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 Karada ,
Ralph T. Schermuly, PhD,
Norbert Weissmann, PhD,
Werner Seeger, MD and
Friedrich Grimminger, MD*
Department of Internal Medicine, University Hospital Giessen, Giessen, Germany
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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.
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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).
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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.
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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.
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