[Combination of oral endothelin-A receptor antagonist and oral prostacyclin analogue is superior to each drug alone in ameliorating pulmonary hypertension in rats].
OBJECTIVE
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 ET-A receptor antagonist was effective for PH; however, the effect of both administrations is unclear.


METHODS
We administered the oral ET-A receptor antagonist TA-0201 and/or the oral PGI2 analogue beraprost sodium(BPS) to monocrotaline-induced PH rats for 19 days in the following groups: 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 systolic pressure and Pp/Ps were markedly higher in the PH group than in the Control group. The increased right ventricular systolic pressure and Pp/Ps were significantly and comparably depressed in the PH + TA group and PH + BPS group; it was more greatly depressed in the PH + TA + BPS group than in the groups with each drug alone. The indices of right ventricular hypertrophy showed the same tendency as the increase in right ventricular systolic pressure in the five groups. The expression of beta-myosin heavy chain mRNA in right ventricle 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 PH + TA + BPS group. Combined treatment also ameliorated PH even if it started from the post-onset of PH.


CONCLUSIONS
The combination of an oral ET-A receptor antagonist and an oral PGI2 analogue is superior to the single use of each drug alone in inhibiting the progression of PH.
Ueno
Michihiko
M
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8575.
Miyauchi
Takashi
T
Sakai
Satoshi
S
Yamauchi-Kohno
Rikako
R
Goto
Katsutoshi
K
Yamaguchi
Iwao
I
D000284:Administration, Oral; D000818:Animals; D004357:Drug Synergism; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000008:administration & dosage*; D011464:Epoprostenol / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D051381:Rats; D014665:Vasodilator Agents / Q000008:administration & dosage*
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D014665:Vasodilator Agents; C048081:beraprost; D011464:Epoprostenol