord. It is generally believed
that PVS requires an intact spinal cord at the level of T11–S4 to
cause antegrade ejaculation (4, 5, 28). However, it is not clear
how the level and completeness of the SCI lesion accurately
predict successful ejaculation (4, 28).
The cardiovascular responses to genital stimulation and
ejaculation in noninjured men are well known and involve a
general autonomic response consisting of increased systolic
(SBP) and diastolic blood pressure (DBP) and increased heart
rate (HR), which all peak at ejaculation and immediately return
to baseline after it (17, 19, 23). However, significant dysfunction of the sympathetic nervous system is associated with SCI,
particularly at higher levels of SCI, and cardiovascular deficits
can be present (15, 20). One of them is autonomic dysreflexia
(AD), which is characterized by episodic hypertension in
response to noxious or nonnoxious stimuli below the level of
the injury and is usually restricted to those with a lesion level
at or above T6. In addition to a sudden rise in blood pressure,
AD is often accompanied by symptoms such as headaches,
anxiety, sweating, and bradycardia (14, 20, 29). There are
reports of AD during PVS and EEJ in men with SCI (7, 10, 12,
22, 27). However, from the available data, the presence of AD
appears variable, and the predictability of AD occurrence with
lesion level is not well described. As such, the primary purpose
of our study was to characterize the cardiovascular responses to
PVS in men with different lesion levels and severity of injury.
We hypothesized that those with cervical injuries would demonstrate a greater degree of AD in response to PVS compared
with men with thoracic injuries based on the higher degree of
sympathetic nervous system disturbance expected at the higher
the lesion level. We also questioned whether the disproportionate rise in blood pressure during PVS in men with SCI could be
altered with use of pharmacological agents. Therapeutic measures to reduce arterial blood pressure during EEJ in men with
SCI include the use of oral nifedipine (27) and intravenous
infusions of prostaglandin E2 (10). There is some evidence
that, in patients with Parkinson’s disease, and those with
multiple system atrophy, orally administered sildenafil citrate
(i.e., Viagra) has a hypotensive effect on mean blood pressure
in the lying, sitting, and standing positions (12). Sildenafil
citrate is a highly selective inhibitor of phosphodiesterase type
5 (PDE5), which is used as an effective treatment of erectile
dysfunction (31) and has been shown to decrease resting blood
Address for reprint requests and other correspondence: W. Sheel, Health and
Integrative Physiology Laboratory, The Univ. of British Columbia, 210-6081
Univ. Blvd., Vancouver, BC, Canada V6T-1Z1 (E-mail: [email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
arterial pressure; cardiovascular; penile vibratory stimulation; sympathetic nervous system
http://www. jap.org
8750-7587/05 $8.00 Copyright © 2005 the American Physiological Society
53
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Sheel, A. William, Andrei V. Krassioukov, J. Timothy Inglis,
and Stacy L. Elliott. Autonomic dysreflexia during sperm retrieval in
spinal cord injury: influence of lesion level and sildenafil citrate.
J Appl Physiol 99: 53–58, 2005. First published March 24, 2005;
doi:10.1152/japplphysiol.00154.2005.—Autonomic dysreflexia (AD)
can occur during penile vibratory stimulation in men with spinal cord
injury, but this is variable, and the association with lesion level is
unclear. The purpose of this study was to characterize the cardiovascular responses to penile vibratory stimulation in men with spinal cord
injury. We hypothesized that those with cervical injuries would
demonstrate a greater degree of AD compared with men with thoracic
injuries. We also questioned whether the rise in blood pressure could
be attenuated by sildenafil citrate. Participants were classified as
having cervical (n ⫽ 8) or thoracic (n ⫽ 5) injuries. While in a supine
position, subjects were instrumented with an ECG, and arterial blood
pressure was determined beat by beat. Subjects reported to the
laboratory twice and received an oral dose of sildenafil citrate (25–100
mg) or no medication. Penile vibratory stimulation was performed
using a handheld vibrator to the point of ejaculation. At ejaculation
during the nonmedicated trials, the cervical group had a significant
decrease in heart rate (⫺5–10 beats/min) and increase in mean arterial
blood pressure (⫹70 –90 mmHg) relative to resting conditions,
whereas the thoracic group had significant increases in both heart rate
(⫹8 –15 beats/min) and mean arterial pressure (⫹25–30 mmHg).
Sildenafil citrate had no effect on the change in heart rate or mean
arterial pressure in either group. In summary, men with cervical
injuries had more pronounced AD during penile vibratory stimulation
than men with thoracic injuries. Administration of sildenafil citrate
had no effect on heart rate or blood pressure during penile vibratory
stimulation in men with spinal cord injury.
54
AUTONOMIC DYSREFLEXIA DURING EJACULATION
Table 1. Level and severity of spinal cord
injury in study subjects
Subject No.
Injury Level
ASIA Score
Time Since Injury, mo
1
2
3
4
5
6
7
8
9
10
11
12
13
C2
C4
C7
C4
C4
C4
C5
C5
T3
T4
T5
T6
T5
A
A
A
B
B
B
B
C
A
A
A
A
C
187
194
110
73
65
285
49
115
99
47
191
257
239
Level and completeness of the lesions were assessed using the American
Spinal Injury Association (ASIA) scale (21).
provided. Participants rested quietly for a minimum of 10 min to
ensure stable baseline measurements. After the rest period, PVS was
applied by a physician experienced in PVS using one or more
handheld vibrators (Ferti Care, Multicept, Rungsted, Denmark) placed
about the glans penis to induce ejaculation. An amplitude of 1.0 –3.5
mm with a frequency of 70 –100 Hz was used. Vibration was performed for a maximum of 3 min, followed by a pause of 1 min before
the cycle was repeated until ejaculation was achieved. The timing of
ejaculation was noted by using a push-button event marker that was
connected to the analog-to-digital converter.
Data and statistical analysis. HR and blood pressure data were
analyzed offline. Resting values for cardiovascular variables were
averaged over the 10-min rest period. Peak values were obtained at
ejaculation. Data were compared by using analysis of variance procedures (Statistica 6.1, Stat Soft, Tulsa, OK). When significant Fratios were detected, Tukey’s test was applied post hoc to ascertain
where the differences resided. The level of statistical significance was
set at P ⬍ 0.05 for all statistical comparisons. All data are presented
as means ⫾ SE.
METHODS
Participants. All experimental procedures and protocols were approved by the Clinical Screening Committee for Research of the
University of British Columbia. A total of 13 men participated in this
study after providing informed, written consent. Before experimentation, subjects underwent neurological assessment and anthropometric
measurements. The level and the severity of SCI were determined by
assessment of motor and sensory impairment according to the American Spinal Injury Association (ASIA) scoring system by a qualified
physician. The ASIA Grade A represents the most severe SCI with
complete motor and sensory impairment, and ASIA Grade D characterizes minor SCI (incomplete and mild motor dysfunction) (21).
Because of the limited number of subjects, the subjects were divided
into two groups according to level of injury only: individuals with
cervical injury (n ⫽ 8) and individuals with thoracic injury (n ⫽ 5).
Instrumentation. Throughout experimentation, subjects remained
in a supine position and were instrumented with a standard ECG
configuration. Beat-by-beat arterial blood pressure was determined by
using a finger pulse photoplethysmograph (Finometer, Finapres Medical Systems, Arnheim, The Netherlands), which was placed on the
midphalaynx of the middle digit of the left hand and was maintained
at the level of the heart for the duration of the experiment. The
photoplethysmograph used a hydrostatic height correction to correct
for movements of the hand with respect to heart level. Blood pressure
and ECG measurements were recorded continuously at 1,000 Hz by
using an analog-to-digital converter (PowerLab/16SP model ML795,
ADI, Colorado Springs, CO) interfaced with a computer. Data were
stored for subsequent analysis by using specialized software (PowerLab V5.02, ADI) where beat-by-beat values of HR, SBP, and DBP
were determined and mean arterial blood pressure (MAP) was calculated.
Experimental design. This was an unblinded, crossover design, and
each participant served as his own control. Subjects reported to the
laboratory on two separate occasions and were randomly assigned to
one of two conditions. On one visit, the participants received an oral
dose of sildenafil citrate (25–100 mg; depending on subjects previous
experience), and on the alternate testing day no medication was
J Appl Physiol • VOL
Subject characteristics and baseline cardiovascular parameters. Individual subject injury characteristics are shown in
Table 1. The cervical group had injuries ranging from C2 to C7
and was classified as ASIA A (n ⫽ 3), B (n ⫽ 4), or C (n ⫽
1). The thoracic group had injuries at T3–T6 and was categorized as ASIA A (n ⫽ 4) or C (n ⫽ 1). Mean descriptive
subject characteristics are shown in Table 2. The groups were
not statistically different for age, height, weight, body mass
index, or time since injury (P ⬎ 0.05). Under resting control
conditions HR, DBP, and MAP were similar between the
cervical and thoracic groups (Table 3; P ⬎ 0.05). Control
resting SBP was lower in individuals with cervical SCI relative
to thoracic (P ⬍ 0.05). Administration of sildenafil citrate had
no effect on resting HR in either group. Relative to the thoracic
group, subjects with cervical injuries had a lower resting SBP,
DBP, and MAP during the sildenafil citrate trial (P ⬍ 0.05).
Compared with control conditions, sildenafil citrate caused a
statistically lower DBP and MAP in the cervical group and a
lower DBP in the thoracic group (P ⬍ 0.05).
Cardiovascular values at ejaculation. Figure 1 shows a
beat-by-beat recording from one subject with a cervical injury
for arterial blood pressure and HR during PVS and at ejaculation. In response to PVS and ejaculation in this subject, there
was a significant rise in both SBP and DBP relative to rest,
whereas HR was reduced relative to rest in control conditions.
Mean values for HR and blood pressure measures at ejaculation are shown in Table 4. During control experiments, absolute values for HR tended to be lower at ejaculation in the
cervical group relative to the thoracic group, but this was
variable and did not reach statistical significance (P ⫽ 0.06).
The blood pressure response at ejaculation was different between groups where SBP, DBP, and MAP were higher in the
cervical group compared with the thoracic group (P ⬍ 0.05).
Table 2. Mean subject characteristics
Group
Time Since
Injury, mo
Age,
yr
Height, cm
Mass, kg
Body Mass
Index, kg/m2
Cervical
Thoracic
135⫾30
167⫾38
32⫾2
35⫾3
161⫾2
160⫾2
73.6⫾3.3
76.4⫾4.1
28.4⫾1.5
29.8⫾2.0
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RESULTS
pressure in healthy volunteers (12). However, to our knowledge, administration of sildenafil citrate and its potential role in
reducing arterial blood pressure during PVS in men with SCI
have not been systematically investigated. Therefore, our secondary purpose was to determine whether sildenafil citrate
would attenuate the rise in blood pressure that can accompany
PVS in men with SCI.
55
AUTONOMIC DYSREFLEXIA DURING EJACULATION
Table 3. Resting heart rate and blood pressure values
Control
Sildenafil Citrate
Group
HR, beats/min
SBP, mmHg
DBP, mmHg
MAP, mmHg
HR, beats/min
SBP, mmHg
DBP, mmHg
MAP, mmHg
Cervical
Thoracic
62⫾4
64⫾5
95⫾8*
121⫾9
64⫾5
72⫾7
82⫾7
86⫾8
61⫾3
66⫾4
75⫾7*†
115⫾9
44⫾4*†
67⫾6†
54⫾5*†
83⫾6
Values are means ⫾ SE. HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial blood pressure. *Significantly
different from thoracic group, P ⬍ 0.05. †Significantly different from control group, P ⬍ 0.05.
Fig. 1. Beat-by-beat recording from one subject (cervical injury; control trial)
for heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure
(DBP) responses to penile vibratory stimulation (PVS) and at ejaculation.
J Appl Physiol • VOL
DISCUSSION
This is the first study to systematically characterize the
cardiovascular responses to PVS with and without sildenafil
citrate in men with different SCI lesion levels. The principal
findings of this investigation are threefold. First, we have
demonstrated that in men with SCI there is profound AD
during sperm retrieval that is dependent on lesion level. Specifically, men with cervical injuries demonstrated greater AD
compared with men with thoracic injuries. Second, we have
shown that sildenafil citrate has no effect on the cardiovascular
responses to PVS and ejaculation in men with SCI. Third, we
observed that resting blood pressure in the cervical group was
lower than in the thoracic group and that administration of
sildenafil citrate significantly decreased resting blood pressure
in the cervical group but not the thoracic group.
Autonomic dysreflexia. Mortality and morbidity of people
with SCI have decreased, and their life expectancy has approached that of able-bodied individuals (18). As with a
growing fraction of the able-bodied population, cardiovascular
disease is now one of the leading causes of death in those with
SCI (18). Normal sexual function has become an important
consideration for the management of the SCI patient. In a
recent large survey of SCI individuals (681 participants; 51%
quadriplegic individuals and 49% paraplegic individuals), the
importance of sexual function was underscored where both
quadriplegic and paraplegic individuals shared similar priorities when ranking bladder and bowel control and sexual function as the first and second important factor affecting quality of
life (1). However, as we have shown in the present study,
assisted reproductive technologies such as PVS in men with
SCI can be accompanied by AD. Our findings demonstrate
profound AD in men with cervical injuries and that AD is also
present, but to a lesser degree, in men with thoracic injuries
(see Fig. 2). The HR and blood pressure response to PVS was
variable in the thoracic group where some subjects did not
demonstrate AD but rather had a response that was similar to
what would be predicted for an able-bodied person. We found
that, relative to rest, HR was reduced (⫺5–10 beats/min) in the
cervical group at ejaculation. This was accompanied by large
increases in SBP (⫹90 –115 mmHg), DBP (⫹70 – 80 mmHg),
and MAP (⫹70 –90 mmHg), and there was no effect of
sildenafil citrate. In the thoracic group, there was a modest rise
in HR (⫹8 –15 beats/min), SBP (⫹35– 40 mmHg), DBP
(⫹25–30 mmHg), and MAP (⫹25–30 mmHg), and there was
also no sildenafil citrate effect. The typical able-bodied response to sexual arousal and ejaculation in young men involves
increases in HR, SBP, DBP, and MAP, which are accompanied
by increases in circulating catecholamines. These values can
vary depending on the sexual activity and degree of arousal (7,
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There was no effect of sildenafil citrate on cardiovascular
variables at ejaculation (P ⬎ 0.05). Figure 2 shows the cardiovascular response to ejaculation in relative terms. The cervical
group demonstrated a reduction in HR relative to rest, whereas
the thoracic group demonstrated a modest rise in HR. There
was no effect of sildenafil citrate. Values for blood pressure
(SBP, DBP, and MAP) were significantly higher in the cervical
group compared with the thoracic group (P ⬍ 0.05), and there
was no effect of sildenafil citrate (P ⬎ 0.05).
56
AUTONOMIC DYSREFLEXIA DURING EJACULATION
Table 4. Heart rate and blood pressure at ejaculation
Control
Sildenafil Citrate
Group
HR, beats/min
SBP, mmHg
DBP, mmHg
MAP, mmHg
HR, beats/min
SBP, mmHg
DBP, mmHg
MAP, mmHg
Cervical
Thoracic
52⫾6
77⫾7
189⫾14*
158⫾17
135⫾11*
97⫾14
151⫾10*
114⫾13
57⫾6
75⫾7
188⫾15*
158⫾19
121⫾9*
104⫾12
143⫾11*
122⫾14
Values are means ⫾ SE. *Significantly different from thoracic group, P ⬍ 0.05. Note: HR was not significantly different between the cervical and thoracic
groups, but there was a nonsignificant trend (P ⫽ 0.06) for HR be lower in the cervical group.
activation of sensory input entering the spinal cord below the
level of the lesion. Bladder or colorectal distension and urinary
tract infections are among the most common causes of this
condition (29). No subjects in the present study had a urinary
tract infection.
Because PVS to the point of ejaculation triggers an increase
in arterial blood pressure, baroreceptors activate the vagus to
depress HR. Bradycardia is therefore present, but, because
blood pressure can only be modulated above the lesion after
SCI, bradycardia persists (7). Our observations of hypertension
and bradycardia are consistent with other findings of AD
during PVS in men with SCI (7), and the AD seen in the
cervical group may have been partly due to dysfunction in the
baroreceptor reflex pathway. However, because we did not
directly test this hypothesis, we cautiously make this statement.
Sympathetic hyperactivity and ␣-adrenoreceptor hyperresponsiveness may have also played a mechanistic role in the AD
observed, and it is not known what the relative contributions
are (29).
Sildenafil citrate. Sildenafil citrate is a selective inhibitor of
the enzyme PDE5 (2), which is found predominantly in the
corpora cavernosa of the penis (3) and also has vasodilator
effects on the pulmonary vasculature (25). cGMP is responsible for penile smooth muscle relaxation and erection via the
nitric oxide-cGMP mediated relaxation pathway. Inhibition of
Fig. 2. Change in HR, SBP, DBP, and mean
arterial blood pressure (MAP) from rest to
ejaculation. Values are means ⫾ SE. *Significantly different (P ⬍ 0.05). No differences were detected between the control and
sildenafil citrate (P ⬎ 0.05).
J Appl Physiol • VOL
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17, 19). Our data are the first to show that the level of injury
affects the degree of AD during PVS where more pronounced
AD was present in higher level injuries.
SCI disturbs blood pressure control, which typically depends
on supraspinal regulation of sympathetic preganglionic neurons (11). Reflexes within the spinal circuits generally contribute minimally to cardiovascular control in intact humans and
animals. After SCI, central nervous system regulation of arterial pressure is dominated by spinal reflex control of these
neurons, and the unchecked reflexes can lead to AD (16).
Specific AD mechanisms include 1) sympathetic hyperactivity
in the isolated spinal cord due to loss of tonic central inhibitor
inputs, 2) plastic changes within spinal autonomic circuits, 3)
impaired baroreceptor reflex function, and 4) ␣-adrenoreceptor
hyperresponsiveness (29).
It was shown previously that resting arterial blood pressure
in individuals with SCI is lower than in able-bodied subjects,
with disabling episodes of orthostatic hypotension (6, 20).
Despite the lower blood pressure, life-threatening episodes of
hypertension, known as AD, may occur, where SBP can reach
up to 300 mmHg, potentially leading to stroke and death (9, 20,
29, 30). These cardiovascular abnormalities are attributed to
autonomic instability caused by a combination of changes
occurring within the spinal autonomic circuits in acute and
chronic stages after SCI (20, 29). AD is usually induced by
AUTONOMIC DYSREFLEXIA DURING EJACULATION
J Appl Physiol • VOL
comprehensive evaluation of the degree of AD in relation
to SCI.
ACKNOWLEDGMENTS
We thank our subjects for their participation. The authors thank Maureen
McGrath for technical assistance in data acquisition.
GRANTS
This study was principally supported by the British Columbia Neurotrauma
Fund (S. L. Elliott). Additional support came from the Natural Sciences and
Engineering Research Council of Canada (A. W. Sheel). A. W. Sheel was
supported by a Scholar Award from the Michael Smith Foundation for Health
Research (British Columbia, Canada). A. V. Krassioukov was supported by
Christopher Reeve Paralysis Foundation (USA) and the Heart and Stroke
Foundation of Canada.
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PDE5 allows for enhancement of erection by blocking the
degradation of cGMP. In healthy volunteers, a single oral dose
of sildenafil citrate (50, 100, and 200 mg) has a significant
lowering effect on supine arterial blood pressure (31). The
mean decrease in resting SBP and DBP after a dose of 100 mg
was 10.2 and 6.8 mmHg, respectively. Although the abovementioned blood pressure-lowering effects can be considered
modest in healthy subjects, they are potentially important to the
SCI patient undergoing penile stimulation for two reasons: it
may make the resting hypotension associated with cervical
injuries symptomatically worse, and it may be protective in
blunting the severe increases in blood pressure seen at ejaculation. We observed a significantly lower resting DBP in both
the cervical and thoracic groups with administration of sildenafil citrate compared with the control condition. Sildenafil
citrate caused resting MAP to be lower in the cervical group
but not the thoracic group. As with previous reports (13), we
found that sildenafil citrate had no effect on resting HR. The
modest and variable hypotensive effects of sildenafil citrate we
observed at rest had no effect on arterial blood pressure at
ejaculation (see Fig. 2). It appears that sildenafil citrate has no
protective effect on the onset of AD in men with SCI undergoing PVS.
Interestingly, administration of sildenafil citrate significantly
decreased resting SBP, DBP, and MAP in the cervical group
and DBP in the thoracic group (Table 3). Our experimental
approach was not designed to address this question. Nonetheless, a significant hypotensive effect of sildenafil citrate was
present in the cervical group, which may have implications for
blood pressure regulation during orthostatic challenges.
Critique of methods. We used photoelectric plethysomography to measure arterial blood pressure. Although plethysmographic measurements correlate with intra-arterial measurements during experimental manipulations of arterial pressure
(24), the absolute values (mmHg) can be variable. Nonetheless,
we are confident in the arterial pressure changes (i.e., change in
blood pressure from rest; see Fig. 2) we observed for two
reasons. First, the blood pressure device we used is advantageous because it employs an automated hydrostatic height
correction to compensate for movements of the hand with
respect to heart level. Second, we observed no systematic
changes in blood pressure during the rest period, which confirms that our baseline values were stable and our approach to
compare resting values with peak values was appropriate.
We did not utilize a placebo because the effects of sildenafil
citrate are immediately noticeable to the subject. This may
have influenced our results, and we cannot completely rule this
out. However, given that we did not observe any systematic
effect of sildenafil citrate at ejaculation, we do not believe a
lack of a placebo condition influences the interpretation of the
data.
Summary. Our research design and experimental approach
incorporated subjects with cervical and thoracic SCI. We
demonstrated that men with cervical injuries have more pronounced AD during penile vibratory stimulation than men with
thoracic injuries. Administration of sildenafil citrate has no
effect on HR or blood pressure during penile vibratory stimulation in men with SCI in our study. On the basis of our
findings, further studies are warranted using a larger sample of
subjects with a range of injury levels and severity to provide a
57
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