ABSTRACT
AIMS: We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that of another dual endothelin receptor antagonist, bosentan, in a rat model of non-vasoreactive pulmonary hypertension (PH) with particular emphasis on right ventricular (RV) remodeling. METHODS AND RESULTS: Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented a non-vasoreactive PH characterized by the absence of pulmonary dilatation to adenosine. We therefore chose the bleomycin rat model to compare the effects of the maximally effective doses of macitentan and bosentan on pulmonary vascular and RV remodeling. Macitentan (100 mg·kg(-1)·d(-1)), but not bosentan (300 mg·kg(-1)·d(-1)), significantly prevented pulmonary vascular remodeling, RV hypertrophy, and cardiomyocyte diameter increase. Cardiac protection by macitentan was associated with a significant attenuation of genes related to cell hypertrophy and extracellular matrix remodeling. Microautoradiography and high performance liquid chromatography analysis showed greater distribution of macitentan than bosentan in the RV and pulmonary tissue. CONCLUSIONS: Macitentan was more efficacious than bosentan in preventing the development of pulmonary and RV hypertrophies in a model of non-vasoreactive PH. Greater ability to distribute into the tissue could contribute to the greater structural improvement by macitentan compared with bosentan.
Subject(s)
Endothelin Receptor Antagonists/pharmacology , Heart Ventricles/drug effects , Hypertension, Pulmonary/drug therapy , Hypertrophy, Right Ventricular/prevention & control , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Ventricular Function, Right/drug effects , Ventricular Remodeling/drug effects , Animals , Bleomycin , Bosentan , Disease Models, Animal , Gene Expression Regulation , Heart Ventricles/metabolism , Heart Ventricles/physiopathology , Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/genetics , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/physiopathology , Hypertrophy, Right Ventricular/chemically induced , Hypertrophy, Right Ventricular/genetics , Hypertrophy, Right Ventricular/metabolism , Hypertrophy, Right Ventricular/physiopathology , Male , Pulmonary Artery/drug effects , Pulmonary Artery/metabolism , Pulmonary Artery/physiopathology , Rats, Wistar , Time Factors , Vascular Remodeling/drug effectsABSTRACT
This study explored whether common rules exist for the distribution patterns across tissues in tissue distribution studies. To investigate this we tested whether tissue:plasma partition coefficients (PCs) of radioactivity are correlated with muscle:plasma PCs. The relationships between PCs of radioactivity in muscle and those in other tissues were investigated in 25 tissues for 20 structurally unrelated drug candidates. Tissue distribution data were obtained by quantitative whole-body autoradiography. Linear regression analysis was performed for each tissue. Radioactivity from basic and acidic/neutral compounds was analyzed separately. Results for acidic/neutral compounds: for the majority of the tissues investigated, the tissue:plasma PCs were well correlated with muscle:plasma PCs (R2 > 0.7). Correlations were worse (R2 < 0.7) in blood, white fat, excretory organs and tissues protected by a penetration barrier (e.g. brain). Slope factors for the regression ranged from 0.2 (blood) to 3.8 (Harderian gland) and were correlated with neutral lipid contents in tissues. Results for basic compounds: in most tissues, slope factors appeared to be higher than for acidic/neutral compounds. Correlations, however, were poorer than for acidic/neutral compounds. Overall, the present study demonstrates that muscle:plasma PCs are indicative of the overall tissue distribution of drug-related material, as they are well correlated with tissue:plasma PCs in most other tissues. Correlations for acidic/neutral compounds differ from those for basic compounds. The found PC relationships provide an explanation for the distribution pattern across tissues usually seen in tissue distribution studies.
