Original Article
Hemodynamic Effects of Sildenafil in Men with Severe Coronary Artery Disease
N Engl J Med 2000; 342:1622-1626June 1, 2000
- Abstract
Background
The cardiovascular effects of sildenafil are important because of the frequent presence of underlying cardiac disease in men with erectile dysfunction and reports indicating serious cardiac events temporally associated with the use of this drug.
Methods
We assessed the systemic, pulmonary, and coronary hemodynamic effects of oral sildenafil (100 mg) in 14 men (mean [±SD] age, 61±11 years) with severe stenosis of at least one coronary artery (stenosis of >70 percent of the vessel diameter) who were scheduled to undergo percutaneous coronary revascularization. Blood-flow velocity and flow reserve were assessed with a Doppler guidewire in 25 coronary arteries, including 13 severely diseased arteries (mean degree of stenosis, 78±7 percent) and 12 arteries without stenosis, used as a reference; maximal hyperemia was induced (to assess flow reserve) with the intracoronary administration of adenosine both before and after sildenafil.
Results
Oral sildenafil produced only small decreases (<10 percent) in systemic arterial and pulmonary arterial pressures, and it had no effect on pulmonary-capillary wedge pressure, right atrial pressure, heart rate, or cardiac output. There were no significant changes in average peak coronary flow velocity, coronary-artery diameter, volumetric coronary blood flow, or coronary vascular resistance. Coronary flow reserve at base line was lower in the stenosed arteries (1.26±0.26) than in the reference arteries (2.19± 0.44) and increased about 13 percent in both groups of arteries combined after the administration of sildenafil (from 1.70±0.59 to 1.92±0.72, P=0.003). The ratio of coronary flow reserve in coronary arteries with stenosis to that in the reference arteries (0.57±0.14) was not affected by sildenafil.
Conclusions
No adverse cardiovascular effects of oral sildenafil were detected in men with severe coronary artery disease.
Media in This Article
Figure 2
Individual and Mean (±SD) Values for Coronary Flow Reserve.Figure 1
Individual and Mean (±SD) Values for Average Peak Coronary Blood Velocity at Base Line and after the Administration of Sildenafil in All 25 Coronary Arteries.Article Activity
- Article
Erectile dysfunction affects up to 30 million men in the United States1 and may be particularly common in patients with heart disease, because of the presence of overlapping risk factors, including older age, diabetes mellitus, hypertension, and hypercholesterolemia.2 Sildenafil (Viagra, Pfizer, New York) inhibits cyclic guanosine monophosphate (cGMP)–specific phosphodiesterase type 5 in the corpus cavernosum and significantly improves erectile function and the rate of successful sexual intercourse in men with erectile dysfunction.3
Post-marketing surveillance data after approval of sildenafil by the Food and Drug Administration revealed a number of serious cardiovascular events, including myocardial infarction and sudden death from cardiac causes, temporally associated with the use of the drug.4 Although it has been suggested that these events were not unexpected given the characteristics of the population of men who were prescribed sildenafil,5 a few of the events occurred shortly after ingestion of sildenafil and before any attempt at sexual intercourse.6 It is not possible to determine whether these events were directly related to the use of sildenafil, the patient's underlying cardiovascular disease, or a combination of these and other factors. Since phosphodiesterase is also present in vascular smooth muscle,7 we hypothesized that if sildenafil had direct adverse cardiovascular effects, they could be detected by measuring the systemic and coronary hemodynamic effects of this drug in men with severe coronary artery disease.
Methods
Study Subjects
We studied the effects of sildenafil in 14 men with a mean (±SD) age of 61±11 years. All the men had severe stenosis (of >70 percent of the vessel diameter) in at least one coronary artery, and had been referred for percutaneous revascularization. All study subjects provided written informed consent, and the protocol was approved by the institutional review board at the University of Pennsylvania.
Study Protocol
All the men had stable symptoms that permitted the discontinuation of nitrates at least 24 hours before the start of the study; other medications, including beta-blockers, aspirin, heparin, and angiotensin-converting–enzyme inhibitors, were continued as clinically indicated. The men were studied while in a supine position and while fasting after premedication with oral diphenhydramine and diazepam.
Hemodynamic measurements included arterial blood pressure, recorded from a 7-French guide catheter in the coronary orifice; pulmonary-artery pressure and pulmonary-capillary wedge pressure, measured from the distal port of a 7-French Swan–Ganz catheter; and right atrial pressure, measured from the proximal port of the Swan–Ganz catheter. Heart rate and cardiac output determined by thermodilution were also recorded. A Doppler steerable guidewire (0.036 cm [0.014 in.] in diameter) (Flowire, Endosonics, Rancho Cordoba, Calif.) was then advanced into the coronary artery and coupled to a real-time spectrum analyzer and videocassette recorder. Angiography was performed with a nonionic contrast medium. The average peak velocity and coronary flow reserve at base line were measured before and after the administration of intracoronary adenosine (12 μg in the right coronary artery and 18 μg in the left coronary artery).8 After base-line measurements were obtained, 100 mg of sildenafil was administered orally, and all measurements were repeated, starting 45 minutes later (mean time between measurements, approximately 60 minutes).
A previous study has demonstrated a peak serum concentration of sildenafil 0.8 to 0.9 hour after a 100-mg oral dose.9 The hemodynamic and coronary flow measurements reported were the average of 10 beats and the average of three observations, respectively. Quantitative coronary angiographic assessments of the severity of stenosis and coronary diameter at the tip of the Doppler wire were made with digital electronic calipers and methods that have been previously validated.10,11 Percutaneous coronary revascularization was performed at the conclusion of the study.
Calculations
Standard hemodynamic formulas were used to calculate systemic and pulmonary vascular resistance and their indexes. Coronary flow reserve was measured in real time as the ratio of peak hyperemic velocity after the administration of adenosine to average peak velocity at base line. Measurements from 13 of 14 target vessels that underwent revascularization were analyzed. Measurements obtained in the proximal portion of a bypassed left anterior descending artery, which was the target vessel for intervention in one man, were discarded because of interference with the profile of flow velocity from retrograde coronary flow. Measurements were also obtained in the branch of the left coronary artery without stenosis (reference artery) in 12 men (measurements were not obtained in 2 men who underwent right-coronary-artery intervention). Thus, a total of 25 coronary arteries in the 14 men were studied, including 13 severely diseased arteries and 12 reference arteries.
Coronary blood flow was calculated as follows: (the average peak velocity ÷ 2) × the cross-sectional area of the coronary artery, calculated as π × (diameter of the artery ÷ 2)2, which assumes a time-averaged parabolic velocity profile and a cylindrical coronary artery.8 Coronary vascular resistance (in millimeters of mercury per milliliter per minute) was calculated for the reference vessels as the mean arterial pressure divided by the coronary blood flow. Relative coronary flow velocity reserve in 11 men who had flow measurements in both a stenosed target vessel and a reference vessel was calculated as the ratio of the coronary flow reserve of the target vessel to the coronary flow reserve of the reference vessel.12
Statistical Analysis
The hemodynamic variables are shown as mean values ±SD. For individual variables, values after the administration of sildenafil were compared with base-line values by paired t-test. Differences were considered significant when P values were less than 0.05. All data were analyzed with SPSS statistical software (SPSS, Chicago).
Results
Clinical Characteristics
The study subjects were 14 men with stable angina and at least one severely stenosed coronary artery (mean degree of stenosis, 78±7 percent) who had been referred for percutaneous coronary revascularization. Among these men, there were high rates of hypertension (57 percent), diabetes mellitus (43 percent), and smoking (57 percent) (Table 1Table 1
Base-Line Characteristics of the Study Population.).Systemic and Pulmonary Hemodynamic Effects
The systemic and pulmonary hemodynamic effects of oral sildenafil are shown in Table 2Table 2
Hemodynamic Variables at Base Line and after Oral Sildenafil.. There were small but significant decreases (all less than 10 percent) in arterial blood pressure (systolic, diastolic, and mean pressure) and pulmonary pressure (systolic and mean pressure). The slightly smaller reductions in calculated systemic vascular resistance and pulmonary vascular resistance, and in the indexes of these measures, which are normalized for body-surface area, did not reach statistical significance. There were no significant changes in pulmonary-capillary wedge pressure, right atrial pressure, heart rate, cardiac output, or cardiac index. The heart rate times the systolic blood pressure (the double product) fell significantly, from 9435±1739 mm Hg per minute to 8641± 1722 mm Hg per minute (P=0.02).Coronary Hemodynamic Effects
The effects of oral sildenafil on the diameter of coronary arteries and on flow velocity before and after adenosine administration were measured in 25 arteries in 14 men, including 13 severely diseased arteries and 12 reference arteries in the same men. The mean results for all the men are shown in Table 3Table 3
Coronary Hemodynamic Effects of Oral Sildenafil..The average peak velocities at base line were 17.9± 12.5 cm per second in the stenosed arteries and 29.4±13.3 cm per second in the reference arteries. The mean base-line coronary blood flow and coronary vascular resistance were calculated as 33.01± 23.32 ml per minute and 3.34±1.49 mm Hg per milliliter per minute, respectively. Coronary flow reserve, assessed after intracoronary administration of adenosine, was lower in the severely stenosed arteries than in the reference arteries (1.26±0.26 vs. 2.19± 0.44, P<0.05).
Sildenafil caused no significant changes in the average peak velocity at base line (Figure 1Figure 1
Individual and Mean (±SD) Values for Average Peak Coronary Blood Velocity at Base Line and after the Administration of Sildenafil in All 25 Coronary Arteries.), coronary-artery diameter, coronary blood flow, or coronary vascular resistance. However, the hyperemic average peak velocity and coronary flow reserve increased 13 percent after the administration of sildenafil (Figure 2Figure 2Individual and Mean (±SD) Values for Coronary Flow Reserve.). These effects were consistently observed in reference arteries as well as severely stenosed arteries.Finally, relative coronary flow reserve was assessed in 11 men in whom measurements were made in both a severely stenosed artery and a reference vessel. The relative coronary flow reserve, calculated as the ratio of coronary flow reserve in diseased vessels to that in reference vessels, was unchanged by sildenafil (base line, 0.57±0.14; after sildenafil, 0.57±0.15; P=0.90).
Adverse Effects
There were no adverse effects attributable to the research procedures that were performed in this study. Subacute stent thrombosis developed in one man shortly after intervention, necessitating urgent repeated revascularization. None of the men had hypotension, chest pain, or any other side effect that could be attributed to sildenafil.
Discussion
Sildenafil is now frequently prescribed for men with erectile dysfunction. The relaxation of vascular smooth muscle in the corpus cavernosum that is necessary for penile erection is mediated by nitric oxide, which activates guanylate cyclase to produce cGMP. Sildenafil is a highly selective inhibitor of phosphodiesterase type 5, which degrades cGMP.13
Knowledge of the cardiovascular effects of sildenafil is important for a number of reasons. First, many men with erectile dysfunction may have cardiovascular disease. Risk factors for erectile dysfunction as well as for cardiovascular disease include older age, atherosclerosis, diabetes, hypertension, hyperlipidemia, and smoking.2 Second, serious cardiovascular events, including myocardial infarction and sudden death due to cardiac causes, have been reported in temporal association with sildenafil use.4-6 Finally, although sildenafil is highly selective for phosphodiesterase type 5, inhibition of this isozyme, which is present in platelets and vascular smooth muscle, as well as weak inhibition of other isozymes present in the heart, could potentially cause adverse cardiovascular effects.7
In this study of men with severe coronary artery disease, no adverse cardiovascular effects of oral sildenafil could be detected by measurement of systemic, pulmonary, or coronary hemodynamic variables. Previous studies of the hemodynamic effects of intravenous and oral sildenafil in normal men and men with stable ischemic heart disease have demonstrated a small but consistent decrease in systemic and pulmonary blood pressure after administration of the drug.9 The results of the present study confirm these findings in men with anatomically severe coronary disease. In addition, we investigated the effects of sildenafil on coronary hemodynamics.
Our data show that oral sildenafil does not adversely affect coronary blood flow, coronary vascular resistance, or coronary flow reserve. On the basis of the decrease in the heart rate–systolic blood pressure double product (a surrogate measure of myocardial oxygen demand), we might have expected a parallel decrease in coronary blood flow due to autoregulation. The absence of such a finding in our study may reflect the inaccuracy of the double product as a true measure of myocardial demand, variations in the calculated values for coronary blood flow and resistance, or a vasodilatory effect of sildenafil that blunts the expected reduction in coronary blood flow.
Interestingly, hyperemic coronary blood flow after the administration of adenosine, reflected as an increase in coronary flow reserve, increased in all the men treated with sildenafil. Adenosine dilates coronary resistance vessels by stimulating the production of cyclic AMP.14 It is possible that adenosine and sildenafil interact and that their interaction potentiates their individual effects on coronary resistance. The doses of adenosine used in our study have been shown to provide maximal coronary vasodilation,15 but our data suggest that further vasodilation is possible.
In this regard, a preliminary study demonstrated a slight increase in resting coronary blood flow and a more marked increase in coronary flow after exercise in dogs given sildenafil.16 Both the results of that study and our data in humans suggest that phosphodiesterase type 5 may play an important part in the regulation of coronary blood flow.
Our study did not address the mechanism for the previously reported adverse cardiovascular events after the use of sildenafil, but our results do suggest that this mechanism is not the result of an adverse effect on coronary hemodynamics. Others have speculated that cardiac events may be due to interactions with other drugs (particularly with nitrates17), to an increased risk of myocardial infarction due to an increase in myocardial oxygen demand resulting from sexual activity in a man with coronary disease, or to the shared risk factors for erectile dysfunction and coronary artery disease.5,18,19
Our study has several limitations. The Doppler guidewire was carefully placed to optimize signal strength and to ensure an accurate measurement of peak velocity. Nevertheless, this method assumes a time-averaged parabolic flow velocity, negates the effects of vessel tortuosity on alterations in pulsatility and the shape of the flow field, and assumes that the coronary artery is cylindrical and that the cross-sectional area can be accurately assessed by a single angiographic measurement.8 In addition, the measurements of coronary flow reserve incorporate both epicardial resistance and microvascular abnormalities. For this reason, we also measured relative coronary flow reserve, which is independent of microvascular flow, aortic pressure, and the rate–pressure double product.12,20 This measure confirmed the absence of an adverse effect of sildenafil on the coronary circulation. We cannot rule out the possibility that, because of variability among individual men, sildenafil could have an adverse effect in some patients or in those with other cardiovascular conditions and different hemodynamic status.
In conclusion, this study demonstrates that oral sildenafil has no direct adverse cardiovascular effects in men with severe coronary artery disease. In addition, a small positive effect on coronary blood-flow reserve was identified. Our data support the consensus position of the American College of Cardiology and the American Heart Association that sildenafil is safe for patients with stable coronary artery disease who are not taking medications containing nitrates.21
Presented in preliminary form at the 72nd Scientific Sessions of the American Heart Association, Atlanta, November 7–10, 1999.
Supported by a grant from Pfizer.
We are indebted to Morton J. Kern, M.D., for his thoughtful suggestions and to Renee Brown for secretarial assistance.
Source Information
From the Cardiovascular Division, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia.
Address reprint requests to Dr. Herrmann at the Hospital of the University of Pennsylvania, 9 Founder's Pavilion, 3400 Spruce St., Philadelphia, PA 19104, or at herrmann@mail.med.upenn.edu.
- References
References
1
NIH Consensus Development Panel on Impotence
CrossRef | Web of Science2
Feldman HA ,Goldstein I ,Hatzichristou DG ,Krane RJ ,McKinlay JB . Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151:54-61
Web of Science | Medline3
Goldstein I ,Lue TF ,Padma-Nathan H ,Rosen RC ,Steers WD ,Wicker PA . Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998;338:1397-1404[Erratum, N Engl J Med 1998;339:59.]
Full Text | Web of Science | Medline4
Viagra (sildenafil citrate). New York: Pfizer, June 1999 (package insert, rev.).
5
Zusman RM ,Morales A ,Glasser DB ,Osterloh IH . Overall cardiovascular profile of sildenafil citrate. Am J Cardiol 1999;83:35C-44C
CrossRef | Web of Science | Medline6
Feenstra J ,van Drie-Pierik RJHM ,Lacle CF ,Stricker BHCH . Acute myocardial infarction associated with sildenafil. Lancet 1998;352:957-958
CrossRef | Web of Science | Medline7
Wallis RM ,Corbin JD ,Francis SH ,Ellis P . Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol 1999;83:3C-12C
CrossRef | Web of Science | Medline8
Doucette JW ,Corl PD ,Payne HM , et al. Validation of a Doppler guide wire for intravascular measurement of coronary artery flow velocity. Circulation 1992;85:1899-1911
Web of Science | Medline9
Jackson G ,Benjamin N ,Jackson N ,Allen MJ . Effects of sildenafil citrate on human hemodynamics. Am J Cardiol 1999;83:13C-20C
CrossRef | Web of Science | Medline10
Scoblionko DP ,Brown BG ,Mitten S , et al. A new digital electronic caliper for measurement of coronary arterial stenosis: comparison with visual estimates and computer-assisted measurements. Am J Cardiol 1984;53:689-693
CrossRef | Web of Science | Medline11
Theron HD ,Lambert CR ,Pepine CJ . Videodensitometry versus digital calipers for quantitative coronary angiography. Am J Cardiol 1990;66:1186-1190
CrossRef | Web of Science | Medline12
Baumgart D ,Haude M ,Goerge G , et al. Improved assessment of coronary stenosis severity using the relative flow velocity reserve. Circulation 1998;98:40-46
Web of Science | Medline13
Ballard SA ,Gingell CJ ,Tang K ,Turner LA ,Price ME ,Naylor AM . Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J Urol 1998;159:2164-2171
CrossRef | Web of Science | Medline14
Matherne GP, Headrick JP, Liang BT. Adenosine receptor subtypes and cardioprotection in cardiac myocyte and transgenic models. In: Burnstock G, Dobson JG Jr, Liang BT, Linden J, eds. Cardiovascular biology of purines. Vol. 209. Dordrecht, the Netherlands: Kluwer Academic, 1998:86-107.
15
Wilson RF ,Wyche K ,Christensen BV ,Zimmer S ,Laxson DD . Effects of adenosine on human coronary arterial circulation. Circulation 1990;82:1595-1606
CrossRef | Web of Science | Medline16
Traverse JH ,Du R ,Chen YJ , et al. Sildenafil (Viagra) improves coronary blood flow distal to a coronary stenosis during exercise. Circulation 1999;100:Suppl I:I-489 abstract.17
Arora RR ,Timoney M ,Melilli L . Acute myocardial infarction after the use of sildenafil. N Engl J Med 1999;341:700-700
Full Text | Web of Science | Medline18
Muller JE ,Mittleman A ,Maclure M ,Sherwood JB ,Tofler GH . Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exertion. JAMA 1996;275:1045-1049
CrossRef | Web of Science19
Kloner RA ,Jarow JP . Erectile dysfunction and sildenafil citrate and cardiologists. Am J Cardiol 1999;83:576-582
CrossRef | Web of Science | Medline20
Gould KL ,Kirkeeide RL ,Buchi M . Coronary flow reserve as a physiologic measure of stenosis severity. J Am Coll Cardiol 1990;15:459-474
CrossRef | Web of Science | Medline21
Cheitlin MD ,Hutter AM Jr ,Brindis RG , et al. Use of sildenafil (Viagra) in patients with cardiovascular disease. Circulation 1999;99:168-177[Erratum, Circulation 1999;100:2389.]
Web of Science | Medline
- Citing Articles (95)
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1
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Alin Stirban, Ronald Tamler, Ioan Andrei Veresiu. (2011) Effects of phosphodiesterase type 5 inhibitors on endothelial function and cardiovascular autonomic nerve function in men. Journal of Men's Health 8:2, 109-118
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M T Rosenberg, M M Miner, A L Barnes, S W Janning. (2011) Stopwatch-assessed duration of erection: a new measure of the efficacy of erectile dysfunction treatments. International Journal of Impotence Research 23:1, 9-16
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CrossRef7
T. Reffelmann, R. A. Kloner. (2009) Phosphodiesterase 5 inhibitors: are they cardioprotective?. Cardiovascular Research 83:2, 204-212
CrossRef8
Haiying Zhang, Praveen Pakeerappa, Hyon Jae Lee, Steven A. Fisher. (2009) Induction of PDE5 and de-sensitization to endogenous NO signaling in a systemic resistance artery under altered blood flow. Journal of Molecular and Cellular Cardiology 47:1, 57-65
CrossRef9
Josep Maria Pomerol Monseny. (2009) Disfunción eréctil en el paciente con enfermedad cardiovascular. Medicina Clínica 132:8, 309-310
CrossRef10
Charalambos Vlachopoulos, Nikolaos Ioakeimidis, Konstantinos Rokkas, Christodoulos Stefanadis. (2009) Cardiovascular Effects of Phosphodiesterase Type 5 Inhibitors. Journal of Sexual Medicine 6:3, 658-674
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Alin Stirban, Dominique Laude, Jean-Luc Elghozi, Denise Sander, Marcus W. Agelink, Max J. Hilz, Dan Ziegler. (2009) Acute effects of sildenafil on flow mediated dilatation and cardiovascular autonomic nerve function in type 2 diabetic patients. Diabetes/Metabolism Research and Reviews 25:2, 136-143
CrossRef12
Robert A. Vigersky. 2009. Impotence. , 385-393.
CrossRef13
Yuan James Rao, Lei Xi. (2009) Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts. Acta Pharmacologica Sinica 30:1, 1-24
CrossRef14
Stefan Schäfer, Peter Kolkhof. (2008) Failure is an option: learning from unsuccessful proof-of-concept trials. Drug Discovery Today 13:21-22, 913-916
CrossRef15
Hyun Jun Park, Nam Cheol Park, Hong Bang Shim, Jong Kwan Park, Sung Won Lee, Kwangsung Park, Sae Woong Kim, Ki Hak Moon, Dong Hyeon Lee, Sang Jin Yoon. (2008) An Open-Label, Multicenter, Flexible Dose Study to Evaluate the Efficacy and Safety of Viagra ® (Sildenafil Citrate) in Korean Men with Erectile Dysfunction and Arterial Hypertension who are Taking Antihypertensive Agents. The Journal of Sexual Medicine 0:0, 080507065403859-???
CrossRef16
F Bellotto, M Ruscazio, G Bonanni, R Montisci, A Cutolo, C Sarais, T Setzu, A Borrini, S Iliceto. (2008) Immediate- and late-hemodynamic coronary effects of tadalafil in men with erectile dysfunction and coronary artery disease. International Journal of Impotence Research 20:2, 168-172
CrossRef17
Lorenzo Ghiadoni, Daniele Versari, Stefano Taddei. (2008) Phosphodiesterase 5 inhibition in essential hypertension. Current Hypertension Reports 10:1, 52-57
CrossRef18
Thorsten Reffelmann, Arne Kieback, Robert A Kloner. (2008) The cardiovascular safety of tadalafil. Expert Opinion on Drug Safety 7:1, 43-52
CrossRef19
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CrossRef20
Marco Guazzi, Michele Samaja, Ross Arena, Marco Vicenzi, Maurizio D. Guazzi. (2007) Long-Term Use of Sildenafil in the Therapeutic Management of Heart Failure. Journal of the American College of Cardiology 50:22, 2136-2144
CrossRef21
Steven R. Goldsmith. (2007) Type 5 Phosphodiesterase Inhibition in Heart Failure. Journal of the American College of Cardiology 50:22, 2145-2147
CrossRef22
Fuminobu Ishikura, Shintaro Beppu, Hiroaki Ueda, Ajay Nehra, Bijoy K. Khandheria. (2007) Effect of Sildenafil Citrate (Viagra) on Coronary Flow in Normal Subjects. Echocardiography 0:0, 070822040948004-???
CrossRef23
Steven W. Werns. (2007) Are nitrates safe in patients who use sildenafil? Maybe*. Critical Care Medicine 35:8, 1988-1990
CrossRef24
John D. Parker, Bradley A. Bart, David J. Webb, Michael J. Koren, Richard L. Siegel, Hao Wang, Bimal Malhotra, Frank Jen, Paul Glue. (2007) Safety of intravenous nitroglycerin after administration of sildenafil citrate to men with coronary artery disease: A double-blind, placebo-controlled, randomized, crossover trial*. Critical Care Medicine 35:8, 1863-1868
CrossRef25
Antonio Aversa, Roberto Bruzziches, Cristiana Vitale, Giuseppe Marazzi, Davide Francomano, Giuseppe Barbaro, Giovanni Spera, Giuseppe MC Rosano. (2007) Chronic sildenafil in men with diabetes and erectile dysfunction. Expert Opinion on Drug Metabolism & Toxicology 3:3, 451-464
CrossRef26
Oleg E. Osadchii. (2007) Myocardial Phosphodiesterases and Regulation of Cardiac Contractility in Health and Cardiac Disease. Cardiovascular Drugs and Therapy 21:3, 171-194
CrossRef27
S Doggrell. (2007) Do vardenafil and tadalafil have advantages over sildenafil in the treatment of erectile dysfunction?. International Journal of Impotence Research 19:3, 281-295
CrossRef28
Michael Kirby. (2007) Helping the failing heart and penis. International Journal of Clinical Practice 61:5, 716-718
CrossRef29
Gautham Ravipati, John A. McClung, Wilbert S. Aronow, Stephen J. Peterson, William H. Frishman. (2007) Type 5 Phosphodiesterase Inhibitors in the Treatment of Erectile Dysfunction and Cardiovascular Disease. Cardiology in Review 15:2, 76-86
CrossRef30
E R Schwarz, V Kapur, J Rodriguez, S Rastogi, S Rosanio. (2007) The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems. International Journal of Impotence Research 19:2, 139-148
CrossRef31
Anna Nachtnebel, Claudia Stöllberger, Marek Ehrlich, Josef Finsterer. (2006) Aortic Dissection After Sildenafil-induced Erection. Southern Medical Journal 99:10, 1151-1152
CrossRef32
Jonathan W. Weinsaft, Kathleen Hickey, Sabahat Bokhari, Arsalan Shahzad, Alun Bedding, Timothy M. Costigan, Margaret R. Warner, Jeffrey T. Emmick, Steven R. Bergmann. (2006) Effects of tadalafil on myocardial blood flow in patients with coronary artery disease. Coronary Artery Disease 17:6, 493-499
CrossRef33
Graham Jackson, Piero Montorsi, Melvin D. Cheitlin. (2006) Cardiovascular safety of sildenafil citrate (Viagra®): An updated perspective. Urology 68:3, 47-60
CrossRef34
F. Philippe, P. Bondil. (2006) La dysfonction érectile, un nouveau symptôme pour le cardiologue. Annales de Cardiologie et d'Angéiologie 55:4, 187-191
CrossRef35
Hossein A. Ghofrani, Ian H. Osterloh, Friedrich Grimminger. (2006) Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nature Reviews Drug Discovery 5:8, 689-702
CrossRef36
M. C. Sighinolfi, A. Mofferdin, S. De Stefani, A. Celia, S. Micali, A. F. G. Cicero, G. Bianchi. (2006) Changes in peak systolic velocity induced by chronic therapy with phosphodiesterase type-5 inhibitor. Andrologia 38:3, 84-86
CrossRef37
Mario Habek, Damir Petravi??. (2006) Stroke-An Adverse Reaction to Sildenafil. Clinical Neuropharmacology 29:3, 165-167
CrossRef38
Gregory D. Lewis, Christian Witzke, Pedro Colon-Hernandez, J. Luis Guerrero, Kenneth D. Bloch, Marc J. Semigran. (2006) Sildenafil Improves Coronary Artery Patency in a Canine Model of Platelet-Mediated Cyclic Coronary Occlusion After Thrombolysis. Journal of the American College of Cardiology 47:7, 1471-1477
CrossRef39
Howard C. Herrmann, Laurence A. Levine, Joseph Macaluso, Michelle Walsh, Danielle Bradbury, Stanley Schwartz, Emile R. Mohler, Stephen E. Kimmel. (2006) Can Atorvastatin Improve the Response to Sildenafil in Men with Erectile Dysfunction Not Initially Responsive to Sildenafil? Hypothesis and Pilot Trial Results.. The Journal of Sexual Medicine 3:2, 303-308
CrossRef40
T. J. Beckman, H. S. Abu-Lebdeh, L. A. Mynderse. (2006) Evaluation and Medical Management of Erectile Dysfunction. Mayo Clinic Proceedings 81:3, 385-390
CrossRef41
Graham Jackson, Raymond C. Rosen, Robert A. Kloner, John B. Kostis. (2006) The Second Princeton Consensus on Sexual Dysfunction and Cardiac Risk: New Guidelines for Sexual Medicine. The Journal of Sexual Medicine 3:1, 28-36
CrossRef42
P. DEIBERT, Y.-O. SCHUMACHER, G. RUECKER, O. G. OPITZ, H. E. BLUM, M. ROSSLE, W. KREISEL. (2006) Effect of vardenafil, an inhibitor of phosphodiesterase-5, on portal haemodynamics in normal and cirrhotic liver - results of a pilot study. Alimentary Pharmacology and Therapeutics 23:1, 121-128
CrossRef43
Sivaprakasam Sivalingam, Hashim Hashim, Hartwig Schwaibold. (2006) An Overview of the Diagnosis and Treatment of Erectile Dysfunction. Drugs 66:18, 2339-2355
CrossRef44
Arslan Ardicoglu, Ercan Kocakoc, Veysel Yuzgec, Zulkif Bozgeyı ık, Halit Canatan, Adem Kiris. (2005) Hemodynamic Effects of Sildenafil Citrate (Viagra) on Segmental Branches of Bilateral Renal Arteries. International Urology and Nephrology 37:4, 785-789
CrossRef45
R A Kloner. (2005) A case of erectile dysfunction and risk factors for coronary artery disease. International Journal of Impotence Research 17, S7-S11
CrossRef46
Ahmed Tawakol, Kusai Aziz, Raymond Migrino, Justyna Watkowska, Randall Zusman, Nathaniel M. Alpert, Alan J. Fischman, Henry Gewirtz. (2005) Effects of sildenafil on myocardial blood flow in humans with ischemic heart disease. Coronary Artery Disease 16:7, 443-449
CrossRef47
Ahmed I El-Sakka. (2005) Cardiovascular system as a ‘core’ of sexual life. Expert Opinion on Pharmacotherapy 6:13, 2223-2230
CrossRef48
Sharron H Francis, Jackie D Corbin. (2005) Sildenafil: efficacy, safety, tolerability and mechanism of action in treating erectile dysfunction. Expert Opinion on Drug Metabolism & Toxicology 1:2, 283-293
CrossRef49
Murat Koksal, Huseyin Ozdemir, Sebnem Kargi, Cetin Yesilli, Sühan Tomaç, Kamran Mahmutyazicioglu, Aydin Mungan. (2005) The effects of sildenafil on ocular blood flow. Acta Ophthalmologica Scandinavica 83:3, 355-359
CrossRef50
G. Jackson, H. Gillies, I. Osterloh. (2005) Past, present, and future: a 7-year update of Viagra® (sildenafil citrate). International Journal of Clinical Practice 59:6, 680-691
CrossRef51
R Kloner, H Padma-Nathan. (2005) Erectile dysfunction in patients with coronary artery disease. International Journal of Impotence Research 17:3, 209-215
CrossRef52
Thorsten Reffelmann, Robert A Kloner. (2005) Pharmacotherapy of erectile dysfunction: focus on cardiovascular safety. Expert Opinion on Drug Safety 4:3, 531-540
CrossRef53
Graham Jackson, Matyas Keltai, Miklos Csanady, Istvan Edes, Gregory R. Bellamy, Petr Widimsky, Libor Lisa, Hunter Gillies. (2005) Hemodynamic Effects of Sildenafil Citrate and Isosorbide Mononitrate in Men with Coronary Artery Disease and Erectile Dysfunction. The Journal of Sexual Medicine 2:3, 407-414
CrossRef54
Ercan Kocakoc, Arslan Ardicoglu, Zulkif Bozgeyik, Adem Kiris, Veysel Yuzgec, Erkin Ogur. (2005) Effects of sildenafil on major arterial blood flow using duplex sonography. Journal of Clinical Ultrasound 33:4, 173-175
CrossRef55
Sheila A Doggrell. (2005) Comparison of clinical trials with sildenafil, vardenafil and tadalafil in erectile dysfunction. Expert Opinion on Pharmacotherapy 6:1, 75-84
CrossRef56
Andrea Salonia, Alberto Briganti, Piero Montorsi, Tommaso Maga, Federico Deh??, Giuseppe Zanni, Bruno Mazzoccoli, Nazareno Suardi, Patrizio Rigatti, Francesco Montorsi. (2005) Safety and Tolerability of Oral Erectile Dysfunction Treatments in the Elderly. Drugs & Aging 22:4, 323-338
CrossRef57
Stephen L Archer, Ferrante S Gragasin, Linda Webster, Derek Bochinski, Evangelos D Michelakis. (2005) Aetiology and Management of Male Erectile Dysfunction and Female Sexual Dysfunction in Patients with Cardiovascular Disease. Drugs & Aging 22:10, 823-844
CrossRef58
Marco Guazzi, Gabriele Tumminello, Fabio Di Marco, Cesare Fiorentini, Maurizio D. Guazzi. (2004) The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. Journal of the American College of Cardiology 44:12, 2339-2348
CrossRef59
Shahzad G. Raja, Suneela H. Nayak. (2004) Sildenafil: Emerging Cardiovascular Indications. The Annals of Thoracic Surgery 78:4, 1496-1506
CrossRef60
A. Boshier, L.V. Wilton, S.A.W. Shakir. (2004) Evaluation of the safety of sildenafil for male erectile dysfunction: experience gained in general practice use in England in 1999. BJU International 93:6, 796-801
CrossRef61
Robert A. Kloner. (2004) Erectile dysfunction in the cardiac patient. Comprehensive Therapy 30:1, 50-54
CrossRef62
Ansu Basu, Robert E J Ryder. (2004) New Treatment Options for Erectile Dysfunction in Patients with Diabetes Mellitus. Drugs 64:23, 2667-2688
CrossRef63
Culley C. Carson. (2003) Sildenafil: A 4-year update in the treatment of 20 million erectile dysfunction patients. Current Urology Reports 4:6, 488-496
CrossRef64
Robert A. Kloner. (2003) Erectile dysfunction in the cardiac patient. Current Urology Reports 4:6, 466-471
CrossRef65
Sharron H. Francis, Jackie D. Corbin. (2003) Molecular mechanisms and pharmacokinetics of phosphodiesterase-5 antagonists. Current Urology Reports 4:6, 457-465
CrossRef66
Virendra N. Sehgal, Govind Srivastava. (2003) Erectile Dysfunctions. SKINmed 2:6, 350-357
CrossRef67
S. Bhatia, R. P. Frantz, C. J. Severson, L. A. Durst, M. D. McGoon. (2003) Immediate and Long-term Hemodynamic and Clinical Effects of Sildenafil in Patients With Pulmonary Arterial Hypertension Receiving Vasodilator Therapy. Mayo Clinic Proceedings 78:10, 1207-1213
CrossRef68
Melvin D. Cheitlin. (2003) Should the Patient With Coronary Artery Disease Use Sildenafil?. Preventive Cardiology 6:3, 161-165
CrossRef69
Yoram Vardi, Mondir Bulus, Shimon Reisner, Suliman Nassar, Louis Aboud, Elliot Sprecher, Ilan Gruenwald. (2003) Effects of Sildenafil Citrate (Viagra®) on Hemodynamic Parameters during Exercise Testing and Occurrence of Ventricular Arrhythmias in Patients with Erectile Dysfunction and Cardiovascular Disease. European Urology 43:5, 544-551
CrossRef70
IOANNIS STANOPOULOS, DIMITRIOS HATZICHRISTOU, STAVROS TRYFON, VASILIOS TZORTZIS, APOSTOLOS APOSTOLIDIS, PARASKEVI ARGYROPOULOU. (2003) Effects of Sildenafil on Cardiopulmonary Responses During Stress. The Journal of Urology 169:4, 1417-1421
CrossRef71
Culley C Carson. (2003) Long-term use of sildenafil. Expert Opinion on Pharmacotherapy 4:3, 397-405
CrossRef72
Shigetake Sasayama, Nobuhisa Ishii, Fuminobu Ishikura, Gombei Kamijima, Satoshi Ogawa, Katsuo Kanmatsuse, Yasusuke Kimoto, Ichiro Sakuma, Hiroshi Nonogi, Akira Matsumori, Yasuhiro Yamamoto. (2003) Men's Health Study. Circulation Journal 67:8, 656-659
CrossRef73
Diane Tran, Laurence Guy Howes. (2003) Cardiovascular Safety of Sildenafil. Drug Safety 26:7, 453-460
CrossRef74
Jackie Corbin, Stephen Rannels, Doss Neal, Paul Chang, Kennard Grimes, Alfreda Beasley, Sharron Francis. (2003) Sildenafil citrate does not affect cardiac contractility in human or dog heart. Current Medical Research and Opinion 19:8, 747-752
CrossRef75
Andrea Salonia, Patrizio Rigatti, Francesco Montorsi. (2003) Sildenafil in erectile dysfunction: a critical review. Current Medical Research and Opinion 19:4, 241-262
CrossRef76
Stuart D. Katz. (2003) Potential Role of Type 5 Phosphodiesterase Inhibition in the Treatment of Congestive Heart Failure. Congestive Heart Failure 9:1, 9-15
CrossRef77
N Danchin. (2002) Le sildenafil (Viagra®), 5 ans après : données actuelles en pathologie cardiovasculaire. Annales de Cardiologie et d'Angéiologie 51:6, 341-345
CrossRef78
Donald Richardson, Aaron Vinik. (2002) Etiology and treatment of erectile failure in diabetes mellitus. Current Diabetes Reports 2:6, 501-509
CrossRef79
Julian P.J Halcox, Khaled R.A Nour, Gloria Zalos, Rita Mincemoyer, Myron A Waclawiw, Candido E Rivera, Georgia Willie, Samer Ellahham, Arshed A Quyyumi. (2002) The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia. Journal of the American College of Cardiology 40:7, 1232-1240
CrossRef80
Harin Padma-nathan, Ian Eardley, Robert A Kloner, Alan M Laties, Francesco Montorsi. (2002) A 4-year update on the safety of sildenafil citrate (Viagra®). Urology 60:2, 67-90
CrossRef81
BERNARD TH??BAUD, EVANGELOS MICHELAKIS, XI-CHEN WU, GWYNETH HARRY, KYOKO HASHIMOTO, STEPHEN L. ARCHER. (2002) Sildenafil Reverses O2 Constriction of the Rabbit Ductus Arteriosus by Inhibiting Type 5 Phosphodiesterase and Activating BKCa Channels. Pediatric Research 52:1, 19-24
CrossRef82
Yoram Vardi, Lavi Klein, Suliman Nassar, Elliot Sprecher, Ilan Gruenwald. (2002) Effects of sildenafil citrate (viagra) on blood pressure in normotensive and hypertensive men. Urology 59:5, 747-752
CrossRef83
Ian H. Osterloh, Alan Riley. (2002) Clinical update on sildenafil citrate. British Journal of Clinical Pharmacology 53:3, 219-223
CrossRef84
John A. Thomas. (2002) Pharmacological Aspects of Erectile Dysfunction. The Japanese Journal of Pharmacology 89:2, 101-112
CrossRef85
Gerald B. Brock, Derek Bochinski. (2001) Modern pharmacotherapy for erectile dysfunction: evolving concepts with central and peripheral acting agents. Current Opinion in Urology 11:6, 625-630
CrossRef86
Peter N Schlegel. (2001) What’s new in urology11No competing interests declared.. Journal of the American College of Surgeons 193:2, 179-201
CrossRef87
I. Osterloh, R. Hargreaves. (2001) Editor's comment on: ‘Press release: Further research supports Viagra™ safety profile’. BJU International 87:9, 905-907
CrossRef88
Harin Padma-Nathan, Francois Giuliano. (2001) ORAL DRUG THERAPY FOR ERECTILE DYSFUNCTION. Urologic Clinics of North America 28:2, 321-334
CrossRef89
E Boyce. (2001) Sildenafil citrate: A therapeutic update. Clinical Therapeutics 23:1, 2-23
CrossRef90
Karin Przyklenk, Robert A Kloner. (2001) Sildenafil citrate (Viagra) does not exacerbate myocardial ischemia in canine models of coronary artery stenosis. Journal of the American College of Cardiology 37:1, 286-292
CrossRef91
John P. Pryor. (2000) Safety of sildenafil. Current Opinion in Urology 10:6, 613-615
CrossRef92
. (2000) Acuut myocardinfarct als gevolg van combinatie van sildenafil, nitroglycerine sildenafil, myocardinfarct sildenafilsildenafil met nitroglycerine. Medisch-Farmaceutische Mededelingen 38:10, 205-205
CrossRef93
(2000) Hemodynamic Effects of Sildenafil. New England Journal of Medicine 343:13, 967-968
Full Text94
&NA;. (2000) Sildenafil has no direct adverse cardiovascular effects. Reactions Weekly &NA;:805, 3
CrossRef95
&NA;. (2000) Sildenafil has no direct adverse cardiovascular effects. Inpharma Weekly &NA;:1241, 20
CrossRef
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