Effect of metoprolol on activity of beta-adrenoceptor coupled to guanine nucleotide binding regulatory proteins in adriamycin-induced cardiotoxicity.
Prevention of cardiotoxicity without interfering with the therapeutic efficacy of adriamycin is a very crucial question. We have investigated the activity of beta-adrenoceptor coupled to guanine nucleotide binding regulatory proteins (G-proteins) and Ca(2+)-ATPase activity in experimental adriamycin-induced cardiotoxicity and the influence of metoprolol treatment on these variables. Adriamycin was administered to rats intravenously as a single dose of 6 mg/kg, and metoprol was continuously given by means of implanted osmotic pumps. beta-Adrenoceptor characteristics were measured by radioligand-binding experiments and by basal and stimulated adenylyl cyclase activity. Northern blot and dot blot analysis was used to quantify G-protein mRNA. It was shown that adriamycin did not induce any change in the total beta-adrenoceptor density, nor did the high affinity agonist binding to beta-adrenoceptor change. Adriamycin did not induce any alteration in the amount of mRNA encoding for stimulatory (Gs) or inhibitory (Gi) G-proteins. Also, basal and stimulated adenylyl cyclase activities were identical in the different experimental groups. In contrast, the Ca(2+)-ATPase was shown to increase in adriamycin-treated rats compared to control rats (45 +/- 3.8 versus 23 +/- 1.2 mumol Pi/mg/h, P less than .01). Metoprolol was shown to normalize this increase (29 +/- 2.1 mumol Pi/mg/h). Thus, it may be concluded that in experimental adriamycin-induced cardiotoxicity, despite Ca(2+)-overloading, the beta-adrenoceptor-G protein-adenylyl cyclase system remains intact. Metoprolol seems to prevent Ca(2+)-overloading independently of the beta-adrenoceptors studied here.
Fu
L X
LX
Wallenberg Laboratory, Division of Cardiology, Sahlgren's Hospital, University of Göteborg, Sweden.
Bergh
C H
CH
Hoebeke
J
J
Liang
Q M
QM
Sjögren
K G
KG
Waagstein
F
F
Hjalmarson
A
A
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D004317:Doxorubicin; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism*; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol; D007700:Kinetics; D008297:Male; D008566:Membranes / Q000378:metabolism; D008790:Metoprolol / Q000494:pharmacology*; D009693:Nucleic Acid Hybridization; D010869:Pindolol / Q000031:analogs & derivatives; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D004317:Doxorubicin; D020120:Iodocyanopindolol; D010869:Pindolol; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D000252:Calcium-Transporting ATPases; D008790:Metoprolol