J Sex Med 2005; 2: 407–414

407

Blackwell Science, LtdOxford, UKJSMJournal of Sexual Medicine1743-6095Journal of Sexual Medicine 2005 200523407414Original Article

Hemodynamic Effects of SildenafilJackson et al.

ORIGINAL RESEARCH—PHARMACOTHERAPY

Hemodynamic Effects of Sildenafil Citrate and Isosorbide Mononitrate in Men with Coronary Artery Disease and Erectile Dysfunction

Graham Jackson,* Matyas Keltai,

†

Miklos Csanady,

‡

Istvan Edes,

§

Gregory R. Bellamy,

¶

Petr Widimsky,** Libor Lisa,

††

and Hunter Gillies

‡‡

*St. Thomas Hospital, London, UK;

†

Hungarian Institute of Cardiology, Budapest, Hungary;

‡

Albert Szent-Gyorgy Medical Center, Szeged, Hungary;

§

University of Debrecen—Cardiology, Debrecen, Hungary;

¶

John Hunter Hospital—Cardiovascular Unit, Newcastle, New South Wales, Australia; **University Hospital Kralovske Vinohrady—Cardiocentre, Prague, Czech Republic;

††

University Hospital Kralovske Vinohrady;

‡‡

Pfizer Ltd—PGRD, Sandwich, UK

Corresponding Author:

Graham Jackson, St. Thomas Hospital, Cardiac Department, Lambeth Palace Road, London,SE1 7 EH, UK. Tel: 44 (207) 407-5887; Fax: 44 (207) 357-7408; E-mail: gjcardiol@talk21.com

A B S T R A C T

Introduction.

Mild hemodynamic effects have been reported with sildenafil citrate therapy.

Aim.

To compare the hemodynamic effects of sildenafil and isosorbide mononitrate (ISMN) inmen with coronary artery disease and erectile dysfunction.

Methods.

A total of 31 men aged 35 years or older with coronary artery disease (at least 50%narrowing of the left main stem or at least 70% narrowing of any other coronary artery) and erectiledysfunction (receiving medication for erectile dysfunction or scoring less than 26 out of a maximumscore of 30 on the erectile function domain questions of International Index of Erectile Function)were randomized to sildenafil 100 mg (n

=

10), ISMN 40 mg (n

=

11), or placebo (n

=

10) in thissingle-dose multicenter study.

Main Outcome Measures.

Hemodynamic parameters were measured at baseline, 1, 2, 4, and6 hours post dose.

Results.

Compared with baseline, cardiac index increased slightly with sildenafil (0.29 L/min/m

2

at 1 hour) and decreased slightly with placebo (

-

0.12 L/min/m

2

at 4 hours) and ISMN (

-

0.14 L/min/m

2

at 1 hour). The stroke volume index increased from baseline at each time point post dosewith sildenafil (4.4 mL/m

2

at 2 hours), but decreased with ISMN (

-

5.8 mL/m

2

at 1 hour) andplacebo (

-

2.8 mL/m

2

at 4 hours). ISMN reduced mean arterial pressure more than sildenafil did(

-

22 vs.

-

10 mm Hg at 2 hours, respectively). Both sildenafil and ISMN increased heart rate (4 vs.7 beats/minute at 1 hour, respectively) and decreased systemic vascular resistance, but sildenafilproduced greater reductions in pulmonary vascular resistance. There were no serious adverseevents in the sildenafil group.

Conclusions.

Sildenafil 100 mg was well tolerated and induced smaller changes in central andperipheral hemodynamic pressures compared with ISMN 40 mg. Moreover, sildenafil selectivelyreduced pulmonary resistance, which may have clinical importance in pulmonary hypertension.

Key Words.

Male Erectile Disorder; Male Oral Vasoactive Agents; Sildenafil

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J Sex Med 2005; 2: 407–414

Introduction

he incidence of sexual dysfunction has beenreported to range from 39% to 64% in men

with a history of heart disease, vascular surgery,or myocardial infarction [1]. In fact, erectile dys-function (ED) and cardiovascular disease sharecommon risk factors and frequently coexist [2,3].Sildenafil citrate, a phosphodiesterase type 5inhibitor indicated for the treatment of ED, wasoriginally developed as an antianginal drug andhas mild hypotensive effects [4,5]. Sildenafil hasbeen well tolerated by patients with ED andhypertension [6,7], chronic heart failure [8], andcoronary artery disease (CAD) [9–11]. In an open-label study in patients with CAD, hemodynamiceffects associated with sildenafil administrationwere limited to small reductions (

<

10%) in sys-temic and pulmonary arterial pressures [12]. Com-pounds that contain nitric oxide or release nitricoxides (nitrates) are potent vasodilators and arecommonly prescribed for the treatment ofischemia associated with CAD [13].

Aims

We conducted a double-blind, placebo-controlledtrial to compare the hemodynamic effects ofsildenafil and isosorbide mononitrate (ISMN) inmen with ED and CAD.

Methods

A single-dose, double-blind, randomized, parallelgroup study comparing the hemodynamic effectsof 100 mg sildenafil, 40 mg ISMN, and placebo inpatients with CAD and ED was conducted at sixcenters. The maximum recommended dose ofsildenafil (100 mg) was chosen to maximize thepotential of eliciting a clinically relevant change inhemodynamic parameters. ISMN dosages of 20and 40 mg twice daily have been shown to beeffective and well tolerated as antianginal therapy[14], and hence the higher dose of 40 mg ISMNwas chosen as a comparator for this study. Thestudy was conducted in accordance with the Dec-laration of Helsinki (revised 1996) and with locallaws and regulations in the country where it wascarried out. The protocol was approved by thelocal institutional review board or by an indepen-dent ethics committee at each center.

Study Population

Eligible patients were men aged 35 years or older,with CAD and ED (defined as receiving medica-

T

tion for ED or scoring less than 26 out of a max-imum score of 30 on the erectile function domainquestions of International Index of Erectile Func-tion) [15,16] who presented for coronary angiog-raphy as a regular part of their medical care. Onlypatients who demonstrated at least 50% narrow-ing of the left main stem or at least 70% narrowingof any other coronary artery during coronaryangiography performed at the second study visitwere randomized to receive study medication.Additional entry criteria included a history ofangina pectoris, a body mass index less than 32 kg/m

2

, and no clinically important laboratory abnor-malities. Major exclusion criteria were unstableangina; need for immediate intervention (e.g., per-cutaneous transluminal coronary angioplasty) fol-lowing the diagnostic angiogram; hypotension(systolic blood pressure

<

100 mm Hg; diastolicblood pressure

<

60 mm Hg); hypertension (sys-tolic blood pressure

>

170 mm Hg; diastolic bloodpressure

>

105 mm Hg); a medical condition thatwould preclude hemodynamic monitoring; lessthan 3 months since coronary artery bypass graft-ing or percutaneous transluminal coronary angio-plasty; clinically significant disease that could altersystemic exposure to sildenafil (e.g., renal, hepatic,or gastrointestinal disorder); and clinically impor-tant valvular or congenital heart disease.

Study Design

During the first study visit, the investigatorexplained the nature, purpose, and risks of thestudy and provided a written copy of this informa-tion to the patient. Patients electing to participategave written informed consent and underwentscreening evaluations that included a physicalexamination; measurement of supine blood pres-sure and heart rate; a 12-lead electrocardiogram;collection of blood samples for laboratory safetytests; and administration of the erectile functiondomain questions of International Index ofErectile Function, if the patient was not alreadyreceiving treatment for ED.

The second study visit was scheduled within1 week of the initial visit. Supine blood pressureand heart rate were recorded, and diagnostic car-diac catheterization was performed. Patients withangiographic evidence of at least 50% narrowingof the left main stem or at least 70% narrowing ofany other coronary artery were randomized toreceive 100 mg sildenafil, 40 mg ISMN, or pla-cebo. Background cardiovascular medication wascontinued during the study with the followingexceptions. The morning dose was omitted for

Hemodynamic Effects of Sildenafil

409

J Sex Med 2005; 2: 407–414

those receiving alpha blockers; nitrate therapyprescribed as needed was not allowed for 24 hoursbefore the second study visit through 24 hoursafter study drug was taken; nitrates or nitric oxidedonors that were part of combination daily anti-anginal therapy were withdrawn 5 days before,and daily nitrate antianginal monotherapy 7 daysbefore the second study visit. Sildenafil use wasnot allowed for 96 hours before this study visit.

Hemodynamic monitoring was performed onall randomized subjects. Following coronary andleft ventricular angiography, a femoral venoussheath was inserted, through which a Swan-Ganzcatheter was threaded into pulmonary artery. Anarterial blood pressure monitoring transducer wasattached to the side arm of the femoral arterialsheath. After a minimum 1-hour recovery period,baseline hemodynamic measurements were begunwith at least three measurements taken until threeconsecutive stable readings (

£

15% difference fromthe mean of the three measurement values) of thecardiac output, mean arterial pressure, and heartrate were recorded. The mean of these three val-ues was taken as the baseline value. Patients inwhom a stable baseline could not be achievedwithin 3 hours of the start of baseline measure-ments were discontinued.

Study drug was administered after a stable base-line had been established. Hemodynamic mea-surements were obtained, and blood samples fordetermination of sildenafil plasma concentrationswere collected at baseline, 1, 2, 4, and 6 hours postdose. Cardiac output, mean arterial pressure, heartrate, systolic arterial pressure, diastolic arterialpressure, pulmonary arterial capillary wedge pres-sure, mean pulmonary arterial pressure, and rightatrial pressure were measured at each time point.Cardiac index, stroke volume, systemic vascularresistance, and pulmonary vascular resistance werederived from these measurements. All pressureand heart rate measurements were made in dupli-cate, and the cardiac output was measured in trip-licate; the mean of these values was recorded foreach time point.

Femoral sheaths were removed after hemody-namic measurements were completed; patientsthen remained on bed rest for 6 hours and weredischarged after an overnight stay. A follow-upvisit was scheduled 7–10 days later during whichinvestigators recorded any reported adverse eventsand concomitant medications.

Main Outcome Measures

No formal statistical analysis was performed in thisstudy. The main outcomes measures were changesin hemodynamic parameters following adminis-tration of sildenafil, ISMN, or placebo in patientswith CAD and ED. The study was not poweredto test a specific hypothesis for the end pointsdescribed, and hence no formal sample size calcu-lation was made.

The differences in means between treatmentgroups (sildenafil–ISMN and sildenafil–placebo)were estimated by using an analysis of covariancemodel for each time point and hemodynamic mea-sure. Two-sided 95% confidence intervals werecalculated for each difference in the means.

Results

Of 53 patients screened, 31 patients were random-ized and received double-blind treatment. Meanage was 60 years, mean duration of ED was2.9 years, and mean duration of CAD was5.9 years (Table 1).

Sildenafil Plasma Concentrations

The mean (standard deviation) total plasmasildenafil concentration decreased over time withvalues of 253 (296) ng/mL, 186 (135) ng/mL, 130(66) ng/mL, and 112 (58) ng/mL at 1, 2, 4, and6 hours post dose, respectively.

Hemodynamic Effects

Sildenafil vs. Placebo

After adjusting for differences at baseline, sildena-fil produced greater mean reductions that werewell separated (95% confidence interval for the

Table 1

Patient characteristics

Demographic characteristic Placebo (n

=

10) Sildenafil (n

=

10) ISMN (n

=

11)

Age, mean (SD), years 60.7 (9.7) 59.6 (8.0) 58.6 (10.9)Weight, mean (SD), kg 83.3 (11.2) 83.3 (9.5) 84.4 (9.2)Height, mean (SD), cm 170.9 (4.7) 173.2 (4.4) 172.5 (5.8)CAD duration, mean (range), years 7.2 (0.5–28) 4.5 (0.3–15.3) 5.9 (0.2–18)ED duration, mean (range), years 2.4 (0.5–5.8) 2.7 (1.0–6.0) 3.5 (0.2–10.0)

CAD

=

coronary artery disease; ED

=

erectile dysfunction; ISMN

=

isosorbide mononitrate.

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J Sex Med 2005; 2: 407–414

mean difference does not contain zero) fromchanges observed with placebo (Figure 1A,E, I, Jand Table 2) in systolic pressure (at 2 hours),mean pulmonary arterial pressure (at 4 hours),systemic vascular resistance (at 1 hour and4 hours), and pulmonary vascular resistance (at1 hour and 4 hours). A small increase in cardiacindex that separated from placebo was observed at1 hour post dose with sildenafil (Figure 1G). Val-ues for all other hemodynamic measures forsildenafil did not separate from values for placebotreatment.

Sildenafil vs. ISMN

After adjusting for differences at baseline, greatermean decreases that were well separated from

changes with sildenafil were observed withISMN (Figure 1A,C–E and Table 3) in systolicpressure (at all time points), mean arterial pres-sure (at all time points), mean pulmonary arterialpressure (at 1 hour and 2 hours), and pulmonarycapillary wedge pressure (at 1 hour, 2 hours, and4 hours). Increases with sildenafil, but decreaseswith ISMN, were noted in cardiac index andstroke volume index (values separated at 1 hourand 2 hours, Figure 1G,H). A greater meanreduction in pulmonary vascular resistance wasnoted with sildenafil at all time points; however,values separated at 1 hour only (Figure 1J).Values for all other hemodynamic measures forsildenafil compared with ISMN treatment didnot separate.

Table 2

Difference in adjusted means (95% confidence limits)* of changes from baseline in hemodynamic variables between sildenafil and placebo over time

Sildenafil–Placebo

1 hour 2 hours 4 hours 6 hours

Systolic pressure, mm Hg

-

9.6 (

-

20.2, 1.1)

-

13.5 (

-

24.8,

-

2.2)

†

-

5.3 (

-

16.5, 6.0)

-

6.0 (

-

17.8, 5.8)Diastolic pressure, mm Hg

-

3.8 (

-

11.5, 3.9)

-

5.2 (

-

12.8, 2.4)

-

5.0 (

-

11.7, 1.7)

-

4.3 (

-

10.8, 2.2)Mean arterial pressure, mm Hg

-

5.4 (

-

13.3, 2.4)

-

6.5 (

-

15.1, 2.0)

-

5.3 (

-

12.6, 2.0)

-

4.6 (

-

12.7, 3.4)Pulmonary capillary wedge

pressure, mm Hg

-

0.4 (

-

2.2, 1.4)

-

0.2 (

-

1.8, 1.4) 0.6 (

-

1.1, 2.3) 0.3 (

-

1.4, 2.0)

Mean pulmonary arterypressure, mm Hg

-

1.5 (

-

4.0, 1.0)

-

1.4 (

-

3.5, 0.7)

-

2.6 (

-

4.9,

-

0.4)

†

-

1.5 (

-

3.3, 0.3)

Heart rate, beats/minute 5.0 (

-

0.2, 10.2) 0.6 (

-

4.2, 5.4)

-

1.2 (

-

5.2, 2.9)

-

1.2 (

-

6.5, 4.1)Cardiac index, L/min/m

2

0.33 (0.01, 0.65)

†

0.33 (

-

0.02, 0.67) 0.24 (

-

0.09, 0.58) 0.04 (

-

0.36, 0.44)Stroke volume index, mL/m

2

2.0 (

-

2.6, 6.7) 5.4 (

-

0.61, 11.4) 4.4 (

-

1.1, 10.0) 1.9 (-4.7, 8.6)Systemic vascular

resistance, dyne/second/cm5-254.7 (-498.3, -11.1)† -242.4 (-500.3, 15.6) -199.3 (-374.7, -23.9)† -113.5 (-343.4, 116.4)

Pulmonary vascularresistance, dyne/second/cm5

-28.2 (-55.7, -0.7)† -28.0 (-56.5, 0.4) -65.2 (-96.7, -33.7)† -23.4 (-53.8, 7.0)

* 95% CI for the mean difference, adjusted for baseline, based on adjusted means.† 95% CI for the difference between adjusted means does not include zero.

Table 3 Difference in adjusted means (95% confidence limits)* of changes from baseline in hemodynamic variables between sildenafil and isosorbide mononitrate (ISMN) over time

Sildenafil–ISMN

1 hour 2 hours 4 hours 6 hours

Systolic pressure, mm Hg 18.8 (8.2, 28.3)† 19.7 (8.5, 30.9)† 25.1 (14.0, 36.1)† 20.2 (8.6, 31.8)†

Diastolic pressure, mm Hg 4.7 (-2.9, 12.2) 2.8 (-4.6, 10.2) 1.2 (-5.3, 7.8) -1.0 (-7.3, 5.3)Mean arterial pressure, mm Hg 11.0 (3.3, 18.7)† 12.1 (3.7, 20.5)† 11.2 (4.0, 18.4)† 8.2 (0.4, 16.1)†

Pulmonary capillary wedgepressure, mm Hg

3.1 (1.3, 4.8)† 3.2 (1.7, 4.8)† 1.7 (0.1, 3.4)† 1.2 (-0.4, 2.8)

Mean pulmonary arterypressure, mm Hg

3.1 (0.7, 5.5)† 2.7 (0.7, 4.7)† 1.6 (-0.6, 3.7) 0.4 (-1.4, 2.1)

Heart rate, beats/minute -3.3 (-8.4, 1.9) -4.3 (-9.0, 0.5) -2.7 (-6.7, 1.4) -3.3 (-8.5, 1.9)Cardiac index, L/min/m2 8.8 (4.1, 13.4)† 9.5 (3.4, 15.6)† 3.4 (-2.2, 9.0) 3.1 (-3.7, 9.8)Stroke volume index, mL/m2 8.8 (4.1, 13.4)† 9.5 (3.4, 15.6)† 3.4 (-2.2, 9.0) 3.1 (-3.7, 9.8)Systemic vascular

resistance, dyne/second/cm5-19.7 (-258.0, 218.6) 73.0 (-179.3, 325.3) 118.8 (-52.8, 290.3) -113.5 (-343.4, 116.4)

Pulmonary vascularresistance, dyne/second/cm5

-30.1 (-57.0, -3.2)† -22.0 (-49.8, 5.8) -11.1 (-41.9, 19.7) -9.6 (-39.3, 20.2)

* 95% CI for the mean difference, adjusted for baseline, based on adjusted means.† 95% CI for the difference between adjusted means does not include zero.

Hemodynamic Effects of Sildenafil 411

J Sex Med 2005; 2: 407–414

Figure 1 Comparison of changes in hemodynamic measures (mean, 95% CI) over time following administration of 100 mgsildenafil (�), 40 mg isosorbide mononitrate (ISMN) (�), or placebo (�). For clarity, only one side of the 95% CI is shown.

412 Jackson et al.

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SafetySeven patients (n = 1 for sildenafil, n = 5 forISMN, and n = 1 for placebo) reported nineadverse events, either during the 6-hour studyperiod or within 7 days after receiving study drug.Only three adverse events (headache and hypoten-sion experienced by two patients in the ISMNgroup and myocardial infarction experienced by apatient receiving placebo) were considered to betreatment-related.

Discussion

The findings of the present study are in generalagreement with those of Herrmann et al. [12],who reported small but significant reductions insystemic and pulmonary arterial blood pressure(<10% at 1 hour after sildenafil administration);slightly smaller reductions in pulmonary and sys-temic vascular resistances; and a lack of effect onpulmonary capillary wedge pressure, right atrialpressure, heart rate, and cardiac index withsildenafil in men with severe stenosis of at leastone coronary artery. The longer observationperiod in the current study allowed for furtherrefinement of these findings, suggesting that theeffects of sildenafil on most hemodynamicmeasures were greatest at 1–2 hours after admin-istration and were at or near baseline values at the6-hour time point. An interesting exception waspulmonary vascular resistance, which continued tofall to a mean value that was 25% lower thanbaseline at 4 hours after sildenafil dosing.

Although the current study was limited by asmall sample size, which prohibited testing of spe-cific hypotheses for the end points, and use of asingle dose of study medication, inclusion ofplacebo and ISMN treatment groups did help tofurther define the magnitude of the effects ofsildenafil on hemodynamics in men with severeCAD. Compared with ISMN, sildenafil producedmore modest reductions in systemic and pulmo-nary hemodynamics. Although the effects ofsildenafil and ISMN on most hemodynamicparameters were generally in the same direction,sildenafil produced a reduction in pulmonary vas-cular resistance and a modest increase in cardiacindex as early as 1 hour after treatment, whereaspulmonary vascular resistance increased and car-diac index decreased in the first 2 hours followingISMN administration. Hemodynamic effects pro-duced by sildenafil that were well separated fromthose produced by placebo were limited to reduc-tions in systemic and pulmonary vascular resis-

tances at 1 hour and 4 hours, a reduction insystolic blood pressure at 2 hours, a reduction inmean pulmonary arterial pressure at 4 hours, anda slight increase in cardiac index at 1 hour.

Halcox et al. [17] also reported mild vasodila-tion following administration of 100 mg sildenafilin patients with known or suspected CAD. At45 minutes after administration of sildenafil,supine mean pulmonary arterial and wedge pres-sures were significantly reduced by 13% ± 3% and18% ± 6%, respectively. Smaller reductions inpulmonary and systemic vascular resistancesand mean arterial pressures, and increases incardiac output were also observed but were notsignificant.

These investigators additionally compared theeffects of 100 mg sildenafil, 10 mg isosorbide dini-trate, and placebo in patients with known CADand ischemia during exercise. Although a lowerdose of a nitrate was used than in the current study,Halcox et al. [17] reported similar findings. Theseincluded that both the nitrate and sildenafilreduced systolic and diastolic pressures comparedwith placebo; however, the nitrate produced agreater effect and additionally increased heart rate.Isosorbide dinitrate was shown to improve myo-cardial ischemia during exercise, whereas theeffect of sildenafil was intermediate between thatof the nitrate and placebo. These data are in keep-ing with those of Fox et al. [10], who reportedfavorable trends in treadmill exercise duration andtime to the onset of angina with sildenafil. Arruda-Olsen et al. [18] reported that sildenafil produceda similar slight decrease in blood pressure at restwith no change in heart rate and had no effect onthe presence or extent of exercise-inducedischemia in patients with known or highly sus-pected CAD.

Studies in patients with pulmonary hyper-tension have further corroborated that sildenafilproduces mild systemic vasodilatory effects andapparently selective vasodilatory effects on thepulmonary vasculature. Significant reductions inmean pulmonary arterial pressure and pulmonaryvascular resistance without significant decreasesin mean systemic arterial pressure have beenreported with sildenafil administration in patientswith severe pulmonary arterial hypertension (NewYork Heart Association class III and IV) [19–22].Wilkens et al. [19] reported a duration of thepulmonary vasodilatory effects with sildenafil(100 mg cumulative dose) of up to 4.5 hours,which is similar to our findings. In a study directlycomparing inhaled nitric oxide and sildenafil,

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sildenafil was shown to increase cardiac index anddecrease pulmonary artery wedge pressure,whereas inhaled nitric oxide produced oppositeeffects on these hemodynamic measures [20]. Sas-try et al. [23] reported significant improvements inexercise tolerance, cardiac index, and quality-of-life measures in patients with primary pulmonaryhypertension following 6 weeks of treatment withsildenafil (25–100 mg three times daily). Similarimprovements in pulmonary hemodynamics, exer-cise capacity, and clinical status were reported byMikhail et al. [24] in patients with pulmonary arte-rial hypertension after 3 months of treatment with50 mg sildenafil three times daily. Improved exer-cise capacity and pulmonary hemodynamics werealso reported with long-term adjunct sildenafiltherapy (9–12 months) in patients with severe pul-monary hypertension experiencing deteriorationdespite ongoing treatment with inhaled iloprost[25].

Conclusions

Sildenafil 100 mg induced smaller changes in cen-tral and peripheral hemodynamic pressures com-pared with ISMN 40 mg. These hemodynamicchanges were well tolerated in both groups. Theapparent selectivity of sildenafil over ISMN forreducing pulmonary resistance is consistent withthe differential expression of phosphodiesterasetype 5 in the pulmonary vascular beds. The clinicalrelevance of the effects of sildenafil on pulmonaryvasculature in patients with pulmonary hyperten-sion is being studied.

Conflict of Interest. All the authors are study investigatorsfor Pfizer Inc, except for Hunter Gillies, who is anemployee of Pfizer. This research was supported byPfizer Inc.

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