Sildenafil is a selective vasodilator that prolongs the action of cGMP, the primary mediator in the corpus cavernosum of the penis, by selectively inhibiting cGMP-specific phosphodiesterase type 5 (PDE5) isozyme.1 Sildenafil induces mild, transient, non-dose-dependent decreases in blood pressure with no change in heart rate.2 Concern of temporally related cardiovascular events, including myocardial infarction, arrhythmias, and death, reported after the release of sildenafil to the market raised questions regarding the safety of sildenafil in patients with cardiovascular disease.3 A recent study by Phillips and colleagues demonstrated a significant increase in muscle sympathetic nerve activity (MSNA) in healthy young men after a single 100-mg dose of sildenafil.4 The MSNA increase did not, however, result in an increase in heart rate, from which the authors concluded that the sympathetic activation they observed was selective for the vascular sympathetic drive only. Given the highly differentiated nature of autonomic efferent effect activity, the measurement of MSNA as a pure index of peripheral sympathetic outflow might allow no definitive conclusions to be made about the autonomic control of the sinoatrial node. A non-invasive method for evaluation of autonomic cardiac control involves standardized investigation of heart rate variability (HRV). To our knowledge, this is the first well-designed trial examining the effects of sildenafil on heart rate variability under standardized conditions in healthy humans when given at a maximum dose.
We prospectively studied 20 healthy male volunteers (age, 24 ± 2 years; mean ± SD). Subjects weighed 78 ± 12 kg, were 183 ± 6 cm in height, and none were taking any medications. The study was conducted according to the Declaration of Helsinki (Edinburgh Amendment 2000) and German regulations. Written informed consent from the subjects and approval from the University Hospital Ethics Committee (Erlangen, Germany) were obtained.
Subjects were randomized in a double-blind crossover fashion to receive a single oral 100-mg dose of sildenafil citrate or placebo on 2 separate study days. Both sildenafil and placebo preparations were contained in identical capsules so that subjects and study investigators were not aware of which preparation was being administered. On each study day, ECG recordings were conducted during 5 minutes of undisturbed supine rest in carefully standardized conditions before drug intake. Identical measurements were subsequently recorded during metronomic breathing (6 cycles per minute) and bicycle ergometry at 75 watts. All measurements were repeated at 60 minutes after intake of sildenafil and placebo.
Heart Rate Variability
Heart rate analysis was carried out with the computer program Chart (AD Instruments, Castle Hill, Australia). The ECG signal was digitized at a sample rate of 400 per second. Respiration was monitored by registration of chest movements. Following ECG recording during relaxed rest, subjects were instructed to breathe deeply at a frequency of 6 cycles per minute (6 s of inspiration, 4 s of expiration) as deep respiration was previously demonstrated to produce maximal HRV in healthy volunteers.5 Subsequently, subjects performed bicycle ergometry at 75 watts for 5 minutes. The root mean square of successive differences of R-R intervals (RMSSD) and standard deviation of normal-to-normal intervals (SDNN) were calculated from 200 artefact free beats.
The statistical analysis of all data was performed with the SPSS software package for Microsoft Windows application (version 11.5). Differences between baseline and treatment conditions were calculated for heart rate and RMSSD. Evaluation was done with Kruskall-Wallis and Wilcoxon 2-sample tests, as the parameters were found not normally distributed. Statistical significance was accepted at P < 0.05.
As it is outlined in Table 1, heart rate was not found to be influenced by sildenafil during relaxed rest, metronomic breathing, or with the subjects performing bicycle ergometry. Physical activity increased heart rate and decreased HRV as compared to resting conditions. Administration of sildenafil did not have a significant effect on the RMSSD nor SDNN assessed under conditions of relaxed rest, metronomic breathing and physical activity.
In the present study sildenafil had no effect on heart rate and time domain measures of heart rate variability assessed under conditions of relaxed rest, metronomic breathing and standardized physical activity when given at single oral doses of 100 mg. By contrast, Fogari and colleagues previously reported an increase in heart rate and a decrease in HRV after oral administration of 50 mg of sildenafil in a small-sized mixed gender study with healthy humans.6 Piccirillo and co-workers described an increase in sympathetic outflow to heart and a decrease in cardiac vagal tone by means of HRV analysis in subjects with chronic heart failure who received single oral doses of 50 mg of sildenafil.7 In a naturalistic study, no significant effect of sildenafil on heart rate and HRV was observed when given at single doses up to 50 mg to patients with erectile dysfunction.8 Cornolo and colleagues examined the influence of sildenafil in a small number of healthy humans when being exposed to great heights and could not detect any effect.9 Heart rate variability depends on autonomic sympathovagal balance. In patients with proven coronary heart disease, a decrease in HRV (which reflects a predominance of sympathetic activity over parasympathetic activity) precedes the onset of clinical signs of acute myocardial ischemia, i.e., pain and sweating. A reduction of vagal tone (measured as a reduction in HRV) is associated with an increased cardiovascular morbidity and mortality; such an association has been demonstrated in various disease populations, including those with alcoholism, diabetes mellitus, and myocardial infarction.10-14 Ben-David and Zipes emphasized that autonomous nervous system integrity is important for preventing, promoting, or precipitating cardiac arrhythmias and sudden cardiac death.15 Vagal activity appears to have myocardioprotective and antiarrhythmogenic effects, which arise, on the one hand, because of direct inhibition of the myocardium and, on the other, through interference with sympathetic neurons.16 Against this background, our observation that sildenafil does not influence HRV and neurocardiac balance in healthy humans is certainly worthy of attention in the debate concerning a potential relationship between the autonomic nervous system effects of sildenafil and cases of sudden cardiovascular death. However, well-controlled studies in subjects with cardiovascular risk factors are needed to further explore the effects of sildenafil on autonomic cardiac control.
1. Boolell M, Allen MJ, Ballard SA, et al. Sildenafil: an orally type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res
2. Jackson G, Benjamin N, Jackson N, et al. Effects of sildenafil citrate on human hemodynamics. Am J Cardiol
. 1999;83(Suppl 5A):13C-20C.
3. Drory Y, Shapira I, Fisman EZ, et al. Myocardial ischemia during sexual activity in patients with coronary artery disease. Am J Cardiol
4. Phillips BG, Kato M, Pesek CA, et al. Sympathetic activation by sildenafil. Circulation
5. Siepmann M, Krause S, Joraschky P, et al. The effects of St. John's wort extract on heart rate variability, cognitive function and quantitative EEG: a comparison with amitriptyline in healthy men. Br J Clin Pharmacol
6. Fogari R, Mugellini A, Preti P, et al. Effect of sildenafil on blood pressure and heart rate in healthy normotensive volunteers. Am J Hypertens
7. Piccirillo G, Nocco M, Lionetti M, et al. Effects of sildenafil citrate (viagra) on cardiac repolarization and on autonomic control in subjects with chronic heart failure. Am Heart J
8. Agelink MW, Schmitz T, Rembrink K, et al. Cardiovascular effects of sildenafil citrate (Viagra®): a naturalistic cross over study. Eur J Med Res
9. Cornolo J, Mollard P, Brugniaux JV, et al. Autonomic control of the cardiovascular system during acclimatization to high altitude: effects of sildenafil. J Appl Physiol
10. Ewing DJ, Clarke BF. Autonomic neuropathy: its diagnosis and prognosis. Clin Endocrinol Metab
11. Johnson RH, Robinson BJ. Mortality in alcoholics with autonomic neuropathy. J Neurol Neurosurg Psychiatry
12. Kleiger RE, Miller JP, Bigger JT, et al. Decreased heart variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol
13. La Rovere MT, Bigger JT, Marcus FI, et al. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) investigators. Lancet
14. O'Brien IA, McFadden JP, Corrall RJ. The influence of autonomic neuropathy on mortality in insulin-dependent diabetes. Q J Med
15. Ben-David J, Zipes DP. Autonomic neural modulation of cardiac rhythm: part I - basic concepts. Mod Concepts Cardiovasc Dis
16. Lown B, Verrier RL. Neural activity and ventricular fibrillation. N Engl J Med