Chronic intratracheal application of the soluble guanylyl cyclase stimulator BAY 41-8543 ameliorates experimental pulmonary hypertension

Figures

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  Figure 1. Pharmacokinetics after a single application of BAY 41-8543 The substance was administered either orally or intratracheally. A. Plasma concentrations of the substance one, three and six hours after administration. B. Concentrations of the substance in the lung tissue six hours after a single administration. C. Concentrations of the substance in the broncho-alveolar lavage fluid performed (BAL) six hours after administration. Data presented as mean ± SEM. # p < 0.05 IT 1 mg/kg vs. IT 3 mg/kg group.

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  Figure 2. Acute and chronic effects of BAY 41-8543 on systemic arterial pressure in monocrotaline model of PAH Four weeks after monocrotaline injection, treatment with BAY 41-8543 was started. Representative tracings of the systemic arterial pressure (SAP) monitoring are shown after A. per-oral placebo treatment, B. per-oral treatment with 10 mg/kg of BAY 41-8543, C. intra-tracheal treatment with 3 mg/kg of BAY 41-8543. D. Quantification of the systemic hypotensive effect after a single substance administration is demonstrated. Data presented as delta between SAP values before and 4 hours after drug administration. E. Results of SAP monitoring twice daily in rats treated chronically either per-oral or intra-tracheally. Data presented as mean ± SEM. * p < 0.05 PO 10 mg/kg vs. placebo, § p < 0.05 IT vs. PO 10 mg/kg group.

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  Figure 3. Effects of chronic treatment with BAY 41-8543 on right ventricular systolic pressure and vessel remodeling A. Right ventricular systolic pressure (RVSP) was measured invasively by right heart catheterization after two weeks of treatment. B. Pulmonary artery acceleration time (PAAT) was measured by echocardiography after two weeks of treatment. PAAT was measured from the pulsed-wave Doppler flow velocity profile of the right ventricular outflow tract in the parasternal short-axis view and defined as the interval from the onset to the maximal velocity of forward flow. C. Representative photomicrographs of elastin and double stained lung sections are demonstrated. D. Quantification of the medial wall thickness based on elastin staining. Medial wall thickness was defined as the distance between the lamina elastica interna and the lamina elastica externa. E. Quantification of the degree of vessel wall muscularisation based on double staining. Arteries that contained > 70% of α-actin positive-vessel wall area were set as fully muscularized (on the figure labelled as F); arteries with < 4% of α-actin positive-vessel area were set as non-muscular (on the figure labelled as N). Arteries…

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  Figure 4. Effects of chronic treatment with BAY 41-8543 on the right ventricular remodelling and function A. The heart was dissected and the ratio of the right ventricle weight to left ventricle plus septum weight (RV/LV+S) was calculated. B. Right ventricular internal diameter (RVID), C. Right ventricular free wall thickness (RVWT), and D. Tricuspid annular plane systolic excursion (TAPSE) were measured by echocardiography. E. Cardiac output was calculated using the Fick’s principle and normalized to body weight to obtain cardiac index (CI). F. Representative images of sirius red staining for collagen visualization and WGA staining for cardiomyocyte size measurement from different groups are demonstrated. G. Results of quantification of the sirius red stained heart sections are demonstrated. H. Results of cardiomyocyte cross sectional area quantification are demonstrated. Data presented as mean ± SEM. * p < 0.05 placebo vs. healthy, & p < 0.05 placebo vs. healthy, * p < 0.05 treatment groups vs. placebo.

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  Figure 5. Measurements of BAY 41-8543 concentrations A. in plasma and B. in the lung tissue after chronic treatment. § p < 0.05 IT 3 mg/kg vs. PO 10 mg/kg, # p < 0.05 IT 1 mg/kg vs. IT 3 mg/kg.