Effects of angiotensin II receptor blocker (candesartan) in daunorubicin-induced cardiomyopathic rats.
BACKGROUND
Daunorubicin is an anthracycline anti-tumor agent; anthracycline chemotherapy in cancer can cause severe cardiomyopathy leading to a frequently fatal congestive heart failure; the first-line treatment is diuretics and digoxin. Recently, angiotensin-converting enzyme inhibitors have been shown to be effective in the treatment of such toxicity. The purpose of this study was to investigate the effects of angiotensin II type-1 receptor antagonist (candesartan) in a rat model of daunorubicin-induced cardiomyopathy.


METHODS
Rats were treated with a cumulative dose of 9 mg/kg body weight daunorubicin (i.v.). 28 days later, after the development of cardiomyopathy, animals were randomly assigned to candesartan-treated (5 mg/kg/day, p.o.) or vehicle-treated groups; age-matched normal rats were used as the control group. Candesartan treatment was continued for 28 days. Hemodynamic and echocardiographic parameters were measured, cardiac protein and mRNA were analyzed, and histopathological analyses of myocardial fibrosis, cell size and apoptosis were conducted.


RESULTS
Following cardiomyopathy, left ventricular end diastolic pressure and left ventricular systolic dimension were significantly elevated; while % fractional shortening and Doppler E/A ratio were significantly reduced. Cardiomyopathic hearts showed significant increases in % fibrosis, % apoptosis, and myocyte diameter/body weight ratio; candesartan treatment reversed these changes. Fas-L protein overexpression in myopathic hearts was significantly suppressed by treatment with candesartan. Moreover, SERCA2 mRNA and protein expression were both down-regulated in myopathic hearts and restored to normal by candesartan treatment, significantly.


CONCLUSIONS
Our findings suggest that candesartan treatment significantly improved the left ventricular function and reversed the myocardial pathological changes investigated in this model of daunorubicin-induced cardiomyopathy; suggesting its potentials in limiting daunorubicin cardiotoxicity.
Soga
Mayako
M
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata City, Japan.
Kamal
Fadia A
FA
Watanabe
Kenichi
K
Ma
Meilei
M
Palaniyandi
Suresh
S
Prakash
Paras
P
Veeraveedu
Punniyakoti
P
Mito
Sayaka
S
Kunisaki
Megumi
M
Tachikawa
Hitoshi
H
Kodama
Makoto
M
Aizawa
Yoshifusa
Y
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001713:Biphenyl Compounds; D001794:Blood Pressure; D001835:Body Weight / Q000187:drug effects; D000252:Calcium-Transporting ATPases / Q000235:genetics; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D019610:Cytoprotection / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004562:Electrocardiography; D053222:Fas Ligand Protein; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015996:Survival Rate; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D048069:Tumor Necrosis Factors / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; C506948:Atp2a2 protein, rat; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D048069:Tumor Necrosis Factors; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; C081643:candesartan; D003630:Daunorubicin