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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

PaO2 and PvO2 after each univentilation cycle.Arterial (PaO2) as well as venous (PvO2) partial oxygen pressure of four different groups are shown after each univentilation cycle. Shown are mean values ± SEM out of three to four animals. SEM, standard error of the mean.
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pone-0073502-g007: PaO2 and PvO2 after each univentilation cycle.Arterial (PaO2) as well as venous (PvO2) partial oxygen pressure of four different groups are shown after each univentilation cycle. Shown are mean values ± SEM out of three to four animals. SEM, standard error of the mean.

Mentions: Compared with control, all the vasodilators showed a similar increase in CO despite their distinct mechanisms of action (Fig. 6). Nevertheless, there was no significant difference detected regarding cardiac output (CO) between drug-treated animals and control animals. In a satellite study, arterial and venous O2 partial pressures were measured during the experiment to avoid differences between groups driven by differences in partial O2 pressure leading to the observed differences in the desaturation areas. We did not observe statistically significant differences in arterial or venous partial O2 pressure between the different groups at baseline or during the course of the experiment (Fig. 7).


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)

PaO2 and PvO2 after each univentilation cycle.Arterial (PaO2) as well as venous (PvO2) partial oxygen pressure of four different groups are shown after each univentilation cycle. Shown are mean values ± SEM out of three to four animals. SEM, standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0073502-g007: PaO2 and PvO2 after each univentilation cycle.Arterial (PaO2) as well as venous (PvO2) partial oxygen pressure of four different groups are shown after each univentilation cycle. Shown are mean values ± SEM out of three to four animals. SEM, standard error of the mean.
Mentions: Compared with control, all the vasodilators showed a similar increase in CO despite their distinct mechanisms of action (Fig. 6). Nevertheless, there was no significant difference detected regarding cardiac output (CO) between drug-treated animals and control animals. In a satellite study, arterial and venous O2 partial pressures were measured during the experiment to avoid differences between groups driven by differences in partial O2 pressure leading to the observed differences in the desaturation areas. We did not observe statistically significant differences in arterial or venous partial O2 pressure between the different groups at baseline or during the course of the experiment (Fig. 7).

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