Effect of telmisartan in limiting the cardiotoxic effect of daunorubicin in rats.
OBJECTIVE
Studies have suggested that angiotensin receptor blockers may exert a protective role towards doxorubicin-induced cardiotoxicity, but they have not been extensively investigated in this area. We therefore investigated whether the co-treatment of telmisartan, an angiotensin (Ang II) type-1 receptor blocker, might offer protection against daunorubicin cardiotoxic properties in rats.


METHODS
Daunorubicin was administered at 3 mg/kg/day every other day for 12 days. Telmisartan was administered orally every day for 12 days.


RESULTS
Daunorubicin-treated rats showed cardiac toxicity, evidenced by worsening cardiac function, evaluated by haemodynamic status and echocardiography, elevation of malondialdehyde level and a decreased level of total glutathione peroxidase activity in the heart tissue. These changes were reversed by treatment with telmisartan. Furthermore, telmisartan also downregulated matrix metalloproteinase-2 expression, attenuated the increased protein expression of p22(phox), p47(phox), p67(phox), nuclear factor kappa B and Nox4 in heart tissue, and reduced oxidative-stress-induced DNA damage, which was evaluated by the expression of 8-hydroxydeoxyguanosine. Moreover, telmisartan reduced the myocardial apoptosis induced by daunorubicin.


CONCLUSIONS
The present study indicates that telmisartan may improve cardiac function by inhibiting the action of Ang II via AT-1R, which reverses oxidative stress and myocardial apoptosis. This suggests a beneficial effect of telmisartan treatment in the prevention of daunorubicin-induced cardiotoxicity.
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City, Japan.
Wawaimuli
W
Arozal
Kenichi
K
Watanabe
Punniyakoti T
PT
Veeraveedu
Rajarajan A
RA
Thandavarayan
Meilei
M
Harima
Vijayakumar
V
Sukumaran
Kenji
K
Suzuki
Makoto
M
Kodama
Yoshifusa
Y
Aizawa
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D003630:Daunorubicin / Q000633:toxicity*; D004317:Doxorubicin / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism; D000077333:Telmisartan; D016277:Ventricular Function, Left / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D000903:Antibiotics, Antineoplastic; D001562:Benzimidazoles; D001565:Benzoates; D011945:Receptors, Angiotensin; D008315:Malondialdehyde; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2; D000077333:Telmisartan; D003630:Daunorubicin