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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/H1804    most recent 01078.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Phrommintikul, A. Articles by Krum, H. Search for Related Content PubMed PubMed Citation Articles by Phrommintikul, A. Articles by Krum, H.

Effects of a Rho kinase inhibitor on pressure overload induced cardiac hypertrophy and associated diastolic dysfunction

¹Department of Epidemiology and Preventive Medicine, NHMRC Centre of Clinical Research Excellence in Therapeutics, ²Department of Medicine, Monash University, Melbourne; ⁴Department of Medicine, University of Melbourne, St. Vincent's Hospital, Melbourne, Australia; and ³Faculty of Medicine, Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand

Submitted 17 September 2007 ; accepted in final form 30 January 2008

The RhoA-Rho kinase (ROCK) signaling pathway has an important role in cardiovascular diseases. However, the effect of Rho kinase inhibition on pressure overload-induced cardiac hypertrophy (POH) and associated diastolic dysfunction has not been evaluated. This study examined the effect of a selective ROCK inhibitor (GSK-576371) in a POH model, induced by suprarenal abdominal aortic constriction. POH rats were divided into the following four groups: 1 (GSK 1, n = 9) or 3 (GSK 3, n = 10) mg/kg bid GSK-576371, 1 mg·kg^–1·day^–1 ramipril (n = 10) or vehicle (n = 11) treatment for 4 wk. Sham animals (n = 11) underwent surgery without banding. Echocardiograms were performed before surgery and posttreatment, and hemodynamic data were obtained at completion of the study. Echocardiography showed an increase in relative wall thickness of the left ventricle (LV) following POH + vehicle treatment compared with sham animals. This was attenuated by both doses of GSK-576371 and ramipril. Vehicle treatment demonstrated abnormal diastolic parameters, including mitral valve (MV) inflow E wave deceleration time, isovolumic relaxation time, and MV annular velocity, which were dose dependently restored toward sham values by GSK-576371. LV end diastolic pressure was increased following POH + vehicle treatment compared with sham (6.9 ± 0.7 vs. 3.2 ± 0.7 mmHg, P = 0.008) and was reduced with GSK 3 and ramipril treatment (1.7 ± 0.7, P < 0.01 and 2.9 ± 0.6 mmHg, P < 0.01, respectively). Collagen I deposition in the LV was increased following POH + vehicle treatment (32.2%; P < 0.01) compared with sham animals and was significantly attenuated with GSK 1 (21.7%; P < 0.05), GSK 3 (23.8%; P < 0.01), and ramipril (35.5%; P < 0.01) treatment. These results suggest that ROCK inhibition improves LV geometry and reduces collagen deposition accompanied by improved diastolic function in POH.

Rho kinase; hypertrophy; fibrosis; pressure overload; hypertension; diastolic function; myocardium