Abstract 11237: A Novel Endothelin Receptor Antagonist, Macitentan Markedly Improved Severe Pulmonary Arterial Hypertension in Rats by a Nearly Complete Blockade of Endothelin Receptors
Introduction: Endothelin receptor antagonists (ERAs) have been used for the treatment of pulmonary arterial hypertension (PAH). However, the efficacy of ERAs in severe PAH remains limited, partly because higher doses of ERAs have never been tested due to their adverse effects including hepatotoxicity.
Hypothesis: More rigorous blockade of endothelin receptors using a novel and potent dual ERA, macitentan improves established pulmonary hypertension (PH) and complex occlusive lesions with less major adverse effects using the rat model of severe PAH.
Method and Results: In normal rats, 3-day pretreatment with macitentan (30 mg/kg, by gavage) completely blunted the Big ET-1 induced increases in RV systolic pressure compared with vehicle (-1 % vs. 33 % increase, n = 4 each, p < 0.05), suggesting a nearly complete blockade of endothelin receptors in vivo. A rat model of PAH was prepared by a single subcutaneous injection of 20mg/kg SU5416, a VEGF blocker, followed by exposure to hypoxia (10% O2) for 3 and normoxia (21% O2) for an additional 5 weeks (total 8 weeks). RV systolic pressure increased from 30 ± 1 mmHg (control) to 80 ± 5 mmHg (week 3) and 119 ± 6mmHg (week 8) (n=4-9). The RV hypertrophy (mass ratio of RV/LV+IVS) increased from 0.26 ± 0.01 (control) to 0.55 ± 0.04 (week 3) and 0.68 ± 0.05 (week 8) (n=4-9). Macitentan (30 mg/kg/day, from week 3 to 8) significantly reversed high RV systolic pressure (41 ± 5 mmHg, n=6) and the RV hypertrophy (0.36 ± 0.03, n=7) with the attenuation of complex occlusive lesions. Macitentan treatment did not change heart rate, cardiac output or serum levels of hepatic enzymes. In the ring preparations of intrapulmonary artery isolated from PAH model rats 3 weeks after SU5416 injection, macitentan concentration-dependently inhibited the ET-1 (10 nmol/L) induced contraction. A nearly complete inhibition was observed at 10 μM macitentan.
Conclusion: Chronic treatment with macitentan improved established severe PAH hemodynamically and pathologically without major adverse effects. Our results suggested the possibility that more rigorous blockade of endothelin receptors would dramatically improve the outcome of the treatment in patients with severe PAH.
- © 2013 by American Heart Association, Inc.