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Endothelin receptor (ETR) blockade combined with phosphodiesterase‐5 (PDE5) inhibition prevents right ventricular hypoxia in Pulmonary Hypertension
Author(s) -
Mouchaers Koen Thijs Bert,
Wong YeunYing,
Schalij Ingrid,
Jaspers Richard T,
Nieuw Amerongen Geerten P,
VonkNoordegraaf Anton,
Laarse Willem J
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1209.21
Subject(s) - bosentan , sildenafil , right ventricular hypertrophy , pulmonary hypertension , hypoxia (environmental) , medicine , blockade , endocrinology , endothelin receptor , chemistry , endothelin 1 , endothelin receptor antagonist , cgmp specific phosphodiesterase type 5 , lactate dehydrogenase , pharmacology , receptor , enzyme , oxygen , biochemistry , organic chemistry
Background Pulmonary hypertension (PH) may cause right ventricular (RV) hypoxia, which may contribute to RV failure. Goal To study the effects of current PH therapies on the presence of hypoxia in the RV. Methods PH was induced in Wistar rats by monocrotaline (MCT) (40 mg/kg). From day 14 to 28, rats were treated with Bosentan (ETR antagonist, 300 mg/kg/day), Sildenafil (PDE5 inhibitor, 10 mg/kg/day) or both (all n=3). Healthy rats served as controls (n=3). 1.5 hour prior to sacrifice hypoxyprobe (pimonidazole, 60 mg/kg) was administered i.v. Cryosections (5 μm) of the hearts were incubated with hypoxyprobe antibody and for succinate dehydrogenase (SDH) activity. RV capillary density and cardiomyocyte cross‐sectional area (CSA) were determined. Results PH significantly increased RV pimonidazole binding, and cardiomyocyte CSA, and decreased capillary density, and SDH activity (all p<0.05 vs control). Single treatment with Bosentan or Sildenafil had no effect, whereas combination treatment normalized all parameters (p<0.05 vs MCT rats). Pimonidazole binding related linearly to CSA (r=0.6), SDH activity (r=−0.7), and capillary density (r=−0.8) (all p<0.05). Conclusion Hypoxia in the RV of PH rats is caused by cardiomyocyte hypertrophy, a lowering in mitochondrial activity and a diminished capillary density, and can be prevented by combining ETR blockade and PDE5 inhibition.