Differential role of rho-kinase in pathological and physiological cardiac hypertrophy in rats.
The present study was undertaken to investigate the effect of fasudil, a specific Rho-kinase inhibitor, in pathological cardiac hypertrophy induced by partial abdominal aortic constriction (PAAC) for 4 weeks in comparison with physiological cardiac hypertrophy caused by chronic swimming training (CST) for 8 weeks in rats. Fasudil (15 and 30 mg/kg day(-1) p.o.) treatment was started 3 days before PAAC and CST, and was continued for 4 weeks in PAAC and 8 weeks in the CST experimental model. Left ventricular (LV) function and LV hypertrophy were assessed by measuring LVDP, +dp/dt(max), -dp/dt(max), ratio of LV weight to body weight (LVW/BW), LV wall thickness (LVWT), LV collagen content, protein content and RNA concentration. Further, venous pressure (VP) and mean arterial blood pressure (MABP) were recorded. Moreover, DNA gel electrophoresis was employed to assess myocardial cell death. PAAC but not CST produced LV dysfunction by decreasing LVDP, +dp/dt(max), -dp/dt(max) and increasing LV collagen content. Further, PAAC and CST were noted to produce LV hypertrophy by increasing LVW/BW, LVWT, LV protein content and LV RNA concentration. Moreover, in contrast to CST, PAAC has significantly increased VP, MABP and LV necrotic cell death. Fasudil, a Rho-kinase inhibitor, markedly attenuated PAAC-induced LV dysfunction, LV hypertrophy, increase in VP, MABP and LV necrotic cell death. However, it did not modulate the CST-induced LV hypertrophy. These results have implicated Rho-kinase in PAAC-induced LV dysfunction and pathological cardiac hypertrophy. However, Rho-kinase may not be involved in CST-induced physiological cardiac hypertrophy.
Balakumar
Pitchai
P
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India. pbala@rediffmail.com
Singh
Manjeet
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000222:Adaptation, Physiological; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D003094:Collagen / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013550:Swimming; D016277:Ventricular Function, Left / Q000502:physiology*; D054460:rho-Associated Kinases
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D003094:Collagen; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil