{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:47:10Z","timestamp":1791193630461,"version":"4.1.0"},"reference-count":39,"publisher":"European Respiratory Society (ERS)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2010,2,12]]},"published-print":{"date-parts":[[2010,10]]},"abstract":"<jats:p>Pulmonary arterial hypertension (PAH) still cannot be cured, warranting the search for novel treatments.<\/jats:p><jats:p>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.<\/jats:p><jats:p>MCT (40 mg\u00b7kg body weight<jats:sup>\u22121<\/jats:sup>) 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.<\/jats:p><jats:p>Fasudil significantly improved PAH, to a greater degree than did bosentan and sildenafil.<\/jats:p>","DOI":"10.1183\/09031936.00130209","type":"journal-article","created":{"date-parts":[[2010,3,30]],"date-time":"2010-03-30T03:05:45Z","timestamp":1269918345000},"page":"800-807","source":"Crossref","is-referenced-by-count":85,"title":["Fasudil reduces monocrotaline-induced pulmonary arterial hypertension: comparison with bosentan and sildenafil"],"prefix":"10.1183","volume":"36","author":[{"given":"K.T.B.","family":"Mouchaers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Schalij","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.A.","family":"de Boer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.E.","family":"Postmus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.W.M.","family":"van Hinsbergh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.P.","family":"van Nieuw Amerongen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Vonk Noordegraaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.J.","family":"van der Laarse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2010,3,29]]},"reference":[{"key":"2024102020142742000_36.4.800.1","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1161\/CIRCULATIONAHA.106.632208","article-title":"Right ventricular function and failure. Report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure","volume":"114","author":"Voelkel","year":"2006","journal-title":"Circulation"},{"key":"2024102020142742000_36.4.800.2","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1016\/j.jacc.2008.01.024","article-title":"Pulmonary arterial hypertension","volume":"51","author":"Chin","year":"2008","journal-title":"J Am Coll Cardiol"},{"issue":"Suppl. 1","key":"2024102020142742000_36.4.800.3","doi-asserted-by":"crossref","first-page":"S55","DOI":"10.1016\/j.jacc.2009.04.011","article-title":"Diagnosis and assessment of pulmonary arterial hypertension","volume":"54","author":"Badesch","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"2024102020142742000_36.4.800.4","doi-asserted-by":"crossref","first-page":"H200","DOI":"10.1152\/ajpheart.00893.2008","article-title":"Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension","volume":"297","author":"Mouchaers","year":"2009","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2024102020142742000_36.4.800.5","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.tips.2007.04.006","article-title":"Development of Rho-kinase inhibitors for cardiovascular medicine","volume":"28","author":"Shimokawa","year":"2007","journal-title":"Trends Pharmacol Sci"},{"key":"2024102020142742000_36.4.800.6","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1136\/pgmj.2007.066555","article-title":"New drug targets for pulmonary hypertension: Rho GTPases in pulmonary vascular remodelling","volume":"84","author":"Wojciak-Stothard","year":"2008","journal-title":"Postgrad Med J"},{"key":"2024102020142742000_36.4.800.7","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1164\/rccm.200805-691OC","article-title":"RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling","volume":"179","author":"Guilluy","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2024102020142742000_36.4.800.8","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1161\/CIRCRESAHA.107.156513","article-title":"Endogenous RhoA inhibitor protects endothelial barrier","volume":"101","author":"Nieuw Amerongen","year":"2007","journal-title":"Circ Res"},{"key":"2024102020142742000_36.4.800.9","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1097\/FJC.0b013e3181593774","article-title":"Endothelin-1 and serotonin are involved in activation of RhoA\/Rho kinase signalling in chronically hypoxic hypertensive rat pulmonary circulation","volume":"50","author":"Homma","year":"2007","journal-title":"J Cardiovasc Pharmacol"},{"key":"2024102020142742000_36.4.800.10","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1161\/01.RES.0000111804.34509.94","article-title":"Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats","volume":"94","author":"Abe","year":"2004","journal-title":"Circ Res"},{"key":"2024102020142742000_36.4.800.11","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/dvdy.10212","article-title":"Rho-associated kinases play an essential role in cardiac morphogenesis and cardiomyocyte proliferation","volume":"226","author":"Zhao","year":"2003","journal-title":"Dev Dyn"},{"key":"2024102020142742000_36.4.800.12","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1242\/dev.129.7.1705","article-title":"Inhibition of Rho family GTPases by Rho GDP dissociation inhibitor disrupts cardiac morphogenesis and inhibits cardiomyocyte proliferation","volume":"129","author":"Wei","year":"2002","journal-title":"Development"},{"key":"2024102020142742000_36.4.800.13","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S0008-6363(01)00492-8","article-title":"Fibronectin signaling stimulates BNP gene transcription by inhibiting neuron-restrictive silencer element-dependent repression","volume":"53","author":"Ogawa","year":"2002","journal-title":"Cardiovasc Res"},{"key":"2024102020142742000_36.4.800.14","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.cardiores.2005.06.013","article-title":"Expression and regulation of the atrial natriuretic factor encoding gene Nppa during development and disease","volume":"67","author":"Houweling","year":"2005","journal-title":"Cardiovasc Res"},{"key":"2024102020142742000_36.4.800.15","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.pharmthera.2005.03.005","article-title":"Cardiac transcription factor Csx\/Nkx2-5: its role in cardiac development and diseases","volume":"107","author":"Akazawa","year":"2005","journal-title":"Pharmacol Ther"},{"key":"2024102020142742000_36.4.800.16","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1146\/annurev.physiol.63.1.391","article-title":"Cytoplasmic signaling pathways that regulate cardiac hypertrophy","volume":"63","author":"Molkentin","year":"2001","journal-title":"Annu Rev Physiol"},{"key":"2024102020142742000_36.4.800.17","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.yjmcc.2008.01.011","article-title":"Small GTP-binding proteins and their regulators in cardiac hypertrophy","volume":"44","author":"Lezoualc'h","year":"2008","journal-title":"J Mol Cell Cardiol"},{"key":"2024102020142742000_36.4.800.18","doi-asserted-by":"crossref","first-page":"H1300","DOI":"10.1152\/ajpheart.01359.2006","article-title":"Early changes in rat hearts with developing pulmonary arterial hypertension can be detected with 3-dimensional electrocardiography","volume":"293","author":"Henkens","year":"2007","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2024102020142742000_36.4.800.19","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1016\/j.echo.2006.04.036","article-title":"Sequence of echocardiographic changes during development of right ventricular failure in rat","volume":"19","author":"Hardziyenka","year":"2006","journal-title":"J Am Soc Echocardiogr"},{"key":"2024102020142742000_36.4.800.20","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1161\/CIRCULATIONAHA.108.829713","article-title":"Opposite effects of training in rats with stable and progressive pulmonary hypertension","volume":"120","author":"Handoko","year":"2009","journal-title":"Circulation"},{"key":"2024102020142742000_36.4.800.21","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1378\/chest.126.4.1313","article-title":"New formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure","volume":"126","author":"Chemla","year":"2004","journal-title":"Chest"},{"key":"2024102020142742000_36.4.800.22","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1007\/s00424-007-0334-z","article-title":"A refined radio-telemetry technique to monitor right ventricle or pulmonary artery pressures in rats: a useful tool in pulmonary hypertension research","volume":"455","author":"Handoko","year":"2008","journal-title":"Pflugers Arch"},{"key":"2024102020142742000_36.4.800.23","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/S0022-5223(19)38415-6","article-title":"Reversibility of plexogenic pulmonary arteriopathy following banding of the pulmonary artery","volume":"87","author":"Wagenvoort","year":"1984","journal-title":"J Thorac Cardiovasc Surg"},{"key":"2024102020142742000_36.4.800.24","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1161\/CIRCULATIONAHA.106.676809","article-title":"Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy","volume":"115","author":"Schermuly","year":"2007","journal-title":"Circulation"},{"key":"2024102020142742000_36.4.800.25","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jss.2007.05.042","article-title":"An experimental animal model of postobstructive pulmonary hypertension","volume":"147","author":"Jungebluth","year":"2008","journal-title":"J Surg Res"},{"key":"2024102020142742000_36.4.800.26","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1164\/rccm.200302-282OC","article-title":"Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats","volume":"169","author":"Schermuly","year":"2004","journal-title":"Am J Respir Crit Care Med"},{"key":"2024102020142742000_36.4.800.27","first-page":"967","article-title":"Bosentan, sildenafil, and their combination in the monocrotaline model of pulmonary hypertension in rats","volume":"231","author":"Clozel","year":"2006","journal-title":"Exp Biol Med (Maywood)"},{"key":"2024102020142742000_36.4.800.28","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1016\/j.ejheart.2008.09.016","article-title":"Effects of phosphodiesterase-5 inhibition by sildenafil in the pressure overloaded right heart","volume":"10","author":"Andersen","year":"2008","journal-title":"Eur J Heart Fail"},{"key":"2024102020142742000_36.4.800.29","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1097\/FJC.0b013e31806befe6","article-title":"Effects of combined therapy with a Rho-kinase inhibitor and prostacyclin on monocrotaline-induced pulmonary hypertension in rats","volume":"50","author":"Tawara","year":"2007","journal-title":"J Cardiovasc Pharmacol"},{"key":"2024102020142742000_36.4.800.30","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1136\/hrt.2003.029470","article-title":"Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension","volume":"91","author":"Fukumoto","year":"2005","journal-title":"Heart"},{"key":"2024102020142742000_36.4.800.31","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.healun.2007.01.035","article-title":"Management of pulmonary arterial hypertension with a focus on combination therapies","volume":"26","author":"Benza","year":"2007","journal-title":"J Heart Lung Transplant"},{"key":"2024102020142742000_36.4.800.32","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1183\/09031936.00081706","article-title":"Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension","volume":"29","author":"Mathai","year":"2007","journal-title":"Eur Respir J"},{"key":"2024102020142742000_36.4.800.33","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/bjp.2008.239","article-title":"Therapeutic potential of RhoA\/Rho kinase inhibitors in pulmonary hypertension","volume":"155","author":"Oka","year":"2008","journal-title":"Br J Pharmacol"},{"key":"2024102020142742000_36.4.800.34","doi-asserted-by":"crossref","first-page":"L284","DOI":"10.1152\/ajplung.00449.2004","article-title":"Mechanisms of endothelin-1-induced contraction in pulmonary arteries from chronically hypoxic rats","volume":"290","author":"Weigand","year":"2006","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2024102020142742000_36.4.800.35","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1161\/01.CIR.0000020682.73694.AB","article-title":"Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase","volume":"106","author":"Takemoto","year":"2002","journal-title":"Circulation"},{"key":"2024102020142742000_36.4.800.36","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1097\/00004872-200501000-00017","article-title":"Cardioprotective mechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats","volume":"23","author":"Mita","year":"2005","journal-title":"J Hypertens"},{"key":"2024102020142742000_36.4.800.37","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.cca.2008.11.016","article-title":"Inhibition of the activity of Rho-kinase reduces cardiomyocyte apoptosis in heart ischemia\/reperfusion via suppressing JNK-mediated AIF translocation","volume":"401","author":"Zhang","year":"2009","journal-title":"Clin Chim Acta"},{"issue":"Suppl. 2","key":"2024102020142742000_36.4.800.38","first-page":"49","article-title":"Signaling mechanisms for the activation of an embryonic gene program during the hypertrophy of cardiac ventricular muscle","volume":"87","author":"Chien","year":"1992","journal-title":"Basic Res Cardiol"},{"key":"2024102020142742000_36.4.800.39","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s10741-007-9034-1","article-title":"Return to the fetal gene program protects the stressed heart: a strong hypothesis","volume":"12","author":"Rajabi","year":"2007","journal-title":"Heart Fail Rev"}],"container-title":["European Respiratory Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1183\/09031936.00130209","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T06:32:20Z","timestamp":1740378740000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.ersnet.org\/lookup\/doi\/10.1183\/09031936.00130209"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,3,29]]},"references-count":39,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2010,9,30]]},"published-print":{"date-parts":[[2010,10]]}},"alternative-id":["10.1183\/09031936.00130209"],"URL":"https:\/\/doi.org\/10.1183\/09031936.00130209","relation":{},"ISSN":["0903-1936","1399-3003"],"issn-type":[{"value":"0903-1936","type":"print"},{"value":"1399-3003","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,3,29]]}}}