Fasudil reduces monocrotaline-induced pulmonary arterial hypertension: comparison with bosentan and sildenafil.
Pulmonary arterial hypertension (PAH) still cannot be cured, warranting the search for novel treatments. Fasudil (a Rho kinase inhibitor) was compared with bosentan (an endothelin receptor blocker) and sildenafil (a phosphodiesterase 5 inhibitor), with emphasis on right ventricular (RV) function, in a reversal rat model of monocrotaline (MCT)-induced PAH. In addition, the effects of combining bosentan or sildenafil with fasudil were studied. MCT (40 mg·kg body weight(-1)) induced clear PAH in male Wistar rats (n = 9). After 28 days, echocardiography, RV catheterisation and histochemistry showed that cardiac frequency, stroke volume and RV contractility had deteriorated, accompanied by RV dilatation and hypertrophy, and marked pulmonary arterial wall thickening. Mean pulmonary arterial pressure and pulmonary vascular resistance increased significantly compared to healthy rats (n = 9). After 14 days, MCT-treated rats received a 14-day oral treatment with bosentan, sildenafil, fasudil or a combination of fasudil with either bosentan or sildenafil (all n = 9). All treatments preserved cardiac frequency, stroke volume and RV contractility, and reduced pulmonary vascular resistance and RV dilatation. Fasudil lowered RV systolic pressure and mean pulmonary arterial pressure significantly, by reducing pulmonary arterial remodelling, which reduced RV hypertrophy. Combining bosentan or sildenafil with fasudil had no synergistic effect. Fasudil significantly improved PAH, to a greater degree than did bosentan and sildenafil.
Mouchaers
K T B
KT
Dept of Pulmonary Diseases, Vrije Universiteit Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.
Schalij
I
I
de Boer
M A
MA
Postmus
P E
PE
van Hinsbergh
V W M
VW
van Nieuw Amerongen
G P
GP
Vonk Noordegraaf
A
A
van der Laarse
W J
WJ
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure; D000077300:Bosentan; D065627:Familial Primary Pulmonary Hypertension; D006352:Heart Ventricles / Q000187:drug effects; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D017380:Hypertrophy, Right Ventricular / Q000473:pathology; D016686:Monocrotaline / Q000009:adverse effects*; D010879:Piperazines / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000473:pathology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D014665:Vasodilator Agents; D016686:Monocrotaline; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000068677:Sildenafil Citrate; C049347:fasudil; D000077300:Bosentan