Thromboxane A₂ (TXA₂) is an important multifactorial mediator in the pathogenesis of pulmonary hypertension. Although endothelium-derived TXA₂ causes excessive pulmonary vascular resistance by acting as a potent vasoconstrictor, mitogen of vascular smooth muscle cells and promoter of platelet aggregation, there is no current therapeutic strategy for pulmonary hypertension, targeting TXA₂ formation. The aim of this study is to assess possible beneficial effects of inhibiting TXA₂ synthesis in patients with pulmonary hypertension.

Sixteen client-owned dogs with proven moderate-to-severe pulmonary hypertension were randomly assigned to the treatment (n=8; ozagrel hydrochloride, 5 mg/kg bid PO) or control group (n=8; sildenafil citrate, 1 mg/kg BID PO). All patients have already been treated with standard protocol including sildenafil (1.8±0.6 mg/kg, BID). Pulmonary hypertension associated with left-side heart failure (LA/Ao >1.6 and LVIDDn >1.7) was excluded in the population. Several clinical indices, which relate to hypoxia (lactate, SpO₂, base excess), thrombosis (d-dimer), azotemia (BUN, creatinine), congestion (NT-proBNP) and echocardiographic indices (peak velocity of tricuspid regurgitation, Ao/MPA), were tracked down for four weeks.

The treatment led to significant and gradual decreases in lactate and d-dimer (p<0.01; from 5.6±1.9 mmol/L to 1.8±1.0 and from 7.4±6.8 to 1.2±1.1 μg/ml, respectively) but significantly increased SpO₂ and base excess (p<0.01; from 87±5.3 to 95±1.8% and from -8.4±3.2 to -3.1±1.9 mmol/L, respectively) in the patients. Compared to controls, the treatment group exhibited statistically significant changes in only lactate level (p=0.02) and SpO₂ (p=0.016). However, treatment of TXA₂ synthase inhibitor showed the tendency to improve the other variables, such as NT-proBNP and tricuspid regurgitant flow, implicating the potential role of TXA₂ synthase inhibitor in pulmonary vascular impedance. Abnormal behavior such as licking footpads and joints has been reported to be a putative side effect of the treatment in one case.

These results suggest that TXA₂ synthase inhibitor may contribute to the improvement of pulmonary hemodynamics in pulmonary hypertension by alleviating pulmonary vasoconstriction and preventing thrombosis.

Disclosures

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