JACC
HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK
QUICK SEARCH:   [advanced]


     

J Am Coll Cardiol, 2004; 44:1488-1496, doi:10.1016/j.jacc.2004.06.060
© 2004 by the American College of Cardiology Foundation
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ghofrani, H. A.
Right arrow Articles by Grimminger, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ghofrani, H. A.
Right arrow Articles by Grimminger, F.

PULMONARY HYPERTENSION

Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension

A randomized prospective study

Hossein A. Ghofrani, MD, Robert Voswinckel, MD, Frank Reichenberger, MD, Horst Olschewski, MD, Peter Haredza, Burcu Karadas, Ralph T. Schermuly, PhD, Norbert Weissmann, PhD, Werner Seeger, MD and Friedrich Grimminger, MD*

Department of Internal Medicine, University Hospital Giessen, Giessen, Germany

Manuscript received April 21, 2004; revised manuscript received May 26, 2004, accepted June 7, 2004.

* Reprint requests and correspondence: Dr. Friedrich Grimminger, Department of Internal Medicine, University Hospital Giessen, Klinikstrasse 36, 35392 Giessen, Germany (Email: friedrich.grimminger{at}innere.med.uni-giessen.de).


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We sought to compare the short-termimpact of three different phosphodiesterase-5 (PDE5) inhibitors on pulmonary and systemic hemodynamics and gas exchange parameters in patients with pulmonary arterial hypertension (PAH).

BACKGROUND: The PDE5 inhibitor sildenafil has been reported to cause pulmonary vasodilation in patients with PAH. Vardenafil and tadalafil are new PDE5 inhibitors, recently being approved for the treatment of erectile dysfunction.

METHODS: Sixty consecutive PAH patients (New York Heart Association functional class II to IV) who underwent right heart catheterization received short-term nitric oxide (NO) inhalation and were subsequently assigned to oral intake of 50 mg sildenafil (n = 19), 10 mg (n = 7) or 20 mg (n = 9) vardenafil, or 20 mg (n = 9), 40 mg (n = 8), or 60 mg (n = 8) tadalafil. Hemodynamics and changes in oxygenation were assessed over a subsequent 120-min observation period.

RESULTS: All three PDE5 inhibitors caused significant pulmonary vasorelaxation, with maximum effects being obtained after 40 to 45 min (vardenafil), 60 min (sildenafil), and 75 to 90 min (tadalafil). Sildenafil and tadalafil, but not vardenafil, caused a significant reduction in the pulmonary to systemic vascular resistance ratio. Significant improvement in arterial oxygenation (equally to NO inhalation) was only noted with sildenafil.

CONCLUSIONS: In PAH patients, the three PDE5 inhibitors differ markedly in their kinetics of pulmonary vasorelaxation (most rapid effect by vardenafil), their selectivity for the pulmonary circulation (sildenafil and tadalafil, but not vardenafil), and their impact on arterial oxygenation (improvement with sildenafil only). Careful evaluation of each new PDE5 inhibitor, when being considered for PAH treatment, has to be undertaken, despite common classification as PDE5 inhibitors.

Abbreviations and Acronyms
  cGMP = cyclic guanosine monophosphate
  CI = confidence interval
  mPAP = mean pulmonary arterial pressure
  NO = nitric oxide
  NYHA = New York Heart Association
  PAH = pulmonary arterial hypertension
  PDE = phosphodiesterase
  PVRI = pulmonary vascular resistance index
  SVRI = systemic vascular resistance index

In recent years, several new drugs have been developed for the treatment of pulmonary arterial hypertension (PAH), including continuous intravenous epoprosterenol (1), inhaled iloprost (2), subcutaneous trepostinil (3), oral bosentan (4), and oral beraprost (5,6). In addition, there is increasing evidence for the therapeutic effectiveness of the phosphodiesterase-5 (PDE5) inhibitor sildenafil in PAH (7–9). Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide (NO) (Fig. 1). The phosphodiesterases have different tissue distributions and substrate affinities (10). Interestingly, PDE5 is abundantly expressed in lung tissue (11), thus offering as target molecule for PAH treatment concepts.



View larger version (36K):
[in this window]
[in a new window]
  		Figure 1 Intracellular signaling pathway of nitric oxide (NO), prostanoids, and natriuretic peptides: role of phosphodiesterases (PDEs). Ligands (i.e., NO, atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], and prostanoids) activate membrane-bound or soluble cyclases. Guanylate and adenylate cyclases generate cyclic guanosine monophosphate (cGMP) and adenosine monophosphate (cAMP) from GTP and ATP. These intracellular second messengers, via activation of protein kinases, induce cellular responses (i.e., vasodilation and anti-proliferation). Phosphodiesterases limit the effects of the ligands by degradation of second messengers cGMP and cAMP into inactive GMP and AMP. Thus, by inhibition of the PDEs, the PDE inhibitors augment and prolong the cellular responses to NO, prostanoids, and natriuretic peptides.

 
Recently, the new PDE5 inhibitors vardenafil and tadalafil have been approved for the treatment of erectile dysfunction. These PDE5 inhibitors share major properties with sildenafil, including mechanisms of action and preferential though not fully selective inhibition of PDE5. The clinical efficacy and safety profiles of these medications are linked to their molecular mode of action, their selectivity for PDE5, and their pharmacokinetic properties (12). However, all investigations performed so far have mainly focused on comparing the effects of these substances on erectile dysfunction. No data exist addressing the efficacy and safety of vardenafil and tadalafil, as opposed to sildenafil, on pulmonary and systemic hemodynamics in patients with PAH.

In the present study, we characterized the hemodynamic profile of different doses of vardenafil and tadalafil in patients with PAH. Response profiles were compared with those of inhaled NO (20 to 40 ppm) and sildenafil (50 mg), serving as reference agents, as previously described (7,9,13,14). Dosing of vardenafil and tadalafil was based on the labeling of these substances in their original indication, as well as preliminary investigations of our own group (data not published) addressing dose-response profiles of these agents.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Patients.   Overall, 82 patients were screened, of whom 22 were excluded (12 did not meet inclusion criteria, seven did not provide consent, and three were clinically unstable between screening and study onset). Sixty patients (39 women and 21 men) with chronic PAH, as defined by the recent World Conference on Pulmonary Hypertension (15), were included: 46 with idiopathic PAH, seven with Eisenmenger's disease, four with CREST (calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia), two with porto-pulmonary hypertension, and one with human immunodeficiency virus associated.

All patients were admitted to our pulmonary hypertension center for testing of pulmonary vasoreactivity and evaluation of therapeutic options. Diagnostic procedures preceding patient recruitment included clinical chemistry, immunologic analysis, chest X-ray, lung function testing, echocardiography, and a high-resolution computed tomographic scan of the lung. In all cases, perfusion scintigraphy, spiral computed tomography, and, in selected cases, pulmonary angiography were performed to exclude chronic thromboembolism as the underlying reason for pulmonary hypertension. All patients were tested for the first time and had not been previously treated with pulmonary vasodilators, except for 14 of the patients receiving low-dose calcium channel blocker therapy.

Exclusion criteria were pulmonary hypertension secondary to chronic obstructive or restrictive pulmonary disease, recurrent pulmonary embolism, pulmonary venous congestion, acute or chronic inflammatory lung disease, pregnancy or insufficient contraceptive measures, and previous treatment with PDE inhibitors. The individual response to vasodilators, including inhaled NO, was neither an inclusion nor an exclusion criterion. The study protocol was approved by the Justus-Liebig-University Ethics Committee, and each patient gave written, informed consent. The procedures followed were in accordance with institutional guidelines.

A fiberoptic thermodilution pulmonary artery catheter (Edwards Swan-Ganz, 93A-754H 7.5-F; Baxter Healthcare, Irvine, California) was used to measure central venous pressure, pulmonary artery pressure, pulmonary artery wedge pressure, cardiac output, and mixed venous oxygen saturation. Patients received continuous nasal oxygen throughout the entire test procedure if initial arterial oxygen saturation was below 88%.

Treatment.   After assessment of baseline hemodynamic values, each patient received short-term inhaled NO; the maximum vasodilator response to this agent required 20 to 40 ppm NO. When hemodynamic parameters had returned to baseline values after cessation of NO inhalation, patients received one oral dose of a PDE5 inhibitor. In the first 19 patients presenting with PAH, 50 mg sildenafil was orally administered. Subsequently, PAH patients were randomly assigned to receive either 10 mg (n = 7) or 20 mg (n = 9) oral vardenafil or 20 mg (n = 9), 40 mg (n = 9), or 60 mg (n = 8) oral tadalafil (Fig. 2). Patients were assigned to the therapeutic regimens by using computerized randomization in groups of five; no more than two patients in a row were assigned to one group. Hemodynamic measurements were performed at baseline, during maximum effect of inhaled NO, and 15, 30, 45, 60, 90, and 120 min (and, in selected cases, after 150 min) after ingestion of each PDE5 inhibitor. Calculations were made at peak reduction of pulmonary vascular resistance (PVR).



View larger version (25K):
[in this window]
[in a new window]
  		Figure 2 Hemodynamic and oxygenation response to inhaled nitric oxide (NO), oral sildenafil, oral vardenafil, and oral tadalafil. Deviations from the pre-intervention baseline value are displayed (point estimates of median difference [percentage of baseline = symbols], with exact 95% confidence intervals [bars] for inhaled NO [NO 20 to 40 ppm = solid circles], oral sildenafil [Sil 50 mg = red squares], 10 and 20 mg oral vardenafil [Vard 10 mg and Vard 20 mg = blue diamonds], and 20, 40, and 60 mg oral tadalafil [Tada 20 mg, Tada 40 mg, Tada 60 mg = green inverted triangles]). mSAP = mean systemic arterial pressure; CI = cardiac index; pO2 = partial pressure of arterial oxygen. The p values indicate significant differences of treatment effects, as determined by one-way analysis of variance. ¶Different from NO. ||Different from tadalafil 60 mg (p < 0.05, Scheffé post-test).

 
Statistics.   All baseline data are given as the median and range (minimum to maximum). Hodges-Lehmann point estimates of median difference and exact 95% confidence intervals (CIs) are presented for the response of each parameter to each vasodilator challenge (pre- and post-intervention values). One-way analysis of variance with the Scheffé post-test for multiple comparisons was used to seek for statistical differences between hemodynamic and gas exchange variables in the different treatment groups at baseline and to analyze for statistical differences regarding the responsiveness to each vasodilator.

Role of funding source.   The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Functional classification and baseline hemodynamics.   According to clinical criteria, nine patients were classified as being in New York Heart Association (NYHA) functional class II, 35 patients in class III, and 16 patients in class IV. The mean pulmonary artery pressure (mPAP) was markedly elevated (53.0 mm Hg [range 30 to 87 mm Hg]), and the cardiac index was in the lower normal range (2.2 l/min per m2 [range 1.0 to 4.0 l/min per m2]), with a correspondingly increased PVRI (PVRI 1,569 dynes/cm–5 per m2 [range 402 to 4,099]). Distribution to functional classes, to PAH subgroups, as well as baseline hemodynamics did not significantly differ between the treatment groups (Table 1).


View this table:
[in this window]
[in a new window]
  		Table 1. Baseline Hemodynamic and Gas Exchange Variables
 
Nitric oxide inhalation.   Inhalation of NO caused a rapid decrease in mPAP by –9.8% (CI –7.2 to –13.4), accompanied by a median increase in the cardiac index by 6.0% (CI 2.6 to 9.4), resulting in a PVRI reduction of –15.5% (CI –11.0 to –19.3) (Table 2, Fig. 3). Pulmonary selectivity of the vasodilatory effect was reflected by a reduction of –13.8% (CI –10.5 to –17.9) in the PVR/systemic vascular resistance (SVR) ratio. Concomitantly, a significant increase in arterial pO2 of 9.6% (CI 1.6 to 19.0) was noted. All NO-induced changes returned to baseline within <10 min after stopping inhalation of this agent.


View this table:
[in this window]
[in a new window]
  		Table 2. Peak Effects of Pharmacologic Interventions on Hemodynamics and Gas Exchange Variables
 


View larger version (19K):
[in this window]
[in a new window]
  		Figure 3 Kinetics of peak pulmonary vasodilatory effects of the different phosphodiesterase-5 (PDE5) inhibitors. Deviations from the pre-intervention baseline values (point estimates of median difference [percentage of baseline = symbols], with exact 95% confidence intervals [CIs] [vertical bars]) for PVRI over time; also displayed are point estimates of median difference effects (percentage of baseline = symbols), with exact 95% CIs (horizontal bars). The changes are noted in response to sildenafil (Sil 50 mg = red square), vardenafil (Vard 10 mg = solid blue diamond; Vard 20 mg = open blue diamond), and tadalafil (Tada 20 mg = green hourglass; Tada 40 mg = open green inverted triangle; Tada 60 mg = solid green inverted triangle). The p value indicates significant difference of time to peak pulmonary vasodilation between the different therapeutic agents, as determined by analysis of variance (#different from Tadalafil 40 mg group; p < 0.05, Scheffé post-test). There was no difference in the magnitude of response among the treatment groups (p = 0.185). PVRI = pulmonary vascular resistance index.

 
Sildenafil.   Fifty mg of oral sildenafil caused a significant decrease of mPAP by –16.2% (CI –11.6 to –21.5), accompanied by a median increase in the cardiac index by 13.2% (CI 9.9 to 17.1), resulting in a PVRI reduction of –28.0% (CI –26.1 to –31.2) (Fig. 3). A peak vasodilatory effect was noted at 60 min (CI 52.0 to 67.5) after drug intake (Fig. 4). Despite systemic administration, pulmonary selectivity of the vasodilatory effect was reflected by a –15.5% (CI –11.1 to –21.3) reduction in the PVR/SVR ratio. As with inhaled NO, a concomitant significant increase in arterial pO2 of 8.9% (CI 1.2 to 22.9) was noted. No adverse events were reported during this short-term vasodilatory testing procedure on intake of sildenafil.



View larger version (31K):
[in this window]
[in a new window]
  		Figure 4 Flow chart of participants. The design of the study and assignment of subjects to the therapeutic interventions are shown in this flow chart.

 
Vardenafil.   Oral vardenafil at doses of 10 mg and 20 mg caused a significant decrease of mPAP of –14.3% (CI –5.6 to –23.1) and –12.1% (CI –7.3 to –15.8), respectively. A median increase in the cardiac index of 9.3% (CI 1.8 to 18.7) was noted after 10 mg vardenafil and of 18.4% (CI 9.8 to 25.1) after 20 mg vardenafil, respectively. The PVRI was reduced by –21.6% (CI –10.2 to –32.3) and –26.3 (CI –22.8 to –29.2), respectively (Fig. 3). Peak vasodilatory effect was noted at 41.3 min (CI 22.5 to 60.0) after intake of 10 mg vardenafil and at 45 min (CI 37.5 to 60.0) of 20 mg vardenafil (Fig. 4). By contrast with inhaled NO and oral sildenafil, vardenafil caused almost an equipotent reduction of SVR and PVR, as reflected by the PVR/SVR ratios of –6.9 (CI –24.8 to 15.2) for 10 mg and –0.1 (CI –8.2 to 4.2) for 20 mg of this substance. Arterial oxygenation remained virtually unchanged with both concentrations of this agent (Fig. 3). Despite the lack of pulmonary selectivity, only minor adverse events (such as flushing and a light headache in three of nine patients in the 20-mg group) were reported after intake of vardenafil.

Tadalafil.   Oral tadalafil, given at doses of 20, 40, and 60 mg, caused a significant decrease of mPAP of –12.6% (CI –3.6 to –24.4), –18.3% (CI –13.9 to –21.8), and –10.0% (CI –22.2 to 1.1), respectively. Median increases in the cardiac index of 9.3% (CI –4.8 to 15.4), 7.5% (CI –4.0 to 20.7), and 18.8% (CI 3.3 to 36.7) were noted for 20, 40, and 60 mg of tadalafil. The PVRI was reduced by –18.6% (CI –14.0 to –28.4), –27.1% (CI –14.2 to –39.8), and –26.7 (CI –19.9 to –39.8), respectively (Fig. 3). A peak vasodilatory effect was noted at 75 min (CI 52.5 to 120) after intake of 20 mg, at 90 min (CI 60 to 120) with 40 mg, and at 86.3 min (CI 52.5 to 135) with 60 mg of tadalafil, respectively (Fig. 4). Interestingly, even at the highest dosage of 60 mg tadalafil, selectivity for the pulmonary circulation was reflected by a significant reduction of the PRV/SVR ratio of –11.4% (CI –2.8 to –33.9). As with oral vardenafil, arterial oxygenation remained virtually unchanged with all concentrations of tadalafil employed (Fig. 3). No adverse events were reported after intake of oral tadalafil.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Our data show that despite sharing structural and pharmacologic similarities with sildenafil, vardenafil and tadalafil differ substantially from sildenafil in their effects on the pulmonary circulation.

Lung tissue is a rich source of phosphodiesterases, including PDE5, the major function of which is acceleration of the decay of cyclic guanosine monophosphate (cGMP) (11). Thereby, PDE5 limits the vasodilatory effects of guanylate cyclase stimuli, such as NO and atrial natriuretic peptides (10). Inhaled NO is a widely accepted vasodilatory agent frequently used for the assessment of pulmonary vascular reactivity in patients with chronic pulmonary hypertension (16,17). The rate of so-called responders to this agent (definition for response: fall in mPAP and PVRI of more than 20%; 11 of 60 patients in the current study) is well in line with previously published reports (13,14).

We and others recently showed that the PDE5-selective inhibitor sildenafil causes strong and dose-dependent pulmonary vasodilation (7–9). Notably, even at the high dose of 50 mg sildenafil, the characteristics of preferential pulmonary over systemic vasodilation were found to be preserved in those preceding studies. Based on these results, we employed 50 mg oral sildenafil as a reference agent in the current study. The profile of preferential pulmonary vasodilation was well reproduced, with a maximum PVRI reduction of ~30% and a reduction of PVRI/SVRI ratio of ~15% (Fig. 3). At the time being, our best explanation for the preferential pulmonary vasodilatory effect of sildenafil derives from the assumption of a substantial baseline stimulation of guanylate cyclase in the lung vasculature of patients with chronic pulmonary hypertension, attributable to ongoing pulmonary NO production (18–20) and to circulating natriuretic peptides such as atrial and brain natriuretic peptide (21–23).

Most interestingly, sildenafil not only displays characteristics of pulmonary selectivity but also appears to ameliorate ventilation-perfusion matching ("intrapulmonary selectivity"), thereby improving arterial oxygenation. This has previously been shown in patients with lung fibrosis and secondary pulmonary hypertension, in whom sildenafil simultaneously reduced PVR and improved gas exchange properties (24). In the currently tested patients, ventilation-perfusion matching was not directly assessed, but intrapulmonary selectivity of sildenafil is again indicated by a significant increase of arterial oxygenation. It may be speculated that sildenafil does not act as a nonspecific vasodilator in this vascular bed, but rather amplifies local cGMP-based vasoregulatory loops, thereby improving rather than disturbing adaptation of perfusion to ventilation distribution.

The newly introduced PDE5 inhibitors vardenafil and tadalafil have both been reported to be equally effective as sildenafil with regard to the treatment of erectile dysfunction (25,26). The main differences described so far are related to the rapidity of the onset of effects and to the duration of effects. Furthermore, several reports indicate a slightly different side-effect profile of vardenafil, tadalafil, and sildenafil (27–29). Currently, most authors explain these differences by the different selectivities of sildenafil, vardenafil, and tadalafil for the various PDE subgroups: sildenafil's 50% inhibitory capacityvalues for PDE5 (3.5 nmol), PDE6 (37 nmol), PDE1 (281 nmol), and PDE11 A (2,730 nmol) indicate a high selectivity for PDE5, but not an exclusive effect on this PDE (25). Similarly, vardenafil's selectivity for PDE5 over PDE6, PDE1, and PDE11 A is 25-fold, 500-fold, and 1,160-fold, respectively. By contrast, tadalafil is considerably more selective for PDE5 than for PDE6 (187-fold) but has significantly less selectivity for PDE11 A (fivefold selectivity for PDE5 over PDE11 A). In addition, there are major differences in mean half-lives: 3 to 4 h for sildenafil and vardenafil (30) and ~18 h for tadalafil (31).

Our current observations regarding peak hemodynamic effects being reached after ~40 min with vardenafil, ~60 min with sildenafil, and ~90 min with tadalafil are well in agreement with previous reports addressing kinetics of effects in the erectile dysfunction area (31). However, despite sharing many similarities with sildenafil in terms of structure and pharmacologic properties, vardenafil was found to lack pulmonary selectivity in our currently investigated patient cohort. This observation was true for both the 10-mg and 20-mg vardenafil group, as indicated by virtually equivalent reductions of PVR and SVR in response to both dosages. Further studies are needed to address the question of whether this surprisingly different profile, as compared with sildenafil, is due to the minor differences in the PDE inhibition pattern or to PDE's unrelated, currently unknown modes of actions.

Tadalafil is currently approved for the treatment of erectile dysfunction in dosages of 10 mg and 20 mg per tablet (32). However, in studies investigating the effects of tadalafil on cardiac and circulatory function, single doses up to 50 mg have been reported to be safe in terms of an absence of significant systemic vasodilation (33). In preceding pilot studies in PAH patients (data not given), up to 60 mg tadalafil was found to be well tolerated, without major systemic side effects. Based on these data, we decided to use 20, 40, and 60 mg of oral tadalafil in the current investigation in a randomized fashion. Most interestingly, tadalafil displayed selectivity for the pulmonary circulation, even in the 60-mg group. As expected from previous pharmacokinetic data, the peak hemodynamic effects of tadalafil were noted after ~90 min. We have not extended the observation period over 120 min (and in selected cases up to 150 min), as the entire catheterization and vasoreactivity testing procedure exceeded 6 h on average. Pharmacokinetic studies characterizing the maximum duration of PDE5 effects will be subject to forthcoming investigations.

By contrast with inhaled NO and sildenafil, neither vardenafil nor tadalafil improved arterial oxygenation.As multiple inert gas elimination measurements were not performed in the present study, the underlying mechanisms may not be fully resolved. There was no difference in cardiac output increase between sildenafil on the one side and both vardenafil and tadalafil on the other, and it is thus highly unlikely that differences in central venous oxygen saturation are responsible for the differences in arterial oxygenation. Thus, it may be assumed that sildenafil, as mentioned earlier, exerted a favorable impact on ventilation-perfusion matching, but this was not the case for vardenafil and tadalafil. It is presently fully unknown whether the discussed differences in the PDE inhibition pattern or PDE's unrelated modes of actions of sildenafil may be responsible for this interesting difference.

Conclusions.   The present study is the first to compare the short-termhemodynamic profiles of three different PDE5 inhibitors—sildenafil, vardenafil and tadalafil—in a well-defined patient collective suffering from chronic PAH. Although vardenafil showed the most rapid onset of effects, this substance lacked selectivity for the pulmonary circulation, which was demonstrated for sildenafil and tadalafil, even at high doses of the latter agent. The pulmonary vasodilatory response to tadalafil appeared to be the most long-lasting, as anticipated from previous studies in the field of erectile dysfunction. By contrast with sildenafil, vardenafil and tadalafil did not improve arterial oxygenation. Obviously, we cannot translate short-term effects into long-term effects,because we know that long-term effects may be significantly more efficacious than short-term effects,such as has been observed with epoprostenol; however, the converse may also occur. These findings thus strongly support the notion that careful evaluation of the pulmonary hemodynamic and gas exchange effects of each new PDE inhibitor focusing on cGMP decay is to be undertaken, despite common classification as PDE5 inhibitors.


   Acknowledgments
 
Our gratitude goes to Rory Morty, PhD, for thorough linguistic editing of the manuscript.


   Footnotes
 
This work was supported by the German Research Foundation (DFG; Sonderforschungsbereich 547). Dr. Ghofrani receives grant and contract support from Pfizer Ltd., Altana Pharma AG, and Schering AG; in addition, he serves on the Advisory Board of Pfizer Ltd. Dr. Olschewski receives grant and contract support by Schering AG, Lung Rx, and Myogen; in addition, he serves on the Advisory Boards of Schering AG and Lung Rx. Dr. Seeger receives grant and contract support by Schering AG, Pfizer Ltd., Altana Pharma AG, Lung Rx, and Myogen; in addition, he serves on the Advisory Boards of Schering AG, Altana Pharma AG, and Lung Rx. Dr. Grimminger receives grant and contract support by Pfizer Ltd., Bayer AG, and Altana Pharma AG; in addition, he serves on the Advisory Board of Altana Pharma AG.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Barst RJ, Rubin LJ, Long WA, et al. the Primary Pulmonary Hypertension Study Group A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension N Engl J Med 1996;334:296-302.[Abstract/Free Full Text]
  2. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension N Engl J Med 2002;347:322-329.[Abstract/Free Full Text]
  3. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial Am J Respir Crit Care Med 2002;165:800-804.[Abstract/Free Full Text]
  4. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension N Engl J Med 2002;346:896-903.[Abstract/Free Full Text]
  5. Galie N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial J Am Coll Cardiol 2002;39:1496-1502.[Abstract/Free Full Text]
  6. Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension J Am Coll Cardiol 2003;41:2119-2125.[Abstract/Free Full Text]
  7. Ghofrani HA, Wiedemann R, Rose F, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension Ann Intern Med 2002;136:515-522.[Abstract/Free Full Text]
  8. Wilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension Circulation 2001;104:1218-1222.[Abstract/Free Full Text]
  9. Michelakis E, Tymchak W, Lien D, et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide Circulation 2002;105:2398-2403.[Abstract/Free Full Text]
  10. Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms Physiol Rev 1995;75:725-748.[Abstract/Free Full Text]
  11. Ahn HS, Foster M, Cable M, et al. Ca/CaM-stimulated and cGMP-specific phosphodiesterases in vascular and non-vascular tissues Adv Exp Med Biol 1991;308:191-197.[Medline]
  12. Corbin JD, Francis SH. Pharmacology of phosphodiesterase-5 inhibitors Int J Clin Pract 2002;56:453-459.[Medline]
  13. Sitbon O, Humbert M, Jagot JL, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension (see comments) Eur Respir J 1998;12:265-270.[Abstract]
  14. German PPH Study GroupHoeper MM, Olschewski H, Ghofrani HA, et al. A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension J Am Coll Cardiol 2000;35:176-182.[Abstract/Free Full Text]
  15. Galie N, Torbicki A. Pulmonary arterial hypertension: new ideas and perspectives Heart 2001;85:475-480.[Free Full Text]
  16. Sitbon O, Brenot F, Denjean A, et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension: a dose-response study and comparison with prostacyclin Am J Respir Crit Care Med 1995;151:384-389.[Abstract]
  17. Olschewski H, Walmrath D, Schermuly R, et al. Aerosolized prostacyclin and iloprost in severe pulmonary hypertension Ann Intern Med 1996;124:820-824.[Abstract/Free Full Text]
  18. Hanson KA, Burns F, Rybalkin SD, et al. Developmental changes in lung cGMP phosphodiesterase-5 activity, protein, and message Am J Respir Crit Care Med 1998;158:279-288.[Medline]
  19. Hanson KA, Ziegler JW, Rybalkin SD, et al. Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity Am J Physiol 1998;275:L931-41.[Medline]
  20. Grimminger F, Spriestersbach R, Weissmann N, et al. Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused rabbit lungs J Appl Physiol 1995;78:1509-1515.[Abstract/Free Full Text]
  21. Wiedemann R, Ghofrani HA, Weissmann N, et al. Atrial natriuretic peptide in severe primary and nonprimary pulmonary hypertension: response to iloprost inhalation J Am Coll Cardiol 2001;38:1130-1136.[Abstract/Free Full Text]
  22. Ghofrani HA, Wiedemann R, Rose F, et al. Lung cGMP release subsequent to NO inhalation in pulmonary hypertension: responders versus nonresponders Eur Respir J 2002;19:664-671.[Abstract/Free Full Text]
  23. Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension Circulation 2000;102:865-870.[Abstract/Free Full Text]
  24. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial Lancet 2002;360:895-900.[CrossRef][Medline]
  25. Gresser U, Gleiter CH. Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil—review of the literature Eur J Med Res 2002;7:435-446.[Medline]
  26. Young JM. Vardenafil Expert Opin Investig Drugs 2002;11:1487-1496.[CrossRef][Medline]
  27. Hellstrom WJ, Gittelman M, Karlin G, et al. Sustained efficacy and tolerability of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erectile dysfunction: results of a randomized, double-blind, 26-week placebo-controlled pivotal trial Urology 2003;61:8-14.[Medline]
  28. Kloner RA, Mitchell M, Emmick JT. Cardiovascular effects of tadalafil Am J Cardiol 2003;92:37M-46M.[CrossRef][Medline]
  29. Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction Am J Cardiol 2003;92:9M-18M.[Medline]
  30. Saenz de Tejada I, Angulo J, Cuevas P, et al. The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil Int J Impot Res 2001;13:282-290.[CrossRef][Medline]
  31. Francis SH, Corbin JD. Molecular mechanisms and pharmacokinetics of phosphodiesterase-5 antagonists Curr Urol Rep 2003;4:457-465.[Medline]
  32. Brock GB, McMahon CG, Chen KK, et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses J Urol 2002;168:1332-1336.[CrossRef][Medline]
  33. Porst H. IC351 (tadalafil, Cialis): update on clinical experience Int J Impot Res 2002;14(Suppl 1):S57-64.[Medline]



This article has been cited by other articles:


Home page
 Eur Respir JHome page
M. R. Wilkins, J. Wharton, F. Grimminger, and H. A. Ghofrani
Phosphodiesterase inhibitors for the treatment of pulmonary hypertension
Eur. Respir. J., July 1, 2008; 32(1): 198 - 209.
[Abstract] [Full Text] [PDF]

Home page
 J Clin PharmacolHome page
R. E. Wrishko, J. Dingemanse, A. Yu, C. Darstein, D. L. Phillips, and M. I. Mitchell
Pharmacokinetic Interaction Between Tadalafil and Bosentan in Healthy Male Subjects
J. Clin. Pharmacol., May 1, 2008; 48(5): 610 - 618.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
B. Lubamba, H. Lecourt, J. Lebacq, P. Lebecque, H. De Jonge, P. Wallemacq, and T. Leal
Preclinical Evidence that Sildenafil and Vardenafil Activate Chloride Transport in Cystic Fibrosis
Am. J. Respir. Crit. Care Med., March 1, 2008; 177(5): 506 - 515.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Sports. Med.Home page
L Guidetti, G P Emerenziani, M C Gallotta, F Pigozzi, L Di Luigi, and C Baldari
Effect of tadalafil on anaerobic performance indices in healthy athletes
Br. J. Sports Med., February 1, 2008; 42(2): 130 - 133.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
J. Nagendran, S. L. Archer, D. Soliman, V. Gurtu, R. Moudgil, A. Haromy, C. St. Aubin, L. Webster, I. M. Rebeyka, D. B. Ross, et al.
Phosphodiesterase Type 5 Is Highly Expressed in the Hypertrophied Human Right Ventricle, and Acute Inhibition of Phosphodiesterase Type 5 Improves Contractility
Circulation, July 17, 2007; 116(3): 238 - 248.
[Abstract] [Full Text] [PDF]

Home page
 SEMIN CARDIOTHORAC VASC ANESTHHome page
S. Takaoka, J. L. Faul, and R. Doyle
Current Therapies for Pulmonary Arterial Hypertension
Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2007; 11(2): 137 - 148.
[Abstract] [PDF]

Home page
 CirculationHome page
R. T. Schermuly, S. S. Pullamsetti, G. Kwapiszewska, R. Dumitrascu, X. Tian, N. Weissmann, H. A. Ghofrani, C. Kaulen, T. Dunkern, C. Schudt, et al.
Phosphodiesterase 1 Upregulation in Pulmonary Arterial Hypertension: Target for Reverse-Remodeling Therapy
Circulation, May 1, 2007; 115(17): 2331 - 2339.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
S. Mukhopadhyay, M. Sharma, S. Ramakrishnan, J. Yusuf, M. D. Gupta, N. Bhamri, V. Trehan, and S. Tyagi
Phosphodiesterase-5 Inhibitor in Eisenmenger Syndrome: A Preliminary Observational Study
Circulation, October 24, 2006; 114(17): 1807 - 1810.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
P. Fesler, A. Pagnamenta, B. Rondelet, F. Kerbaul, and R. Naeije
Effects of sildenafil on hypoxic pulmonary vascular function in dogs
J Appl Physiol, October 1, 2006; 101(4): 1085 - 1090.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
H. A. Ghofrani, R. Voswinckel, F. Reichenberger, N. Weissmann, R. T. Schermuly, W. Seeger, and F. Grimminger
Hypoxia- and non-hypoxia-related pulmonary hypertension - Established and new therapies
Cardiovasc Res, October 1, 2006; 72(1): 30 - 40.
[Abstract] [Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
O. Distler and A. Pignone
Pulmonary arterial hypertension and rheumatic diseases--from diagnosis to treatment
Rheumatology, October 1, 2006; 45(suppl_4): iv22 - iv25.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
T. K. Trow
Clinical Year in Review II: Occupational Lung Disease, Pulmonary Vascular Disease, Bronchiectasis, and Chronic Obstructive Pulmonary Disease
Proceedings of the ATS, September 1, 2006; 3(7): 557 - 560.
[Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
S. Jaillard, B. Larrue, P. Deruelle, A. Delelis, T. Rakza, G. Butrous, and L. Storme
Effects of Phosphodiesterase 5 Inhibitor on Pulmonary Vascular Reactivity in the Fetal Lamb.
Ann. Thorac. Surg., March 1, 2006; 81(3): 935 - 942.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. M. Hoeper and L. J. Rubin
Update in pulmonary hypertension 2005.
Am. J. Respir. Crit. Care Med., March 1, 2006; 173(5): 499 - 505.
[Full Text] [PDF]

Home page
 Br J AnaesthHome page
E. B. Lobato, T. Beaver, J. Muehlschlegel, D. S. Kirby, C. Klodell, and A. Sidi
Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension
Br. J. Anaesth., March 1, 2006; 96(3): 317 - 322.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
J. R. Klinger, S. Thaker, J. Houtchens, I. R. Preston, N. S. Hill, and H. W. Farber
Pulmonary hemodynamic responses to brain natriuretic Peptide and sildenafil in patients with pulmonary arterial hypertension.
Chest, February 1, 2006; 129(2): 417 - 425.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
B. M. Tsai, M. W. Turrentine, B. C. Sheridan, M. Wang, A. C. Fiore, J. W. Brown, and D. R. Meldrum
Differential Effects of Phosphodiesterase-5 Inhibitors on Hypoxic Pulmonary Vasoconstriction and Pulmonary Artery Cytokine Expression
Ann. Thorac. Surg., January 1, 2006; 81(1): 272 - 278.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
E. Fung, R. R. Fiscus, A. P. C. Yim, G. D. Angelini, and A. A. Arifi
The Potential Use of Type-5 Phosphodiesterase Inhibitors in Coronary Artery Bypass Graft Surgery
Chest, October 1, 2005; 128(4): 3065 - 3073.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
M. M. Hoeper
From the authors
Eur. Respir. J., July 1, 2005; 26(1): 180 - 181.
[Full Text] [PDF]

Home page
 The Annals of PharmacotherapyHome page
A. J Lee, T. B Chiao, and M. P Tsang
Sildenafil for Pulmonary Hypertension
Ann. Pharmacother., May 1, 2005; 39(5): 869 - 884.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ghofrani, H. A.
Right arrow Articles by Grimminger, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ghofrani, H. A.
Right arrow Articles by Grimminger, F.

HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK