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Abnormal beta-adrenergic transmembrane signaling in rabbits with adriamycin-induced cardiomyopathy
K Nagami1, T Yoshikawa, M Suzuki
1Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
Abstract:
We investigated alterations in the beta-adrenergic receptor-adenylate cyclase system in rabbits with congestive heart failure induced by adriamycin cardiotoxicity. A dose of 24 mg/kg adriamycin was administered over 16 weeks in 16 rabbits. Five of them died and 4 of them could not tolerate the full dose of adriamycin. Complete data were obtained in the remaining 7 rabbits. Another 7 rabbits received physiological saline for the same period and served as controls. Plasma norepinephrine concentration increased in adriamycin-treated rabbits, but not in the control rabbits. Cardiac output was lower in the adriamycin-treated group than in the control group. Both the left and right ventricular end-diastolic pressure were higher in the adriamycin-treated group. The density of myocardial beta-adrenergic receptors and the norepinephrine content were reduced in both ventricles in the adriamycin-treated group. Basal and isoproterenol-, sodium fluoride- and forskolin-stimulated adenylate cyclase activities were lower in the adriamycin-treated group. Thus, alterations in beta-adrenergic signaling occurred in both ventricles in animals with chronic biventricular failure induced by adriamycin. These may be the result of post-receptor abnormalities, including abnormalities of guanine nucleotide-binding proteins or of the catalytic unit of adenylate cyclase.
Insights
Adriamycin-induced heart failure in rabbits impairs beta-adrenergic signaling. This involves reduced receptor density and adenylate cyclase activity, suggesting post-receptor defects in congestive heart failure.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Congestive heart failure (CHF) is associated with altered cardiac adrenergic function.
- Adriamycin (doxorubicin) is a known cardiotoxic agent used to induce experimental heart failure.
Purpose of the Study:
- To investigate the effects of adriamycin-induced cardiotoxicity on the beta-adrenergic receptor-adenylate cyclase system in rabbits.
- To determine if alterations occur in both ventricles during chronic biventricular failure.
Main Methods:
- Rabbits received adriamycin (24 mg/kg over 16 weeks) or saline (control).
- Measurements included plasma norepinephrine, cardiac output, ventricular pressures, myocardial beta-adrenergic receptor density, norepinephrine content, and adenylate cyclase activity.
- Stimulation of adenylate cyclase was performed using isoproterenol, sodium fluoride, and forskolin.
Main Results:
- Adriamycin-treated rabbits showed increased plasma norepinephrine and reduced cardiac output.
- Left and right ventricular end-diastolic pressures were elevated in the adriamycin group.
- Myocardial beta-adrenergic receptor density and norepinephrine content were decreased in both ventricles.
- Basal and stimulated adenylate cyclase activities were significantly lower in adriamycin-treated rabbits.
Conclusions:
- Chronic biventricular failure induced by adriamycin causes significant alterations in beta-adrenergic signaling in both ventricles.
- These signaling abnormalities may stem from post-receptor defects, potentially involving guanine nucleotide-binding proteins or the catalytic unit of adenylate cyclase.
