A combination of oral endothelin-areceptor antagonist and oral prostacyclinanalogue is superior to each drug alone inameliorating pulmonary hypertension in rats

Abstract

Objectives

We sought to investigate whether the combination of an oral endothelin (ET)A receptor antagonist and an oral prostacyclin (PGI₂) analogue is superior to the single use of each drug alone for treating pulmonary hypertension (PH).

Background

Treatment with intravenous PGI₂or an ETA receptor antagonist was effective for PH; however, the effect of both agents is unclear.

Methods

We administered the oral ETA receptor antagonist TA-0201 and/or the oral PGI₂analogue beraprost sodium (BPS) to rats with monocrotaline-induced PH for 19 days. The groups were: normal rats with vehicle treatment (Control group), PH rats with vehicle treatment (PH group), PH rats with TA-0201 treatment (PH + TA group), PH rats with BPS treatment (PH + BPS group) and PH rats with TA-0201 and BPS treatment (PH + TA + BPS group).

Results

Right ventricular (RV) systolic pressure and the ratio of RV systolic pressure to systemic systolic blood pressure (Pp/Ps) were markedly higher in the PH group than in the Control group. The increased RV systolic pressure and Pp/Ps were significantly and comparably depressed in the PH + TA and PH + BPS groups; it was more greatly depressed in the PH + TA + BPS group than in the groups with each drug alone. The indexes of RV hypertrophy showed the same tendency as the increase in RV systolic pressure among the five groups. The expression of beta-myosin heavy chain messenger ribonucleic acid in the RV was markedly augmented in the PH group; the enhancement was inhibited in the PH + TA + BPS group to the greatest degree. Medial wall thickness of the pulmonary artery was markedly increased in the PH group; the increase was depressed in the PH + TA + BPS group. Combined treatment also ameliorated PH, even if it started after the onset of PH.

Conclusions

The combination of an oral ETA receptor antagonist and an oral PGI₂analogue is superior to the single use of each drug alone in inhibiting the progression of PH.