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Published ahead of print on October 2, 2003, doi:10.1164/rccm.200303-346OC

Am. J. Respir. Crit. Care Med., Volume 169, Number 1, January 2004, 34-38

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Submitted on March 14, 2003
Accepted on September 26, 2003

A combination of oral sildenafil and beraprost ameliorates pulmonary hypertension in rats

Takefumi Itoh1, Noritoshi Nagaya2*, Takafumi Fujii3, Takashi Iwase4, Norifumi Nakanishi2, Kaoru Hamada5, Kenji Kangawa6, and Hiroshi Kimura5

1 Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan; Second Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan, 2 Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan, 3 Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Osaka, Japan, 4 Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Suita, Osaka, Japan, 5 Second Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan, 6 Biochemistry, National Cardiovascular Center Research Institute, Suita, Osaka, Japan

* To whom correspondence should be addressed. E-mail: nagayann{at}hsp.ncvc.go.jp.

Sildenafil, an oral phosphodiesterase type-5 inhibitor, has vasodilatory effects through a cGMP-dependent mechanism, whereas beraprost, an oral prostacyclin analogue, induces vasorelaxation through a cAMP-dependent mechanism. We investigated whether the combination of oral sildenafil and beraprost is superior to each drug alone in the treatment of pulmonary hypertension. Rats were randomized to receive repeated administration of saline, sildenafil, beraprost, or both of these drugs twice a day for three weeks. Three weeks after monocrotaline (MCT) injection, there was significant development of pulmonary hypertension. The increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight were significantly attenuated in the Sildenafil and Beraprost groups. Combination therapy with sildenafil and beraprost had additive effects on increases in plasma cAMP and cGMP levels, resulting in further improvement in pulmonary hemodynamics compared to treatment with each drug alone. Unlike MCT rats given saline, sildenafil, or beraprost alone, all rats treated with both drugs remained alive during 6-week follow-up. These results suggest that combination therapy with oral sildenafil and beraprost attenuates the development of MCT-induced pulmonary hypertension compared to treatment with each drug alone.
Key words: pulmonary hypertension, sildenafil, beraprost, monocrotaline




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