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Effects of different pulmonary vasodilators on arterial saturation in a model of pulmonary hypertension.

Becker EM, Stasch JP, Bechem M, Keldenich J, Klipp A, Schaefer K, Ulbrich HF, Truebel H - PLoS ONE (2013)

Bottom Line: The doses were chosen to achieve equal effect on blood pressure by the different pharmacologic principles.Single-lung ventilation resulted in transient increases in mean pulmonary artery pressure (mPAP) and desaturation.Riociguat and bosentan reduced hypoxic mPAP to the greatest extent, while the soluble guanylate cyclase stimulators riociguat and BAY 41-8543 lowered arterial oxygen saturation of hemoglobin the least.

View Article: PubMed Central - PubMed

Affiliation: Bayer Pharma AG, Cardiology Research, Wuppertal, Germany ; University Witten/Herdecke, Fakultät für Gesundheit, Witten, Germany.

ABSTRACT

Background: Approved therapies for pulmonary arterial hypertension can induce oxygen desaturation when administered to patients with secondary forms of pulmonary hypertension (PH), probably due to an increase in ventilation/perfusion mismatch. Thus, so far these treatments have largely failed in secondary forms of PH.

Methods: We established an animal model of heterogeneous lung ventilation to evaluate the desaturation potential of mechanistically distinct vasoactive drugs launched or currently in clinical development for the treatment of PH. Single-lung ventilation was induced in five groups (N = 6) of anesthetized minipigs (7 weeks, 4 to 5 kg BW), and their hemodynamic parameters were monitored before and after intravenous injection of control (vehicle only), endothelin antagonist (bosentan; 0.3, 1, 3, 10 mg/kg), phosphodiesterase type 5 inhibitor (sildenafil; 3, 10, 30, 100 µg/kg), and soluble guanylate cyclase stimulators (BAY 41-8543 and riociguat; 1, 3, 10, 30 µg/kg). Cumulative doses were administered before successive unilateral ventilation cycles. The doses were chosen to achieve equal effect on blood pressure by the different pharmacologic principles.

Results: Single-lung ventilation resulted in transient increases in mean pulmonary artery pressure (mPAP) and desaturation. In contrast to control, all drugs dose-dependently decreased hypoxic mPAP (a positive treatment effect) and increased area under the arterial hemoglobin saturation curve (unwanted desaturation effect). Riociguat and bosentan reduced hypoxic mPAP to the greatest extent, while the soluble guanylate cyclase stimulators riociguat and BAY 41-8543 lowered arterial oxygen saturation of hemoglobin the least.

Conclusions: Future investigations will be required to confirm these findings in clinical settings.

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Related in: MedlinePlus

Vasodilator capacity to decrease maximal hypoxic mPAP and AUCSaO2.Vasodilator capacity to decrease maximal hypoxic mPAP (positive treatment effect) and AUCSaO2 (unwanted desaturation effect) based on (A) pooled effects at all dose levels tested (N = 6, four doses per group) and (B) at each drug's maximal effective dose (i.e., cumulative dose) (mean ± SEM, N = 6, doses as indicated). *P<0.05 vs vehicle. AUCSaO2, area under the SaO2 curve; SaO2, arterial oxygen saturation of hemoglobin; mPAP, mean pulmonary artery pressure; SEM, standard error of the mean.
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pone-0073502-g008: Vasodilator capacity to decrease maximal hypoxic mPAP and AUCSaO2.Vasodilator capacity to decrease maximal hypoxic mPAP (positive treatment effect) and AUCSaO2 (unwanted desaturation effect) based on (A) pooled effects at all dose levels tested (N = 6, four doses per group) and (B) at each drug's maximal effective dose (i.e., cumulative dose) (mean ± SEM, N = 6, doses as indicated). *P<0.05 vs vehicle. AUCSaO2, area under the SaO2 curve; SaO2, arterial oxygen saturation of hemoglobin; mPAP, mean pulmonary artery pressure; SEM, standard error of the mean.

Mentions: To compare the risk:benefit ratio of the different vasodilator mechanisms, we evaluated changes in maximal hypoxic PAP on the one hand and unwanted desaturation on the other. Thus, we compared the mean% changes in maximal hypoxic mPAP and associated% changes in AUCSaO2 independent of the administered doses (Fig. 8). Vice versa, we compared mean% changes in maximal AUCSaO2 increments with associated% changes in mPAP. Across the groups, the overall estimated correlation between both co-primary endpoints (% change in mPAP and% change in AUCSaO2) was 0.35, commonly considered a medium rather than a small correlation.


Effects of different pulmonary vasodilators on arterial saturation in a model of pulmonary hypertension.

Becker EM, Stasch JP, Bechem M, Keldenich J, Klipp A, Schaefer K, Ulbrich HF, Truebel H - PLoS ONE (2013)

Vasodilator capacity to decrease maximal hypoxic mPAP and AUCSaO2.Vasodilator capacity to decrease maximal hypoxic mPAP (positive treatment effect) and AUCSaO2 (unwanted desaturation effect) based on (A) pooled effects at all dose levels tested (N = 6, four doses per group) and (B) at each drug's maximal effective dose (i.e., cumulative dose) (mean ± SEM, N = 6, doses as indicated). *P<0.05 vs vehicle. AUCSaO2, area under the SaO2 curve; SaO2, arterial oxygen saturation of hemoglobin; mPAP, mean pulmonary artery pressure; SEM, standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756006&req=5

pone-0073502-g008: Vasodilator capacity to decrease maximal hypoxic mPAP and AUCSaO2.Vasodilator capacity to decrease maximal hypoxic mPAP (positive treatment effect) and AUCSaO2 (unwanted desaturation effect) based on (A) pooled effects at all dose levels tested (N = 6, four doses per group) and (B) at each drug's maximal effective dose (i.e., cumulative dose) (mean ± SEM, N = 6, doses as indicated). *P<0.05 vs vehicle. AUCSaO2, area under the SaO2 curve; SaO2, arterial oxygen saturation of hemoglobin; mPAP, mean pulmonary artery pressure; SEM, standard error of the mean.
Mentions: To compare the risk:benefit ratio of the different vasodilator mechanisms, we evaluated changes in maximal hypoxic PAP on the one hand and unwanted desaturation on the other. Thus, we compared the mean% changes in maximal hypoxic mPAP and associated% changes in AUCSaO2 independent of the administered doses (Fig. 8). Vice versa, we compared mean% changes in maximal AUCSaO2 increments with associated% changes in mPAP. Across the groups, the overall estimated correlation between both co-primary endpoints (% change in mPAP and% change in AUCSaO2) was 0.35, commonly considered a medium rather than a small correlation.

Bottom Line: The doses were chosen to achieve equal effect on blood pressure by the different pharmacologic principles.Single-lung ventilation resulted in transient increases in mean pulmonary artery pressure (mPAP) and desaturation.Riociguat and bosentan reduced hypoxic mPAP to the greatest extent, while the soluble guanylate cyclase stimulators riociguat and BAY 41-8543 lowered arterial oxygen saturation of hemoglobin the least.

View Article: PubMed Central - PubMed

Affiliation: Bayer Pharma AG, Cardiology Research, Wuppertal, Germany ; University Witten/Herdecke, Fakultät für Gesundheit, Witten, Germany.

ABSTRACT

Background: Approved therapies for pulmonary arterial hypertension can induce oxygen desaturation when administered to patients with secondary forms of pulmonary hypertension (PH), probably due to an increase in ventilation/perfusion mismatch. Thus, so far these treatments have largely failed in secondary forms of PH.

Methods: We established an animal model of heterogeneous lung ventilation to evaluate the desaturation potential of mechanistically distinct vasoactive drugs launched or currently in clinical development for the treatment of PH. Single-lung ventilation was induced in five groups (N = 6) of anesthetized minipigs (7 weeks, 4 to 5 kg BW), and their hemodynamic parameters were monitored before and after intravenous injection of control (vehicle only), endothelin antagonist (bosentan; 0.3, 1, 3, 10 mg/kg), phosphodiesterase type 5 inhibitor (sildenafil; 3, 10, 30, 100 µg/kg), and soluble guanylate cyclase stimulators (BAY 41-8543 and riociguat; 1, 3, 10, 30 µg/kg). Cumulative doses were administered before successive unilateral ventilation cycles. The doses were chosen to achieve equal effect on blood pressure by the different pharmacologic principles.

Results: Single-lung ventilation resulted in transient increases in mean pulmonary artery pressure (mPAP) and desaturation. In contrast to control, all drugs dose-dependently decreased hypoxic mPAP (a positive treatment effect) and increased area under the arterial hemoglobin saturation curve (unwanted desaturation effect). Riociguat and bosentan reduced hypoxic mPAP to the greatest extent, while the soluble guanylate cyclase stimulators riociguat and BAY 41-8543 lowered arterial oxygen saturation of hemoglobin the least.

Conclusions: Future investigations will be required to confirm these findings in clinical settings.

Show MeSH
Related in: MedlinePlus