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EXPERIMENTAL STUDY

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

Michihiko Ueno, MD, PhD^*, Takashi Miyauchi, MD, PhD^*,*, Satoshi Sakai, MD, PhD^*, Rikako Yamauchi-Kohno, PhD, Katsutoshi Goto, PhD and Iwao Yamaguchi, MD, PhD^*

^* Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd., Toda, Saitama, Japan

Manuscript received December 31, 2001; revised manuscript received April 4, 2002, accepted April 8, 2002.

^* Reprint requests and correspondence: Dr. Takashi Miyauchi, Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
t-miyauc{at}md.tsukuba.ac.jp

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 PGI₂ or 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 PGI₂ analogue 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 PGI₂ analogue is superior to the single use of each drug alone in inhibiting the progression of PH.

Abbreviations and Acronyms   BPS   beraprost sodium   BW   body weight   ET   endothelin   IV   intravenous   LV   left ventricle/ventricular   MCT   monocrotaline   MHC   myosin heavy chain   mRNA   messenger ribonucleic acid   PGI2   prostacyclin   PH   pulmonary hypertension/hypertensive   Pp/Ps   ratio of right ventricular systolic pressure to systemic systolic blood pressure   RT-PCR   reverse transcription-polymerase chain reaction   RV   right ventricle/ventricular   TXA2   thromboxane A2

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