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- .Original Article . -
Beneficial effects of switching from β-blockers to nebivolol on the erectile function of hypertensive patients
Michael Doumas1, Alexandros Tsakiris1, Stella Douma1, Alkiviadis Grigorakis2, Angelos Papadopoulos1, Athina Hounta1, Sotirios Tsiodras1, Dimitrios Dimitriou2, Helen Giamarellou1
1Hypertension Outpatient Clinic, Fourth Department of Internal Medicine,
2Urologic Outpatient Clinic, Second
Department of Urology, University of Athens, Attikon Hospital, Athens 12461, Greece
Abstract
Aim:To investigate the effect of substituting
β-blockers with nebivolol on the erectile function of patients suffering
from essential hypertension. Methods: Forty-four young and middle-aged men (31-65 years) with essential
hypertension visited our outpatient clinic and took
b-blocker treatment (atenolol, metoprolol or bisoprolol) for more than 6
months. All the patients completed a questionnaire regarding erectile function (International Index for Erectile Function).
Patients were then switched to an equipotent dose of nebivolol for 3 months and, at the end of this time period, filled
out the same questionnaire. Results: Twenty-nine out of the 44 (65.9%) patients who took
β-blockers (atenolol, metoprolol or bisoprolol) had exhibited erectile dysfunction (ED). Their systolic and diastolic blood pressure did not
change significantly with the treatment switch. In 20 out of these 29 (69%) patients, a significant improvement in the
erectile function score was exhibited after 3 months of nebivolol administration, and in 11 of these 20 patients, erectile
function was normalized. Conclusion: Nebivolol seems to have a beneficial effect on ED (possibly due to increased
nitric oxide availability); however, further prospective, randomized, placebo-controlled studies are needed to confirm
the beneficial effects of nebivolol. (Asian J Androl 2006 Mar; 8: 177-182)
Keywords: erectile dysfunction; essential hypertension; β-blockers; nebivolol
Dr Michael Doumas, First Department of Internal Medicine, Academic Hospital of Alexandroupolis, 68100 Alexandroupolis, Greece.
Tel: +30-694-700-6001, Fax: +30-255-103-0450
E-mail: michalisdoumas@yahoo.co.uk
Received 2004-12-20 Accepted 2005-06-23
1 Introduction
Erectile dysfunction (ED) is defined as the persistent inability to attain or maintain penile erection sufficient for
satisfactory sexual performance. ED is now widely recognized as an entity and its reported incidence has increased
since the introduction of phosphodiesterase-5 inhibitors. It was estimated that approximately 30 million American men
and more than 100 million men worldwide were afflicted with this condition that has a major effect on patients’ and
their sexual partners’ quality of life [1].
Up to 25% of ED cases were related to medication side effects; antihypertensive drugs were the most implicated
class [2]. Several lines of evidence suggested that
β-blockers were associated with an increased risk of ED [3-6].
Nebivolol is a newly developed, highly selective
b1-blocker, which has been shown to cause vasodilatation, possibly by
inducing nitric oxide (NO) production [7-9]. NO was believed to play a crucial role in erectile function, because it
mediates the relaxation of the trabecular muscle of the corpus cavernosum and thus facilitates penile erection [10-12].
The aim of the present study was to investigate the effect of substituting
β-blockers with nebivolol on erectile function in patients with essential hypertension, presenting with or without ED.
2 Materials and methods
2.1 Study population
The present study was an open, prospective study of 44 young and middle-aged men (31-65 years) visited our
outpatient clinic. All patients had arterial hypertension and were taking
β-blockers (atenolol 50-100 mg/d: 40 patients; metoprolol 100 mg/d: two patients; bisoprolol 10 mg/d: two patients) for more than 6 months (range 6months to 22years).
Secondary hypertension was excluded by clinical and, if appropriate, laboratory examinations.
The study was conducted in accordance with the principles of the Helsinki
declaration [13] and was approved by the Hospital Ethics Committee.
All subjects gave informed consent and the procedures followed were in accordance with institutional guidelines.
Patients with renal failure, diabetes mellitus and heart and liver diseases were excluded from the study due to the fact
that there is an association between these conditions and ED.
2.2 History and physical examination
The patients’ demographic data (age and body weight), cigarette consumption and alcohol intake were recorded.
Blood pressure was measured using a mercury
sphygmomanometer (Empire N, Rudolf Riester GMBH, Jungingen,
Germany), following the standard methodology. Three blood pressure recordings were obtained consecu-tively, and
blood pressure was determined as the mean of the second and the third recording.
A thorough physical examination was undertaken, and each patient was assessed for genital abnormalities, such as
phimosis, hypospadias, signs of hypogonadism and prostate hyperplasia. Individuals with such conditions were
excluded from the study and referred on to our urologic outpatient clinic.
2.3 Evaluation of erectile function
An ED evaluation was performed by means of a
standardized questionnaire, using an inform-then-probe type of
questions. First of all, the question: “Many people
experience sexual problems. Has this ever appeared to you?” was
asked to the individuals, in order to reassure them that their symptoms (if present) are not uncommon or embarrassing.
Then the patient was asked to complete a questionnaire regarding ED. The International Index for Erectile
Function (IIEF) was chosen, since it is considered an accurate, widely-used test for defining the area of sexual dysfunction.
Moreover, it provides information on se-veral areas of sexual function, such as erectile function (questions 1-5, 15),
intercourse satisfaction (questions 6-8), orgasmic function (questions 9, 10), sexual desire (questions 11, 12) and
overall satisfaction (questions 13, 14). ED is classified (according to IIEF questionnaire scoring, using six questions)
as severe (6-10 points), moderate (11-16 points), mild (17-25 points) and none (26-30 points).
2.4 Study design
Patients were told that erectile function may be affected by
b-blocker therapy and that the aim of our study was
to investigate the effect of a new b-blocker on erectile function, irrespective of whether ED was present or not.
Moreover, the patients were also told that we did not know the effect of the new drug on erectile function. The doctor
treating the patients was not aware of the status of the patients’ erectile function, because other doctors evaluated the
questionnaire. Thus, every effort was made to ensure the best possible blinding, although the study was open and not
double-blinded.
The patients stopped taking the β-blockers they had been using and nebivolol therapy was initiated. No other
changes were made regarding the management of the patients apart from the
b-blocker switch. The dose of nebivolol (5-10mg/d) was equivalent to (according to the Summaries of Product Characteristics [SPCs] of the two drugs,
product monographs and studies conducted using these two
drugs) previous b-blocker dosing (atenolol
50-100mg/d). The mean dose of atenolol was 63mg/d, while the mean nebivolol dose was 6.45mg/d. Three months later,
patients were asked to complete the same questionnaire.
2.5 Statistical analysis
Data were reported as mean?plusmn; SD. Statistical analyses were carried out using paired
t-test to compare erectile function scores before and after switching from
β-blockers to nebivolol. Associations were considered to be
statistically significant if the P (0.05. Data were processed using the STATISTICA (Version 5.0, Statsoft Inc., Tulsa, OK,
USA) statistical programme for Windows.
3 Results
3.1 Characteristics of study population
The patients’ characteristics before and after nebivolol administration are described in Table 1. There were no
statistically significant differences regarding systolic and diastolic blood pressure, heart rate, body weight, cigarette
consumption and alcohol intake before and three months after the substitution of
β-blockers with nebivolol.
3.2 ED before and after nebivolol
ED of any degree was found in 29 out of 44 patients (65.9%) taking
β-blockers. Severe ED was found in 8 of 44 patients (18.2%), moderate ED was found in 13 of 44 patients (29.5%), and mild ED in 8 of 44 patients (18.2%)
(Figure 1A).
Overall, the erectile function of 20 out of 29 (69.0%)
patients with ED exhibited a statistically significant
improvement after a 3-month period of nebivolol
admini-stration. Normal erectile function re-appeared in 11 of these patients.
Of the eight patients with severe ED, one experienced no change, six experienced an improvement to moderate and
one to mild dysfunction. Of the 13 patients with moderate ED, six experienced no change, one experienced an
improvement to mild ED, five regained normal function, and one deteriorated to severe ED. Of
the eight patients with mild ED, two remained the same class and six improved to normal erectile function. Erectile function remained unaltered
in all patients with normal erectile function, with three patients exhibiting a slight deterioration, and six showing a slight
improvement, while remaining within the normal limits. At the end of the study period, severe ED was found in only two
patients, mode-rate ED in 12 patients, and mild ED in four patients (Figure 1B).
Figure 2 showed the erectile function scores before and after nebivolol administration, and Figure 3 showed the
times of sexual intercourse per month before and after nebivolol. Both of the parameters improved significantly
(P(0.001) after the substitution of β-blockers with nebivolol.
4 Discussion
Our findings indicated that the substitution of
β-blockers with nebivolol resulted in a significant improvement in
the erectile function of patients with essential hypertension; some patients even regained normal erectile function.
β-blockers seem to exert a negative effect on male erectile function [2]. Propranolol exerts this effect in doses
exceeding 120 mg/d. b1-selective blockers, such as atenolol, exhibit a milder negative effect (also dose-related) than
propranolol [3]. Atenolol at doses of 50-100mg/d significantly deteriorates the ability of patients to maintain erections
[4]. Moreover, spouses of younger patients have noted a significant reduction in their partners’ interests and abilities
to fulfill their sexual function. In a previous double-blind, parallel study, atenolol seemed to be inferior to celiprolol in
terms of its effect on sexual activity [4]. Moreover, atenolol seems to negatively
affect erectile function more than other types
of antihypert-ensives, such as lisinopril and valsartan [5, 6]. On the other hand, atenolol at low doses seems to
have a less harmful profile. In the Antihypertensive Interventions and Management (TAIM) study, ED was more
frequent in patients taking 50mg of atenolol than that in patients taking a placebo (11%
vs. 3%), but the difference was not statistically significant [14]. However, atenolol was frequently prescribed at a dose of 100 mg/d, and it
appeared that this amount resulted in ED [15].
The exact mechanism of ED caused by β-blockers remained unclarified. The adverse effect of
β-blockers on sexual activity may be due to an interference with the adrenergic system’s function (which was involved in the integration phase
of erection and ejaculation). However, recent evidence suggested that peripheral vasoconstriction induced by
β-blockers may not explain the effects on erectile function. Carvedilol (a
b-blocker with vasodilatory activity) markedly impaired
sexual function compared with valsartan (an angiotensin II receptor blocker with vasodilatory activity) in a previous study
[16].
Drug therapy seems to account for ED in approximately one of four cases, and ED is mostly readily reversible
when the drug is stopped, or a suitable alternative is given [2]. In a recent study, patients on various antihypertensive
medications were switched to losartan (an angiotensin II receptor antagonist) and exhibited a marked increase in
sexual satisfaction [17]. In our study, the substitution of
β-blockers with nebivolol resulted in a marked improvement
in the erectile function of essential hypertensive patients presenting with ED.
Penile erection is a complex, neurovascular event, involving increased arterial inflow and restricted venous outflow,
coordinated with corpus cavernosum smooth muscle relaxation. NO has recently been recognized to play a key role
in the physiology of penile erection [18]. Accumulating data suggest that NO derived from the autonomic innervation
of the penis, functions locally as a neurotransmitter of nonadrenergic noncholinergic nerves. NO results in increased
intracellular accumulation of cGMP leading to corporeal smooth muscle relaxation. Relaxation of the trabecular smooth
muscle increases the compliance of the sinusoids, thus enhancing the rapid filling and the expansion of the sinusoidal
system. Moreover, the subtunical venular plexuses are compressed between the trabecular and the tunica albuginea
resulting in decreased venous outflow. The role of NO in the physiology of male sexual function establishes its
importance as the principal modulator of penile erection [18]. Thus, drugs that can induce NO liberation may improve
erectile function.
Nebivolol is a recently developed b1-blocker, devoid of intrinsic sympathomimetic activity, with a high selectivity
for b1-adrenoceptors [7]. Nebivolol is a racemic mixture of
D- and L-enantiomeres. The
b1-blocker property resides in the
D-enantiomer. Nebivolol has also been shown to induce vasodilatation both in animal and human, and its
vasorelaxant activity attributes to the L-enantiomer. Several lines of experimental evidence suggested that
endothelium-derived NO played a crucial role in nebivolol-induced vasodilatation. Nebivolol produced endothelium-dependent
relaxation that was abolished by endothelial denudation or NO inhibitors [8, 19]. Human data confirmed animal
observations, because nebivolol increased the forearm blood flow in normotensive and hypertensive subjects, and this
action was antagonized by
NG-monomethyl-L-arginine (L-NMMA, an NO inhibitor) [20]. Moreover, nebivolol has
been shown to increase the basal and stimulated release of endothelial NO in patients with essential hypertension [21].
Thus, nebivolol may exert favorable actions on erectile function through NO release in hypertensive patients.
In conclusion, previous data indicate that β-blockers significantly affect the erectile function of hypertensive patients.
Nebivolol exerts favorable effects on the erectile function of hypertensive patients with ED while taking
β-blockers, possibly because of the increased nitric oxide availability. The results of our study suggest that nebivolol has a beneficial
effect on the erectile function of hypertensive patients with ED while on
b-blocker therapy. However, further larger,
prospective, randomized, placebo-controlled, double-blind studies are needed to confirm our results, and to verify the
beneficial effect of nebivolol on erectile function.
Acknowledgment
The authors would like to acknowledge Dr Antoniou Vicki and Dr Paraskeuakou Giorgia for their contributions to
data management.
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Figure 2. Erectile function score before and after nebivolol administration. (A): Change in each patient's erectile function score due to
nebivolol use; The different types of lines represent the four different categories in the prevalence of erectile dysfunction: severe (6-10
points, dotted black line), moderate (11-16 points, continuous grey line), mild (17-25 points, interrupted black line), and none (26-30
points, continuous black line). (B): Patients' mean erectile function score (+SD) before and after nebivolol administration.
cP < 0.01, compared with patients before nebivolol administration,
n=44.
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