Abnormal beta-adrenergic transmembrane signaling in rabbits with adriamycin-induced cardiomyopathy.
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.
Nagami
K
K
Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
Yoshikawa
T
T
Suzuki
M
M
Wainai
Y
Y
Anzai
T
T
Handa
S
S
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity; D005260:Female; D005355:Fibrosis; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D009638:Norepinephrine / Q000032:analysis / Q000097:blood; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction
D000903:Antibiotics, Antineoplastic; D011943:Receptors, Adrenergic, beta; D004317:Doxorubicin; D000262:Adenylyl Cyclases; D009638:Norepinephrine