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Serotonin 2B Receptor Antagonist PRX-08066 Inhibits Monocrotaline-Induced Pulmonary Hypertension in Rats

R. R. Warburton

K. S. Gannon

O. Guevara

T. Liu

Nicholas Hill


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Conference: 2008 International PHA Conference and Scientific Sessions

Release Date: 06.20.2008

Presentation Type: Abstracts

Warburton R.R.1, Gannon K.S.2, Guevara O.1, Liu T.1, Preston I.R.1, Fanburg B.L.1, Hill N.S.1 

1. Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
2. EPIX Pharmaceutical, Inc., Lexington, MA, USA

BACKGROUND: Serotonin (5-HT) is a potent pulmonary vasoconstrictor, mitogen and stimulator of migration of pulmonary artery smooth muscle cells. 5-HT is thought to play a stimulatory role in pulmonary vascular remodeling seen in pulmonary hypertension.  5-HT exerts its effects through various 5-HT receptors and a 5-HT transporter. Of interest, 5-HT 2B receptor (5-HT2BR) expression is elevated in pulmonary arteries from pulmonary hypertensive mice and from humans with idiopathic pulmonary arterial hypertension, when compared with normal controls. In addition, 5-HT2BR blockade with the selective inhibitor PRX-08066 inhibited hypoxia-induced pulmonary hypertension in rats. We hypothesized that the 5-HT2BR inhibitor PRX-08066, when administered chronically, prevents the development of monocrotaline-induced pulmonary hypertension in rats. 

METHODS: Rats were given one dose (60mg/kg) of monocrotaline and then PRX-08066 (30mg/kg or 100 mg/kg) or placebo was given by oral gavage twice daily for 4 weeks.  Right and left ventricular pressures were recorded following four weeks of treatment. Immunoblot analyses for phospho- and total ERK were performed from whole lung homogenates. The degree of muscularization of the medium-sized and small pulmonary arteries was assessed histologically in blinded fashion.

RESULTS: Monocrotaline produced pulmonary hypertension, characterized by elevations of RVSP and RV/LV+S. In addition, the number of total and partially muscularized pulmonary arteries was significantly higher in the lungs of monocrotaline- compared with saline-treated rats. High dose PRX-08066 significantly inhibited both RVSP and RV/LV+S elevations. Low dose PRX-08066 inhibited RVSP significantly, with the RV/LV+S approaching significance (p=0.059).  PRX-08066 inhibited monocrotaline-induced ERK phosphorylation in whole lung homogenates. In addition, high dose PRX-08066 significantly inhibited monocrotaline-induced muscularization of pulmonary arteries.

Treatment

BW

RVSP

LVPP

RV/LV+S

LV/BW

Muscularization

Sal/placebo

359 + 8

25.7 + 2.1 *

117 + 6.8

.224 + .01 *

1.98 + .05

18.2 + 2.4 *

Mct /placebo

352 + 12

41.8 + 4.6

112 + 6.6

.379 + .04

2.00 + .07

38.4 + 3.2

Mct / 30mg

337 + 9

31.9 + 3.9 *

121 + 7

.307 + .03

2.16 + .04

36.0 + 4.0

Mct / 100mg

343 + 8

30.3 + 1.7 *

123 + 6

.285 + .01 *

2.15 + .07

26.8 + 3.6 *

Sal (saline) Mct (monocrotaline) BW body weight (g); RVSP right ventricular systolic pressure LVSP left ventricular systolic pressure (mm Hg), RV/LV+S right ventricular/left ventricular +septum weight, LV+ S/BW left ventricular+septum/ body weight,  Muscularization % of small vesssels >75% muscularized* p<0.05 vs mct/placebo.

CONCLUSIONSPRX-08066 inhibits monocrotaline-induced pulmonary hypertension. Our results further support the role of 5-HT2BR in the pathogenesis of various forms of pulmonary hypertension and suggest that the selective 5-HT2BR inhibitor, PRX-08066, may be beneficial in the treatment of pulmonary hypertension.