Cardiovascular and survival effects of sympatho-inhibitors in adriamycin-induced cardiomyopathy in rats.
Adriamycin (ADR) is a widely used drug for the treatments of cancers. This study evaluates the effects of moxonidine and metoprolol on cardiac hemodynamics and survival in ADR-induced left ventricular dysfunction (total dose of 20 mg/kg in a 4-week regimen). Rats were treated with the centrally acting I(1)R agonist sympatho-inhibitor, moxonidine, or with the non-selective beta-adrenergic antagonist, metoprolol, during 1 month or until death. Treatments began 1 week after the onset of the ADR administration. Low doses (0.5 and 1 mg/kg/day) of moxonidine and metoprolol (10 mg/kg/day) improved cardiovascular function. High doses of moxonidine (3 mg/kg/day) and metoprolol (150 mg/kg/day) were cardiodepressive. Moxonidine and metoprolol both failed to improve survival. These data indicate that a treatment with these sympatho-inhibitors can reduce the left ventricular dysfunction induced by ADR. Moreover, these cardioprotective effects where obtained even when ADR was used at a dose regimen usually employed for its antineoplastic effects in rodents. Nevertheless, in this particular cardiomyopathy, we did not find any association between improvements of functional parameters and survival whatever the drug and the dose used. This problem points out the difficulty to prevent, at least with sympatho-inhibitory drugs alone, the mortality linked to the chronic cardiotoxicity of ADR.
Thomas
Lionel
L
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, INSERM EMI 333, Faculté de Médecine, Université Louis Pasteur, 11 rue Humann, 67000 Strasbourg, France.
Bellmont
Sandrine
S
Christen
Marie-Odile
MO
La Roche
Benoît
B
Monassier
Laurent
L
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects*; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D008790:Metoprolol / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013565:Sympatholytics / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000401:mortality / Q000517:prevention & control*
D000319:Adrenergic beta-Antagonists; D000903:Antibiotics, Antineoplastic; D007093:Imidazoles; D013565:Sympatholytics; D004317:Doxorubicin; C043482:moxonidine; D008790:Metoprolol