Abstract
Introduction: Pulmonary hypertension (PH) is characterized by thrombus formation, vasoconstriction and vascular remodeling. The normal pulmonary artery, in contrast to the systemic artery, has a unique property to contract in response to thrombin via thrombin receptor Proteinase-activated receptor 1 (PAR1). Hypothesis: We hypothesized that PAR1 plays a key role in the pathogenesis and pathophysiology in PH and examined the therapeutic effects of PAR1 antagonist on PH. Methods and Results: Adult male SD rats developed PH after a single subcutaneous injection of 60 mg/kg monocrotaline (MCT) on day 0. The indexes of pulmonary vascular resistance (PVR: RV systolic pressure/cardiac output) and RV hypertrophy (RVH: RV/LV+septum) increased from 0.33±0.03 (normal, n=5) to 1.3±0.1 mmHg•min/mL (MCT, n=10, p<0.01) and from 0.28±0.01 (n=6) to 0.49±0.02 (n=15, p<0.01), respectively, on day 21. We administered PAR1 antagonist (atopaxar: 30mg/kg/day, p.o.) on day 0 (preventive protocol) or day 14 (treatment protocol) of MCT injection. In comparison with MCT rats, the preventive and treatment protocols significantly reduced PVR (0.68±0.09 and 0.89±0.11 mmHg•min/mL, n=8 and 10, p<0.01 and p<0.05) and RVH (0.37±0.02 and 0.40±0.03, n=10 and 12, p<0.01 and p<0.05). Atopaxar had no effect on systemic blood pressure. In the isolated perfused lung preparations, a bolus infusion of 300 nmol PAR1-activating peptide elevated pulmonary arterial pressure by 0.33±0.08 mmHg in the normal (n=6) and 11.8±2.4 mmHg in MCT (n=9; p<0.01 vs. normal), while attenuated in the preventive protocol (1.99±0.96 mmHg, n=6). Atopaxar significantly prolonged the survival periods of MCT rat (median survival time: 26 days, n=17) in both preventive (median survival time: more than 56 days, n=14, p<0.01) and treatment (median survival time: 30 days, n=17, p<0.05) protocols. Conclusion: The PAR1 activity increased in MCT rats. Inhibiting the increased activity of PAR1 was effective in preventing the progression of PH without decreasing systemic blood pressure. PAR1 is thus a potentially novel therapeutic target for the treatment of PH.
Published Version
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