Effects of sildenafil citrate on human hemodynamics

Effects of Sildenafil Citrate onHuman Hemodynamics

Graham Jackson, MD, Nigel Benjamin, MD, Neville Jackson, MD, andMichael J. Allen, MD

Nitric oxide (NO) induces the formation of intracellularcyclic guanosine monophosphate (cGMP) by guanylatecyclase. Sildenafil, which selectively inhibits phosphodi-esterase type 5 (PDE5) found predominantly in the cor-pora cavernosa of the penis, effectively blocks the deg-radation of cGMP and enhances erectile function in menwith erectile dysfunction. The NO–cGMP pathway alsoplays an important role in mediating blood pressure. Itis, therefore, possible that the therapeutic doses of sil-denafil used to treat erectile dysfunction may have clin-ically significant effects on human hemodynamics. Threestudies were undertaken to assess the effects of intrave-nously, intra-arterially, and orally administered doses ofsildenafil on blood pressure, heart rate, cardiac output,and forearm blood flow and venous compliance inhealthy men. A fourth study evaluated the hemodynamiceffects of intravenous sildenafil in men with stable ische-mic heart disease. In healthy men, significant (p <0.01)decreases in supine systolic and diastolic blood pres-sures were observed with intravenous sildenafil (20, 40,and 80 mg) at the end of the infusion period whenplasma levels of sildenafil were highest (mean decreasesfrom baseline of 7.0/6.9 and 9.2/6.7 mm Hg, for the40- and 80-mg doses, respectively). These changes weretransient and not dose related. Modest reductions insystemic vascular resistance also were observed (maxi-mum decrease 16%), although heart rate was not af-fected by sildenafil administration when compared withplacebo. Single oral doses of sildenafil (100, 150, and

200 mg) produced no significant changes in cardiacindex from 1–12 hours postdose between placebo- andsildenafil-treated subjects. The approved dosagestrengths of sildenafil citrate are 25 mg, 50 mg, and 100mg. The 80-mg intravenous dose and the 200-mg oraldose of sildenafil produced comparable plasma levels attwice the maximum therapeutic dose (recommendedrange, 25–100 mg). After brachial artery infusion ofsildenafil (up to 300 mg/min), there was a modest va-sodilation of resistance arteries and a reversal of nor-epinephrine-induced preconstriction of forearm veins.These hemodynamic effects were similar to but smallerin magnitude than those of nitrates. In a small pilot studyof men with ischemic heart disease, decreases frombaseline in pulmonary arterial pressure (227% at restand 219% during exercise) and cardiac output (27% atrest and 211% during exercise) were observed after40-mg intravenous doses of sildenafil. Sildenafil waswell tolerated by subjects and patients in all studies, withheadache and other symptoms of vasodilation the mostcommonly reported adverse effects of treatment. Mod-est, transient hemodynamic changes were observed inhealthy men after single intravenous or oral doses ofsildenafil even at supratherapeutic doses. In men withstable ischemic heart disease, sildenafil produced mod-est effects on hemodynamic parameters at rest and dur-ing exercise. Q1999 by Excerpta Medica, Inc.

Am J Cardiol 1999;83:13C–20C

N itric oxide (NO) released by nonadrenergic-non-cholinergic neurons and arteriolar endothelial

cells, through the activation of guanylate cyclase, in-duces the formation of intracellular cyclic guanosinemonophosphate (cGMP) from guanosine triphosphate,which in turn leads to the relaxation of vascular andtrabecular smooth muscle of the penis and dilatationof penile arteries.1,2 The increased blood flow andengorgement of the trabecular spaces results in penileerection. Sildenafil is a highly selective inhibitor ofphosphodiesterase type 5 (PDE5),3 the predominantisozyme responsible for the breakdown of cGMP inthe corpora cavernosa.4,5 Inhibition of cGMP degra-dation allows for normal penile erection by the NO-cGMP–mediated relaxation pathway.6,7 In clinicalstudies, sildenafil has been shown to be an effective

and well-tolerated treatment for erectile dysfunc-tion.8,9 In general, its most common side effects areheadache, flushing, and dyspepsia.

In addition to its presence in the corpora cavernosa,PDE5 is found in platelets and vascular smooth mus-cle cells.10 Other inhibitors of PDEs have been foundto decrease vascular resistance and inhibit thrombusformation and platelet aggregation.10 Many of theseagents have been investigated as vasodilators for thetreatment of hypertension, as antithrombotic agents,and as inotropic agents for the treatment of congestiveheart failure, although the inotropic effects are notassociated with PDE5. Sildenafil has modest effectson blood pressure in normal subjects, producing anaverage decrease of approximately 10 mm Hg after asingle oral dose of 100 mg.11 The maximum decreasein blood pressure occurred at the time of peak plasmalevels of the drug, approximately 1 hour after silden-afil administration, and returned to baseline for mostsubjects within 4 hours. A sublingual 500-mg dose ofglyceryl trinitrate produced decreases of systolicblood pressure of 5–10 mm Hg.11 When glyceryl

From the Guys and St. Thomas Hospital, London, United Kingdom(GJ); St. Bartholomew’s and the Royal London School of Medicine andDentistry, London, United Kingdom (NB); Pfizer Central Research,Sandwich, United Kingdom (NJ, MJA).

Address for reprints: Graham Jackson, MD, Cardiac Department,St. Thomas Hospital, Lambeth Palace Road, London SE1 7EH, UnitedKingdom.

13C©1999 by Excerpta Medica, Inc. 0002-9149/99/$20.00All rights reserved. PII S0002-9149(99)00043-0

trinitrate and sildenafil were administered to subjectsin combination, larger but similarly transient effectson blood pressure were observed, consistent with theirknown effects on the NO–cGMP pathway.11,12Hence,sildenafil and nitrate coadministration is contraindicat-ed.12 However, the effects of sildenafil on hemody-namic parameters in healthy subjects and in patientswith angina in the absence of concomitant nitratetherapy are less widely known.

The objective of the present report is to summarizethe effects of sildenafil on hemodynamic parametersin healthy men, including an analysis of the arterio-venous selectivity of sildenafil. Additionally, the he-modynamic effects of sildenafil in men with stableischemic heart disease in the absence of antianginaltherapy are presented.

SUBJECTSEach of the 4 studies reported here was reviewed

and approved by local ethics committees, and all par-ticipants provided written informed consent beforestudy enrollment. Healthy men 18–45 years of agewho weighed 60–90 kg were eligible for the first 3studies. Subjects were evaluated at screening and atthe initial study visit, which included a complete med-ical history and examination, screening of blood pres-sure and heart rate, standard laboratory tests, drugscreening, and a 12-lead electrocardiogram. Subjectswere excluded if they had evidence of any clinicallysignificant disease or clinically significant abnormali-ties on laboratory testing or on physical examination.Other exclusion criteria included treatment with anyprescribed or over-the-counter medications within 2weeks of study entry, treatment with an experimentaldrug within 3 months of study entry, evidence of drugabuse or significant alcohol consumption (.21 U/wk),smoking.5 cigarettes (or use of equivalent tobaccoproducts) per day, personal or family history of ableeding disorder, or a positive hepatitis test.

For the fourth study, men with stable ischemicheart disease, proved either by an exercise test andRP30 isotope scan or by positive angiography or stressechocardiography, were eligible for enrollment. Otherinclusion and exclusion criteria were as described forthe first 3 studies.

METHODSHemodynamic studies (studies 1 and 2): In the first

study, a single-blind, 4-way crossover trial, 8 healthymale subjects were randomly assigned to receive 3escalating single intravenous doses of sildenafil (20,40, and 80 mg) and a randomly scheduled dose ofplacebo. Each dose was administered at 2 mL/minover 40 minutes and was separated by a washoutperiod of at least 7 days. Blood samples were col-lected before study drug administration and at speci-fied intervals during the infusion and for up to 96hours after dosing. Hemodynamic variables also weremeasured before dosing and at specified intervals afterdosing. These included assessments of supine cardiacindex (measured using a transthoracic impedance ap-paratus) for up to 24 hours postdose and supine and

standing blood pressure and heart rate for up to 48 hourspostdose. The systemic vascular resistance index wasderived as the supine mean arterial blood pressuredivided by the cardiac index (CI): systemic vascularresistance index5 [diastolic1 1/3 (systolic 2 dia-stolic)]/CI. Plasma levels of sildenafil and cGMP weremeasured using a high-performance liquid chromatog-raphy assay.3,5 Pharmacokinetic variables were sub-jected to an analysis-of-variance model appropriate tothe study design. cGMP, systemic vascular resistanceindex, blood pressure, and heart rate were analyzedusing 2 approaches: (1) deriving the area under theeffect curve for 12 hours after the start of the infusion;and (2) analyzing data obtained at the end of the40-minute infusion period. These data were subjectedto an analysis-of-variance model, and pairwise com-parisons were made between the placebo and sil-denafil infusions.

In a second study, 8 healthy male subjects wereevaluated in a single-blind, 4-way crossover, dose-escalation trial (100, 150, and 200 mg of sildenafil andrandomly scheduled placebo) to determine the effectsof oral sildenafil on cardiac output. Each dose wasseparated by a washout period of at least 7 days.Cardiac output (measured by transthoracic imped-ance), blood pressure, and heart rate were evaluated at21, 1, 3, 6, 9, and 12 hours relative to study drugadministration. Blood samples for analysis of pharma-cokinetic variables were taken before study drug ad-ministration and up to 96 hours postdose. Pharmaco-kinetic variables were subjected to an analysis-of-variance model appropriate to the study design. cGMPlevels were analyzed by deriving the area under thecurve for 12 hours postdose. These data were sub-jected to an analysis-of-variance model and pairwisecomparisons were made between placebo and silden-afil doses. Data for cardiac output, blood pressure, andheart rate were tabulated by treatment from baseline to12 hours postdose, and means6 standard deviationswere calculated.

Blood flow and venous compliance study (study 3):The third study was an open-label, placebo-controlledtrial to evaluate the effects of escalating brachial-artery infusions of sildenafil (up to 300mg/min) onforearm blood flow and venous compliance in 12healthy male subjects. Studies were performed in atemperature-controlled laboratory. Brachial artery in-fusions were via a 27-guage steel cannula insertedusing 1% lidocaine. The infusion rate was 1.0 mL/min. Because venous tone is low at rest, norepineph-rine 0.5–2.0mg/min was coadministered with silde-nafil to detect effects on venous compliance. Bloodsampling was performed by a separate cannula in-serted into the nondominant arm. The noncannulatedarm served as the control. Blood samples were col-lected immediately before the completion of eachinfusion. Forearm blood flow and venous compliancewere measured in the cannulated and noncannulatedarm using strain-gauge plethysmography during thefinal 5 minutes of each infusion. Venous compliancewas estimated by recording the percent change inforearm volume at venous pressures of 20 mm Hg and

14C THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 83 (5A) MARCH 4, 1999

40 mm Hg, which was achieved by inflation of anupper arm blood pressure cuff. Ratios of the cannu-lated to noncannulated forearm blood flow calculatedat each timepoint and the percent change in forearmvolume were summarized by treatment group.

Hemodynamic study in men with stable ischemicheart disease (study 4): An open-label pilot study eval-uated the acute hemodynamic effects of sildenafil atrest and during exercise in 8 men with stable ischemicheart disease. Antianginal medications, vasodilators,and diuretics were withdrawn at least 48 hours beforethe study period; however, sublingual, short-actingnitrates were allowed until 2 hours before catheteriza-tion. Patients performed an initial supine bicyclewarm-up exercise to determine the workload thatcaused symptoms and that could be maintained for 4minutes without undue discomfort. Catheters werethen introduced into the brachial or radial artery andinto the right side of the heart. Baseline hemodynamicparameters were recorded at 1-minute intervals duringa second 4-minute bicycle exercise test. Patients thenrested for 20 minutes to ensure cardiovascular resta-bilization. Over the next 15 minutes, hemodynamicmeasurements were repeated at 5-minute intervalsduring rest or until there was,10% variation incardiac output, mean arterial pressure, and heart rate.Sildenafil was then infused over four 15-minute peri-ods at rates that delivered doses of 5, 5, 10, and 20 mg(40 mg total), respectively, during a 60-minute period.Patients then repeated the 4-minute bicycle test duringwhich hemodynamic measurements were taken at1-minute intervals. Hemodynamic measurements in-cluded pulmonary arterial occluded pressure, pulmo-nary arterial pressure, right atrial pressure, systolicand diastolic systemic arterial pressure, heart rate, andcardiac output measured by thermodilution. Hemody-namic measurements at rest with and without silden-afil were compared with postexercise measurementswith and without sildenafil. Safety evaluations in-cluded a 12-lead electrocardiogram at screening, base-line, and at follow-up. Plasma sildenafil levels weredetermined by high-pressure liquid chromatography.13

RESULTSHemodynamic studies (studies 1 and 2): In study 1,

the plasma concentration profile of intravenously ad-ministered sildenafil in healthy subjects showed thatlevels increased rapidly, with maximum concentra-tions occurring at the end of the 40-minute infusionperiod in the majority of cases (Table I). The increaseswere approximately proportional with dose over therange studied.

The analysis of variance for blood pressure at theend of the infusion period (0.67 hours, when plasmalevels of sildenafil were highest) showed significantdifferences between sildenafil- and placebo-treatedsubjects, with increasing doses of sildenafil associatedwith significantly greater reductions in blood pressure(Table II). Systolic and diastolic blood pressures de-creased significantly (p,0.01) at the end of the sil-denafil infusion period after the 40-mg and 80-mgdoses (mean decreases from baseline of 7/7 and 9/7

mm Hg, respectively). However, these reductionswere transient as most subjects’ blood pressure re-turned to baseline within 5 hours of receiving silden-afil. There was no evidence of a consistent dose rela-tion at any time postdose. In addition, there was noevidence of an orthostatic effect due to sildenafilbased on the mean differences between standing andsupine blood pressures at any time during treatment(Table III). There were no significant differences inheart rate between the sildenafil- and placebo-treatedsubjects at the end of the infusion period or up to 12hours after dosing. The area-under-the-effect curveanalysis of systolic and diastolic blood pressures andheart rates showed no significant differences betweensubjects receiving placebo and subjects receiving sil-denafil doses over the 12-hour evaluation period.

Sildenafil had a significant effect on vascular re-sistance, as data collected at the end of the infusionperiod showed that decreases in the systemic vascularresistance index were observed between subjects re-ceiving placebo and subjects receiving each of the 3intravenous sildenafil doses (Table II; p,0.001).However, there was no evidence of a linear relationbetween increasing doses of sildenafil and the sys-temic vascular resistance index or between increasingplasma concentrations of sildenafil and the systemicvascular resistance index. There were no significantdifferences between treatments in the mean values forthe area under the systemic-vascular-resistance-index-versus-time curve up to 12 hours after dosing.

In the study evaluating orally administered silden-afil (study 2), the plasma concentrations resultingfrom single doses of 100 and 200 mg showed thatsildenafil was rapidly absorbed, with mean times topeak concentrations of 0.8–0.9 hours (Table I). Com-parison of peak plasma concentrations achieved afteroral or intravenous administration demonstrates thatthe 80-mg/mL intravenous dose of sildenafil is com-parable to the 200-mg oral dose, which is twice themaximum recommended dose. In addition, the expo-sure to and maximum observed plasma concentrationsof sildenafil increased proportionally with dose.

An analysis of cardiovascular parameters in thisstudy found evidence of decreases from baseline insubjects’ systolic and diastolic blood pressures; themean maximum decrease of systolic/diastolic was10/7 mm Hg occurring 3 hours after dosing. However,sildenafil doses of 200 mg, which are twice the rec-ommended dose for the treatment of erectile dysfunc-tion, were not associated with greater decreases inblood pressure relative to the lower doses evaluated(Figure 1). Blood pressure returned to baseline valueswithin 6 hours after sildenafil administration for mostsubjects. The differences between mean standing andsupine blood pressures and heart rates also showed noevidence of an orthostatic effect of sildenafil. Therewere no clinically significant effects on the subjects’heart rate after oral sildenafil administration. Changesin heart rate at 1 hour after sildenafil administrationranged from an increase of 3 beats/min (200 mg) to adecrease of 5 beats/min (100 mg). No significantchanges in cardiac index were observed in subjects

CARDIOVASCULAR DATA ON SILDENAFIL CITRATE 15C

from 1–12 hours after all 3 dose levels (100, 150, and200 mg) of sildenafil relative to the mean cardiacindex value obtained 1 hour after administration ofplacebo (Figure 1). Variations in mean cardiac indexvalues from 3–12 hours after dosing were similar forsildenafil- and placebo-treated subjects. The overallvariations in cardiac index observed during the 12-hour period were substantially greater than any effectsthat could be attributed to sildenafil.

Data from both hemodynamic studies showed thatincreasing doses of sildenafil were associated withincreasing plasma cGMP levels. After administrationof all 3 intravenous doses of sildenafil, cGMP levelswere significantly higher than cGMP levels observedafter administration of placebo (p,0.001; Table IV).When plasma cGMP concentrations for individualsubjects were reviewed, it was found that although theintersubject variability was high, the plasma-concen-tration-versus-time curve (area under the curve) for

cGMP generally increased with increasing systemicexposure to sildenafil. In study 2, significant differ-ences were observed between subjects treated withsildenafil or placebo in the area under the curve forcGMP plasma concentrations over 12 hours (TableIV). The mean area under the curve for cGMP was 32pmol/mL z h after placebo and increased from 43 to 46pmol/mL z h as the oral dose of sildenafil increasedfrom 100–200 mg (p,0.001).

Blood flow and venous compliance (study 3): Meanratios of cannulated-to-noncannulated forearm bloodflow increased with the infusion rate of sildenafilcompared with placebo, demonstrating a reduction inforearm vascular resistance (Figure 2). After the es-tablishment of the norepinephrine infusion, ratio val-ues ranged from a mean at baseline of 0.76 up to 1.15at the end of the highest infusion rate of sildenafil, a50% increase. The percent change in forearm volumeafter upper arm occlusion also increased with increas-

TABLE I Pharmacokinetic Effects of Increasing Intravenous and Oral Doses of Sildenafil

Study 1: Intravenous Sildenafil(n 5 8)

Study 2: Oral Sildenafil(n 5 8)

20 mg 40 mg 80 mg 100 mg 150 mg 200 mg

Cmax (ng/mL) 331 833 1822 746 1030 1551Tmax (h) 0.67 0.58 0.69 0.9 0.8 0.9AUCt (ng/mL z h) 714 1554 3711 2089 3281 4714

AUCt 5 area under the curve; Cmax 5 maximum plasma concentration; Tmax 5 time to Cmax.

TABLE II Effects of Intravenous Sildenafil on Blood Pressure, Heart Rate, and Systemic Vascular Resistance Index at the End of theInfusion (0.67 hours)

ParameterPlacebo(n 5 8)

Intravenous Sildenafil (n 5 8)

20 mg 40 mg 80 mg

SBP (mm Hg) 131 6 12 129 6 12 124 6 14* 122 6 13†

DBP (mm Hg) 71 6 12 68 6 12 64 6 12† 64 6 11†

HR (beats/min) 64 6 10 67 6 13 64 6 12 66 6 14SVR index 30 6 5 26 6 5* 26 6 4* 25 6 3†

Values represent the mean 6 SD.*p ,0.01 vs placebo.†p ,0.001 vs placebo.DBP 5 diastolic blood pressure; HR 5 heart rate; SBP 5 systolic blood pressure; SVR index 5 systemic vascular resistance index, derived from the mean arterial

pressure divided by the cardiac index.

TABLE III Maximum Mean Difference Between Standing and Supine Diastolic and Systolic Blood Pressures

Diastolic Systolic

Maximum MeanDifference Between Supine

and Standing Pressures(mm Hg)

Time AfterStudy Drug

(h)

Maximum MeanDifference Between Supine

and Standing Pressures(mm Hg)

Time AfterStudy Drug

(h)

Placebo 13.1 6 6.3 4 5.3 6 11.3 6Sildenafil dose (IV)

20 mg 12.5 6 5.9 0.33 9.4 6 13.5 1240 mg 13.8 6 4.4 0.67 4.6 6 5.9 380 mg 13.8 6 4.0 0.67 4.6 6 13.1 5

Values represent the mean 6 SD; n 5 8 per group.IV 5 intravenous.


ing infusion rates of sildenafil compared with placebo,indicating an increase in venous compliance (Figure2). From a baseline value of 1.1%, a cuff pressure of20 mm Hg produced a maximum increase in forearmvolume of 1.4%, or a 26% increase from baseline.With a cuff pressure of 40 mm Hg, forearm volumevalues increased from a baseline value of 1.9% to2.0%–2.3% during sildenafil treatment (a 23% maxi-

mum increase over baseline). No substantial changesin blood flow or venous compliance occurred in sub-jects during the placebo infusions. The highest dosage(300 mg/min) would be expected to result in localforearm blood concentrations of approximately 10mg/mL. This is .10 times the plasma concentration ob-served after the highest recommended oral dose ofsildenafil (100 mg).

FIGURE 1. Hemodynamic changes after the administration of increasing oral doses of silden-afil in healthy men. (A) Supine systolic blood pressure changes from baseline; (B) mean supinecardiac index. Values are mean 6 SD; n 5 8 per group.


Hemodynamic effects in men with stable ischemicheart disease (study 4): All 8 patients with ischemicheart disease successfully completed the active studyperiod and were scheduled for follow-up visits. Themean time since diagnosis of angina was 1.7 years(range, 0.5–3.0 years), and the ages of the patientswere 52–70 years. The results of this study are shownin Table V. Small reductions in the patients right atrialpressure, pulmonary arterial occluded pressure, andsystolic and diastolic systemic arterial pressures oc-curred at rest, whereas heart rate remained essentiallyunchanged relative to baseline. The percent changesfrom baseline were220% for pulmonary arterial oc-cluded pressure,227% for pulmonary arterial pres-sure,228% for right atrial pressure,26% for systolicsystemic arterial pressure, and210% for diastolicsystemic arterial pressure. There was also a smallreduction in cardiac output,27% from baseline.Blood pressure was well maintained in patients duringresting infusions of sildenafil and cardiovascular func-tion was not compromised. During the exercise test

after the sildenafil infusion, changes from baseline inpulmonary arterial occluded pressure (223%) andmean pulmonary arterial pressure (219%) were ob-served. Systolic and diastolic systemic arterial pres-sures both decreased 6%. Cardiac output was alsodecreased 11% from baseline during the postsildenafilexercise test. The heart rate during exercise remainedunchanged between baseline and sildenafil treatment.Patients were able to maintain a level of exerciseworkload after sildenafil equivalent to that during thebaseline evaluation, suggesting that the hemodynamicresponse to exercise was not impaired after sildenafiltreatment. There were no clinically relevant changesin the electrocardiogram at screening, baseline, andfollow-up.

Safety: No laboratory abnormalities related to pla-cebo or sildenafil treatment were reported in any of thestudies. Adverse events reported during sildenafiltreatment were generally mild to moderate. Headache,dizziness, and flushing were the most commonly re-ported events. Altered vision (described as a distur-

FIGURE 2. Changes in forearm blood flow and venous compliance during intraarterial infusion of sildenafil and placebo in healthymen. (A) represents the ratio of cannulated-to-noncannulated forearm blood flow in subjects administered increasing doses of silden-afil. (B) represents percent changes in forearm volume in subjects treated with increasing doses of sildenafil and using 2 different cuffpressures, 20 mm Hg or 40 mm Hg. The baseline infusion (0) consisted of dextrose (5%), norepinephrine and mannitol (5%). Data arepresented as mean values 6 SD; n 5 8 per group.

TABLE IV Effects of Intravenous and Oral Sildenafil on AUC0–12h for cGMP Concentrations*

Placebo Sildenafil

20 mg 40 mg 80 mgStudy 1, IV (n 5 8) 32 6 5 41 6 10† 40 6 7‡ 49 6 13§

100 mg 150 mg 200 mgStudy 2, PO (n 5 8) 32 6 6 43 6 5§ 42 6 4§ 46 6 4§

*Values represent the mean 6 SD (pmol/mL z h).AUC 5 area under the plasma-concentration-versus-time curve; cGMP 5 cyclic guanosine monophosphate; IV 5 intravenous; PO 5 by mouth.†p ,0.01 vs placebo.‡p ,0.05 vs placebo.§p ,0.0001 vs. placebo.


bance of color vision) was reported by 8 subjectsreceiving oral doses of sildenafil above 100 mg; how-ever, these events resolved spontaneously. In addition,1 subject receiving orally administered sildenafil (100mg) reported severe dizziness after drug administra-tion. There were no reports of serious adverse events,and there were no discontinuations related to adverseevents or laboratory abnormalities. In the study ofpatients with ischemic heart disease, no treatment-related adverse events or laboratory abnormalitieswere reported. One patient reported moderate backpain 7 days after receiving the sildenafil infusion, butthis event resolved spontaneously after 3 days and wasnot considered by the study investigator to be relatedto sildenafil treatment.

DISCUSSIONGiven the role of nitric oxide donors in the treat-

ment of angina, it was postulated that sildenafil couldhave clinically useful cardiovascular effects by way ofpotentiation of the nitric oxide-cGMP vasodilationpathway. Thus, sildenafil was initially evaluated as atherapy for patients with angina pectoris. In the pilotstudies presented here, no clinically adverse hemody-namic effects were observed when sildenafil was ad-ministered at high doses to healthy men. In 8 men withischemic heart disease, the administration of sildenafilresulted in modest effects on hemodynamic parame-ters in the absence of concurrent therapy with nitrates.The changes were similar to but smaller in magnitudethan those reported by Parker and Parker for therapeu-tic doses of nitrates.14

The first of these studies evaluated the effects ofintravenous infusions of sildenafil on the systemicvascular resistance index and blood pressure inhealthy men. As expected, increasing doses of silden-afil were significantly associated with increases incGMP plasma concentrations. However, when vari-ables were assessed using the area-under-the-curvemethod, which evaluated the treatment effects of sin-gle infusions of sildenafil over a 12-hour period, sil-denafil did not appreciably affect the systemic vascu-lar resistance index, blood pressure, or pulse rate.

These data indicate that the effects of sildenafil onhemodynamic parameters are transient in nature. In-deed, treatment effects were more pronounced at theend of the infusion period when plasma levels ofsildenafil were highest, with significant decreases inthe systemic vascular resistance index and blood pres-sure (p,0.01) but no change in heart rate. Thechanges were of short duration and did not seem to beassociated with increases in dose of 20–80 mg. In anevaluation of 8 healthy men, small increases wereobserved in the cardiac index immediately after sub-jects received oral doses of 100 and 200 mg of silden-afil. These modest changes, however, were not sus-tained, and the cardiac index values were similar be-tween sildenafil and placebo 3–12 hours postdose. Itshould be noted that the 80-mg intravenous dose andthe 200-mg oral dose resulted in similar peak plasmalevels of sildenafil. These doses are supratherapeutic,representing twice the recommended maximum ther-apeutic dose of 100 mg orally.

Sildenafil is a modest vasodilator, producing a he-modynamic balance between decreased arterial resis-tance and increased venous compliance. In the thirdstudy, mean ratios of cannulated-to-noncannulatedforearm blood flow increased as the arterial infusionrate of sildenafil was increased, as did the mean per-cent changes in forearm volume. This effect resemblesthe pharmacology of a mild nitrate-like antianginalmedication,14 but without the potential to produce amarked effect when administered alone. The mecha-nism is likely to be due to a potentiation of theendogenous NO–cGMP pathway.1,7

Sildenafil has a modest effect on the hemodynam-ics of patients with stable ischemic heart disease.Blood pressure was maintained in these patients, withno evidence of cardiovascular compromise either atrest or during exercise, despite the relatively high doseof sildenafil administered. The peak plasma concen-trations of sildenafil after stepwise intravenous admin-istration of 40 mg in this study were 1–3 times higherthan those seen after a single oral dose of 100 mg, themaximum recommended therapeutic dose for men be-ing treated for erectile dysfunction. During exercise,

TABLE V Effects of Sildenafil on Mean Hemodynamic Parameters at Rest and DuringExercise in Patients With Stable Ischemic Heart Disease

Parameter

At Rest After 4-Minute Exercise Test

Baseline(n 5 7)

Sildenafil(40 mg, IV)

(n 5 8)Baseline(n 5 8)

Sildenafil(40 mg, IV)

(n 5 8)

PAOP (mm Hg) 8.1 6 5.1 6.5 6 4.3 36.0 6 13.7 27.8 6 15.3PAP (mm Hg) 16.7 6 4.0 12.1 6 3.9 39.4 6 12.9 31.7 6 13.2RAP (mm Hg) 5.7 6 3.7 4.1 6 3.7 NR NRSystolic SAP (mm Hg) 150 6 12 141 6 16 200 6 37 188 6 30Diastolic SAP (mm Hg) 74 6 8 66 6 10 85 6 10 80 6 9Cardiac output (L/min) 5.6 6 0.9 5.2 6 1.1 11.5 6 2.4 10.2 6 3.5Heart rate (beats/min) 67 6 11 67 6 12 102 6 12 99 6 20

Values represent the mean 6 SD.IV 5 intravenous; NR 5 not recorded; PAP 5 pulmonary arterial pressure; PAOP 5 pulmonary arterial

occluded pressure; RAP 5 right atrial pressure; SAP 5 systemic arterial pressure.


sildenafil produced changes in the hemodynamic pa-rameters that were consistent with reductions in pre-load and afterload. Cardiac output was decreased as aresult of a reduction in filling pressure in compliancewith the Frank-Starling principle.

The intravenously, intraarterially, and orally ad-ministered doses of sildenafil administered in thesestudies were generally higher than the range currentlyrecommended for the treatment of erectile dysfunc-tion. Sildenafil was generally well tolerated; the ma-jority of adverse events were mild, and none led totreatment withdrawal. Headaches and other symptomsdue to vasodilation were the most commonly reportedeffects of treatment.

These data support findings from large-scale pla-cebo-controlled and open-label trials of sildenafil,which showed that adverse events after single oraldoses of sildenafil of 25–100 mg were generally mildto moderate and well tolerated.8,12 The most com-monly reported adverse events in these Phase II/IIIstudies were headache, flushing, and dyspepsia.8 Con-sistent with its effects on the NO–cGMP pathway,however, sildenafil can augment the hypotensive ef-fects of nitrates. The use of sildenafil in patientsconcurrently using nitrates or NO donors is thereforecontraindicated.12

CONCLUSIONSildenafil produces modest, transient hemody-

namic effects in healthy men or those with stableischemic heart disease not concurrently taking nitratesor other antianginal therapies. Sildenafil is a mixedvasodilator, with its hemodynamic effects resemblingthose of modest nitrates. Sildenafil was well toleratedin these studies, with no discontinuations occurring.

These data are supported by a large safety databasedemonstrating the safety profile and tolerability ofsildenafil in large numbers of patients.8,12

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Effects of sildenafil citrate on human hemodynamics