Right ventricular (RV) remodeling represents a complex set of functional and structural adaptations in response to chronic pressure or volume overload due to various inborn defects or acquired diseases and is an important determinant of patient outcome. However, the underlying molecular mechanisms remain elusive. We investigated the time course of structural and functional changes in the RV in the murine model of pressure overload‐induced RV hypertrophy in C57Bl/6J mice. Using magnetic resonance imaging, we assessed the changes of RV structure and function at different time points for a period of 21 days. Pressure overload led to significant dilatation, cellular and chamber hypertrophy, myocardial fibrosis, and functional impairment of the RV. Progressive remodeling of the RV after pulmonary artery banding (PAB) in mice was associated with upregulation of myocardial gene markers of hypertrophy and fibrosis. Furthermore, remodeling of the RV was associated with accumulation and activation of mast cells in the RV tissue of PAB mice. Our data suggest possible involvement of mast cells in the RV remodeling process in response to pressure overload. Mast cells may thus represent an interesting target for the development of new therapeutic approaches directed specifically at the RV.
Dysfunction of the NO/sGC/cGMP signaling pathway has been implicated in the pathogenesis of pulmonary hypertension (PH). Therefore, agents stimulating cGMP synthesis via sGC are important therapeutic options for treatment of PH patients. An unwanted effect of this novel class of drugs is their systemic hypotensive effect. We tested the hypothesis that aerosolized intra-tracheal delivery of the sGC stimulator BAY41-8543 could diminish its systemic vasodilating effect.Pharmacodynamics and -kinetics of BAY41-8543 after single intra-tracheal delivery was tested in healthy rats. Four weeks after a single injection of monocrotaline (MCT, 60 mg/kg s.c.), rats were randomized to a two-week treatment with either placebo, BAY 41-8543 (10 mg/kg per os (PO)) or intra-tracheal (IT) instillation (3 mg/kg or 1 mg/kg).Circulating concentrations of the drug 10 mg/kg PO and 3 mg/kg IT were comparable. BAY 41-8543 was detected in the lung tissue and broncho-alveolar fluid after IT delivery at higher concentrations than after PO administration. Systemic arterial pressure transiently decreased after oral BAY 41-8543 and was unaffected by intratracheal instillation of the drug. PO 10 mg/kg and IT 3 mg/kg regimens partially reversed pulmonary hypertension and improved heart function in MCT-injected rats. Minor efficacy was noted in rats treated IT with 1 mg/kg. The degree of pulmonary vascular remodeling was largely reversed in all treatment groups.Intratracheal administration of BAY 41-8543 reverses PAH and vascular structural remodeling in MCT-treated rats. Local lung delivery is not associated with systemic blood pressure lowering and represents thus a further development of PH treatment with sGC stimulators.
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