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
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Figure 1 Changes in the ratio of the minor axis (a) of left ventricle (LV) to the major axis (b) of the LV, an index of pulmonary hypertension (PH), in the parasternal short-axis view of the LV by two-dimensional echocardiography. The view was obtained at the level of the papillary muscle. It was evaluated on days 1, 7, 14 and 19 after the start of treatment. Control group (open circles, n = 12); PH group (solid circles, n = 17); PH + TA group (open squares, n = 18); PH + BPS group (solid squares, n = 13); and PH + TA + BPS group (open diamonds, n = 18). *p < 0.05 vs. Control group.  p < 0.05 vs. PH group. #p < 0.05 vs PH + TA + BPS group. ¶p < 0.05 vs. baseline value of each group on day 1. Data are presented as the mean value ± SE. BPS = beraprost sodium; PH = pulmonary hypertension; RV = right ventricle; TA = TA-0201.
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Figure 2 Right ventricular systolic pressure (left) and Pp/Ps ratio (right) in the Control group (n = 12), PH group (n = 17), PH + TA group (n = 18), PH + BPS group (n = 13) and PH + TA + BPS group (n = 18). *p < 0.05 vs. Control group. p < 0.05 vs. PH group. #p < 0.05 vs. PH + TA + BPS group. Each column and bar represents the mean value ± SE. BPS = beraprost sodium; PH = pulmonary hypertension; TA = TA-0201.
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Figure 3 Ratio of right ventricular (RV) wet weight to BW (left) and ratio of RV wet weight to left ventricular (LV) wet weight (right) in the Control group (n = 12), PH group (n = 17), PH + TA group (n = 18), PH + BPS group (n = 13) and PH + TA + BPS group (n = 18). *p < 0.05 vs. Control group. p < 0.05 vs. PH group. #p < 0.05 vs. PH + TA + BPS group. Each column and bar represents the mean ± SE. BPS = beraprost sodium; PH = pulmonary hypertension; TA = TA-0201.
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Figure 4 Ratio of expression level of beta-myosin heavy chain (MHC) messenger ribonucleic acid (mRNA) to alpha-MHC mRNA in the right ventricle in the Control group (n = 12), PH group (n = 17), PH + TA group (n = 18), PH + BPS group (n = 13) and PH + TA + BPS group (n = 18). A typical example of the reverse transcription (RT)-polymerase chain reaction (PCR) product in each group is also shown. *p < 0.05 vs. Control group. p < 0.05 vs. PH group. #p < 0.05 vs. PH + TA + BPS group. Each column and bar represents the mean value ± SE. BPS = beraprost sodium; PH = pulmonary hypertension; TA = TA-0201.
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Figure 5 Photomicrographs of the pulmonary arteries in the Control group (A), PH group (B) and PH + TA + BPS group (C). Histologic examination of the lung showed a marked increase in pulmonary arterial medial wall thickening in the PH group. The increase in the thickening was attenuated in the PH + TA + BPS group. Each section was stained with Azan (x520). BPS = beraprost sodium; PH = pulmonary hypertension; TA = TA-0201.
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Figure 6 Ratio of medial wall thickness to the external diameter of the pulmonary arteries of rats in the Control group (n = 12), PH group (n = 17), PH + TA group (n = 18), PH + BPS group (n = 13) and PH + TA + BPS group (n = 18). Pulmonary arteries with an external size of about 50 µm were chosen. *p < 0.05 vs. Control group. p < 0.05 vs. PH group. #p < 0.05 vs. PH + TA + BPS group. Each column and bar represents the mean value ± SE. BPS = beraprost sodium; PH = pulmonary hypertension; TA = TA-0201.
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