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(Hypertension. 2006;48:622.)
© 2006 American Heart Association, Inc.

Original Articles

Effect of Regular Phosphodiesterase Type 5 Inhibition in Hypertension

James J. Oliver; Vanessa P. Melville; David J. Webb

From the University of Edinburgh, United Kingdom.

Correspondence to David J. Webb, Clinical Pharmacology Unit, Centre for Cardiovascular Science, University of Edinburgh, The Queen’s Medical Research Institute, 3rd Floor East, Room E3.15, 47 Little France Crescent, Edinburgh, EH16 4TJ, United Kingdom. E-mail d.j.webb{at}ed.ac.uk

	Abstract

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There are no published controlled clinical trials of regular phosphodiesterase type 5 inhibitor therapy as a long-term treatment of hypertension. In a randomized, double-blind, 2-way crossover study, 25 otherwise untreated hypertensive subjects were administered 50 mg of sildenafil or matched placebo 3 times daily for 16 days, and the effects on ambulatory blood pressure (BP), clinic BP, arterial wave reflection, carotid-femoral pulse wave velocity, and brachial artery flow-mediated dilatation were assessed. Three subjects were withdrawn because of adverse effects, and the data from the remaining 22 subjects were analyzed. Sildenafil reduced ambulatory BP (mean [SE] change from baseline for average daytime BP: systolic –8 [2] mm Hg versus 2 [2] mm Hg with placebo, P<0.01; diastolic –6 [1] mm Hg versus 0 [1] mm Hg, P<0.01) and clinic BP (change from baseline to 1 hour after drug administration on day 16: systolic –5 [2] mm Hg versus 4 [2] mm Hg, P<0.01; diastolic –5 [1] mm Hg versus 2 [2] mm Hg, P<0.01). Compared with baseline, sildenafil, but not placebo, reduced arterial wave reflection both acutely and after chronic treatment, but the chronic change in arterial wave reflection was not statistically different from the chronic change with placebo. Sildenafil did not affect pulse wave velocity or flow-mediated dilatation. The main adverse effects of sildenafil, which were generally transient and rated as mild or moderate in severity, were dyspepsia, headache, and myalgia. In conclusion, regular sildenafil constitutes effective antihypertensive therapy. Further studies are warranted to evaluate the role of longer-acting phosphodiesterase type 5 inhibitors as antihypertensive agents in clinical practice.

Key Words: phosphodiesterase 5 • sildenafil • hypertension • blood pressure • arterial stiffness

	Introduction

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NO causes vasodilatation by stimulating vascular smooth muscle soluble guanylate cyclase to convert guanosine 5'-triphosphate to cGMP,¹ which leads to a reduction in intracellular calcium concentration.² cGMP is degraded by cGMP-specific, cGMP-binding phosphodiesterase 5 (PDE5), and intracellular concentrations of cGMP are tightly controlled by this enzyme via a number of negative feedback mechanisms.³

Inhibitors of PDE5 increase the intracellular concentration of cGMP, with the consequence that NO-mediated cellular responses, such as vascular smooth muscle relaxation, are promoted. By stimulating vascular relaxation within the corpora cavernosa during sexual stimulation, inhibitors of PDE5 promote penile erection and are effective treatments of male erectile dysfunction.⁴ PDE5 inhibition also causes vasodilatation in the pulmonary vascular bed, and in pulmonary arterial hypertension the PDE5 inhibitor sildenafil substantially reduces pulmonary artery blood pressure (BP) and improves functional capacity.⁵

PDE5 inhibitors are also vasodilators in the systemic circulation.⁶ In healthy subjects, single doses of sildenafil have been found to reduce BP acutely in some^6,7 but not all^8–10 studies. Similarly, some studies have found that sildenafil reduces BP acutely in patients with coronary artery disease (CAD),^6,11,12 whereas others have found no effect.^11,13 In hypertensive patients, acute reduction in BP with sildenafil has been demonstrated consistently, although only in studies in which other antihypertensive drugs were also being taken by the participants.^14–16 Although enhancement of the effects of endogenous NO through PDE5 inhibition may reduce BP in hypertension, the potential of regular PDE5 inhibitor therapy for the chronic treatment of hypertension has not been investigated previously in a controlled clinical trial.

Endothelium-dependent vasomotor function is generally assessed in vivo by methodologies that are essentially surrogate measures of endothelial NO generation. As a result, PDE5 inhibitors might be expected to improve these responses. Although this would not constitute an improvement in endothelial function as such, because release of NO and other elements of endothelial function would not be expected to change, it might nevertheless be of clinical benefit, given the general vasculoprotective actions of NO, which are predominantly mediated through simulation of cGMP.¹⁷ Sildenafil has been found to improve endothelium-dependent vasodilatation in some previous studies^11,18–21 but not in all.^9–11,22 There are no published studies on the effect of PDE5 inhibition on endothelium-dependent vasomotor function in hypertension.

In single dose studies, sildenafil has been found to reduce central augmentation index (CAIx), a measure of the effect of peripheral arterial wave reflection on the pressure waveform of the central aorta, in treated hypertensives,¹⁴ hypertensive cardiac transplant patients,¹⁹ and patients with CAD.²³ It also acutely reduced carotid-femoral pulse wave velocity (CF-PWV), a measure of central arterial stiffness, in patients with CAD²³ and heart failure.²⁴ However, the effects of chronic PDE5 inhibition on arterial stiffness and arterial wave reflection have not been investigated previously. The aim of this study was to investigate the effects of chronic treatment with sildenafil on BP (the primary outcome measure), endothelium-dependent vasomotor function, arterial stiffness, and arterial wave reflection in otherwise untreated hypertensives.

	Methods

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The study was of randomized, placebo-controlled, double-blind, 2-way crossover design. It was approved by a local research ethics committee, was performed in accordance with the Declaration of Helsinki, and written informed consent was obtained from all of the subjects.

Subjects
Subjects were identified from primary care and hospital hypertension clinics. The inclusion criteria were: male or female, 3 separate clinic measurements of systolic BP 160 mm Hg or diastolic BP 100 mm Hg, not taking antihypertensives; hypertension confirmed on ambulatory BP monitoring (average daytime systolic BP 145 mm Hg or diastolic BP 95 mm Hg), within 3 months of the screening visit; and subjects with "borderline" hypertension (defined as an average awake systolic BP 135 and <145 mm Hg or diastolic BP 85 and <95 mm Hg) if their calculated 10-year risk of cardiovascular disease was >20% or they had evidence of target organ damage. The exclusion criteria were: history of other major cardiac, respiratory, neurologic, or renal disease; systolic BP consistently >210 mm Hg or diastolic BP consistently >120 mm Hg; current alcohol abuse; diabetes; taking any vasoactive drugs; previous serious drug allergy; and pregnancy.

Potentially suitable subjects attended a screening visit at which a medical history was taken and a physical examination and 12-lead ECG were performed. A nonfasting blood sample was also taken. A 24-hour ambulatory BP monitor was fitted if ambulatory monitoring had not been performed within 3 months.

Measurements
Clinic BP and heart rate (HR) were recorded, with an appropriate sized cuff, using a validated oscillometric sphygmomanometer, the Omron HEM-705CP.²⁵ Ambulatory BP was recorded at the brachial artery using a validated Spacelabs 90217 ambulatory BP monitor.²⁶ Measurements were taken every 30 minutes for 24 hours. BP variability was calculated as the within-subject SD of all of the systolic and diastolic daytime readings.

Radial artery waveforms, calibrated to brachial BP, were measured by applanation tonometry and the SphygmoCor apparatus. The radial augmentation index (RAIx) was derived from averaged radial artery waveforms. CAIx, CAIx adjusted to a standard HR of 75 bpm (CAIx@75), and central aortic BP were calculated from central aortic waveforms, which were derived by applying a generalized transfer function to the directly measured radial waveforms. True mean arterial BP was derived from integration of the radial waveform. The SphygmoCor apparatus was also used to measure CF-PWV. Brachial artery flow-mediated dilatation (FMD) was used to assess endothelium-dependent vasomotor function.²⁷ FMD was quantified both as the peak change from baseline and as the area under the curve of the change from baseline in brachial artery diameter after 5 minutes of forearm ischemia. The response to nitroglycerin, an endothelium-independent control, was not assessed because of the potential for significant hypotension when given with sildenafil.²⁸ Full details of the methodologies used are available in an online supplement at http://hyper.ahajournals.org.

Protocol
Subjects refrained from alcohol for 24 hours and caffeinated drinks, food, and smoking for 12 hours before each visit. Studies were conducted in a quiet room kept at 22°C to 24°C.

The study was composed of 2 periods that, except for the treatment received (sildenafil or placebo), were identical. On day 1, subjects attended the research unit at 8:00 AM. After 30 minutes, supine rest baseline measurements of BP and HR, radial waveforms, CF-PWV, and FMD were recorded in that order. Sildenafil 50 mg or matched placebo (both obtained from Pfizer, United Kingdom) was then administered orally, and the same measurements were repeated 1 hour after dose. Subjects were discharged with a supply of the same tablets to take 3 times daily (morning, early afternoon, and evening). An ambulatory BP monitor was fitted at 8:00 AM on day 15. On day 16, this was removed, and further measurements were made before and 1 hour after sildenafil or placebo, as on day 1. There was a washout period of 6 days between the periods. For all of the measures, except FMD, duplicate recordings were made and mean values entered into the analyses.

Subjects recorded the time they took each tablet on a diary card. During each period, they were provided with 46 tablets, 2 more than required, and were asked to return all of the unused tablets. Subjects were also issued with cards on which they were asked to rate any symptoms as mild, moderate, or severe.

Analyses
Data are given as means and SEs. Means were compared by paired Student t tests. Correlation coefficients were calculated using the Pearson method. The screening ambulatory BP was used as the baseline for both phases of the study.

	Results

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Subjects
Thirty-six subjects underwent screening (34 from primary care and 2 from the hospital clinic). Of those screened, 10 did not meet the entry criteria, and 1 withdrew before starting the study. Of the 25 subjects who started the study, 3 were withdrawn because of adverse effects. Analyses were performed on the data from the remaining 22 subjects. The baseline characteristics of the subjects are given in Table 1. At baseline, there was a nocturnal reduction of >10% in both systolic BP and diastolic BP in all of the subjects (ie, there were no nocturnal nondippers).

View this table: [in this window] [in a new window]   TABLE 1. Subject Baseline Characteristics

Vascular Effects
There were no differences in baseline measures of any parameter between placebo and sildenafil phases of the study. Sildenafil significantly reduced both systolic and diastolic ambulatory 24-hour, daytime, and nighttime BPs compared with both baseline and placebo (Table 2). Higher baseline ambulatory systolic BP but not diastolic BP was associated with a greater reduction with sildenafil (24-hour: r=–0.55, P<0.01; daytime: r=–0.52, P<0.05; nighttime: r=–0.51, P<0.05). There was no effect of either sildenafil or placebo on BP variability (systolic: 13.8 [0.6] mm Hg at baseline, 13.2 [0.6] mm Hg after placebo, and 13.2 [0.6] mm Hg after sildenafil; diastolic: 9.4 [0.6] mm Hg at baseline, 9.1 [0.7] mm Hg after placebo, and 9.1 [0.5] mm Hg after sildenafil; comparisons with baseline and between placebo and sildenafil are all statistically nonsignificant).

View this table: [in this window] [in a new window]   TABLE 2. Effects on Ambulatory BP (mm Hg)

The effects of sildenafil and placebo on clinic BP, arterial wave reflection, CF-PWV, central BP, and FMD are shown in Table 3. Sildenafil reduced clinic systolic BP, diastolic BP, and mean arterial BP acutely (1 hour after administration), but by day 16, the magnitude of this reduction in BP was less than that on day 1. On day 16, BP was generally slightly lower 1 hour after sildenafil administration (time of peak effect) than just before sildenafil administration (time of trough effect). Sildenafil did not affect clinic pulse pressure or HR, either acutely or chronically (data not shown).

View this table: [in this window] [in a new window]   TABLE 3. Effects on Peripheral Clinic BP, Arterial Wave Reflection, Central BP, CF-PWV, and FMD

View this table: [in this window] [in a new window]   TABLE 3. Continued

Sildenafil reduced CAIx, CAIx@75, and RAIx acutely but, as with the effects on clinic BP, the magnitude of these effects on day 16 were reduced compared with those on day 1. When recorded before sildenafil administration on day 16, these measures were not significantly different from baseline, but when recorded 1 hour after sildenafil administration on day 16, they were significantly lower than at baseline. The changes from baseline in CAIx, CAIx@75, and RAIx with sildenafil were significantly different from placebo on day 1 but were not significantly different from placebo either before or after sildenafil administration on day 16. Compared with baseline, sildenafil reduced central systolic BP and central diastolic BP, both at 1 hour and after 16 days of regular treatment. However, the changes in these parameters were not significantly different from the changes observed with placebo when measured before sildenafil administration on day 16. Sildenafil reduced central pulse pressure acutely but not after chronic treatment.

CF-PWV and FMD were unaffected by sildenafil, both acutely and chronically. Sildenafil also did not affect baseline brachial artery diameter or the extent of reactive hyperemia at any point (data not shown).

Adverse Effects
Two subjects were withdrawn while taking sildenafil, 1 because of severe headache (after 3 days) and the other because of back pain and feeling generally unwell (after 6 days), and 1 subject was withdrawn while taking placebo, because of joint pains, nausea, and headache (after 11 days). For a full summary of the symptoms experienced see the online supplement. Dyspepsia occurred in 10 subjects with sildenafil and lasted 5 days. Headaches occurred in 8 subjects and were generally mild and transient. Low back/buttock/leg muscle ache occurred in 7 subjects, was usually responsive to simple analgesia, and tended to settle within a few days. Plasma creatine kinase concentrations were measured in 4 of the subjects who experienced these symptoms, and all were within the normal laboratory reference range. Six of the 18 men in the study reported increased penile erection, which occurred only with sildenafil.

	Discussion

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Sildenafil reduced BP both acutely and after 16 days of regular administration. The reduction in average daytime BP was 8/6 mm Hg compared with baseline and 10/6 mm Hg compared with placebo. This degree of BP reduction is similar to the effect of other, commonly used antihypertensive drugs when they are given as monotherapy in hypertension.²⁹ The correlation between baseline systolic BP and the extent of reduction in systolic BP with sildenafil suggests that in a more hypertensive population, a greater absolute effect on BP may occur.

When given as 50 mg 3 times daily, sildenafil accumulates in the plasma. The accumulation ratio, based on the area under the curve of the plasma concentration versus time curve of 0 to 8 hours, is 1.59 in healthy subjects (Baerbel Wittke, unpublished data, 2006). Despite this, although there was a persistent hypotensive effect of sildenafil for 16 days, the clinic BP data show that there was some attenuation of the acute effect. This may be the result of neurohormonal counterregulatory mechanisms, such as stimulation of the renin–angiotensin system, after the initial vasodilatation-mediated reduction in BP. On day 16 of treatment, clinic BP was higher before the administration of sildenafil than at 1 hour afterward. Although average nighttime BP was reduced, this suggests that the overnight dose interval was sufficiently long for the antihypertensive effect to begin to wane, which may be of clinical relevance given that the early morning surge in BP may be an important trigger of cardiovascular events.³⁰ The use of a modified-release preparation of sildenafil (not currently available) or a longer-acting PDE5 inhibitor might afford better protection at this time. A more stable steady-state plasma concentration that would occur with either a modified-release preparation or a longer acting agent might also result in a greater cumulative reduction in BP. Despite reducing BP, HR was not affected by sildenafil. This has been reported previously and is consistent with an influence on baroreflex regulation.⁶

Sildenafil reduced arterial wave reflection, whether measured as CAIx, CAIx@75, or RAIx and did so in a manner that was similar to the effect on clinic BP, with a greater reduction acutely than was evident after 16 days. However, this effect was relatively small and was no more than would be expected as a simple consequence of the reduction in systemic BP,³¹ suggesting that sildenafil did not act specifically to reduce large artery stiffness. This conclusion may also be supported by the lack of effect of sildenafil on CF-PWV, a more direct measure of large artery stiffness. However, although the effects were not statistically significant, there was a trend to a progressive reduction in CF-PWV (–0.2 m/s at 1 hour, –0.5 m/s on day 16 before sildenafil, and –0.8 m/s on day 16 after sildenafil), and the possibility of a real effect on CF-PWV should not be dismissed; a larger sample size or a longer treatment period may have demonstrated a significant effect. With chronic treatment, sildenafil reduced central BP to an extent similar to its effect on peripheral BP. Measurement of central BP did not, therefore, provide any additional information on the antihypertensive action of sildenafil over and above the measurement of peripheral BP.

Sildenafil had no effect on FMD, indicating that it did not modulate endothelium-dependent vasomotion, either acutely or after chronic treatment. There are conflicting data on the acute effects of sildenafil on endothelium-dependent vasomotor responses, with some reports of an improvement and other reports showing no effect. Although these previous studies have recruited different patients and used different methodologies, there are no apparent consistent differences to explain the different effects observed. For example, there are positive and negative studies that used forearm plethysmography^20,22 or FMD^9,11,21 and that recruited smokers^9,21 or patients with CAD.^11,22 It should be noted that the use of a clamp to hold the ultrasound probe in place, as well as computerized analysis of arterial images, represent best practice in FMD studies, maximizing our confidence that the finding is truly negative.

Given that FMD is largely NO mediated, it would seem logical that sildenafil, by preserving NO-stimulated cGMP, would improve FMD. However, this might only be expected in subjects with impaired endothelium-dependent vasomotor function at baseline. Although we did not include a normotensive control group in the present study, in a further (unpublished) study in our department, mean baseline FMD was 5.6% (±0.4%) in 44 healthy men and women with mean age 42 years. Thus, endothelium-dependent vasomotion was most likely impaired in the hypertensive subjects, even if this was partly because they were, on average, older. A possible explanation for the lack of effect of sildenafil on FMD in the present study is that, compared with healthy subjects,³² NO contributes relatively little to shear stress-induced vasodilatation at the brachial artery in hypertensive subjects. In support of this hypothesis, it has been shown previously that although vasodilatation to bradykinin in the forearm is NO mediated in healthy subjects, in hypertensive subjects it is not only reduced but is also mediated by a different pathway, possibly involving endothelium-dependent hyperpolarization.³³ Although not investigated previously, if similar changes occur in the brachial artery, sildenafil may be expected to have little or no effect on FMD in hypertension.

The relevance of an improvement in FMD to cardiovascular prognosis in hypertension is not clear. Although there is evidence that prognosis is better in patients that demonstrate improvements in FMD after treatment,³⁴ FMD is not consistently improved by antihypertensive drugs of different classes although, with the possible exception of ß-blockers,³⁵ these drugs are substantially equivalent in reducing cardiovascular events.³⁶ Therefore, the lack of effect of sildenafil on FMD should not, in itself, detract from its potential as an antihypertensive in clinical practice.

Adverse effects from regular sildenafil treatment were relatively common but generally transient and of mild-to-moderate severity. Headache was experienced with a similar frequency to that seen in other studies, but dyspepsia was slightly more frequent.⁵ Myalgia (reported as an aching sensation of the low back, buttocks, or legs) has generally been reported to occur in <5% of men taking single doses³⁷ but seems to occur more frequently with repeated administration, for example, in 28% of subjects in the present study and in 14% of subjects with pulmonary arterial hypertension.⁵ The lack of any rise in plasma creatine kinase in 4 of our subjects with myalgia suggests that these symptoms were not because of an underlying myositis.

As a consequence of the range of outcome measures and assessment of these at multiple time points, a large number of statistical comparisons have been made, presenting the possibility of type 1 statistical errors. However, this possibility is of least concern for the data on the effect on ambulatory BP, the primary outcome measure, because ambulatory BP was only assessed at baseline and at the end of each treatment period. Moreover, the effect of sildenafil on both 24-hour and daytime BPs was highly statistically significant (P<0.01).

Perspectives
This is the first controlled clinical trial to demonstrate the potential of regular PDE5 inhibition in the chronic treatment of hypertension. Although sildenafil effectively reduced BP, its use in clinical practice is limited by its relatively short duration of action, requiring it to be administered 3 times daily. A modified-release preparation of sildenafil may overcome this problem but is not currently available. Alternatively, a longer acting PDE5 inhibitor, such as tadalafil, may be more suitable for further studies on PDE5 inhibition in hypertension. Assuming that such an agent is also shown to reduce BP when administered chronically, characterization of its adverse effect profile and an appropriate dosing strategy for chronic use would be research priorities. Clarification of the effects of chronic PDE5 inhibition on CF-PWV would also be of interest. Studies comparing both antihypertensive efficacy and tolerability of PDE5 inhibitors with established antihypertensives would help to determine their place in clinical practice. A potentially valuable indication for the use of PDE5 inhibitors as antihypertensives is in men with erectile dysfunction. However, it would be necessary to demonstrate that the effect of PDE5 inhibition on erectile function is maintained in the long term with the regular dosing pattern that would be required for the treatment of hypertension.

	Acknowledgments

 
Sources of Funding

The study was supported by an educational grant from Pfizer United Kingdom Ltd (>$10 000). J.J.O. was supported by an unrestricted Junior Cardiovascular Research Fellowship from Pfizer United Kingdom Ltd (>$10 000).

Disclosures

None.

Received April 4, 2006; first decision April 24, 2006; accepted July 28, 2006.

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