Activity of receptors coupled to guanine nucleotide binding regulatory protein in doxorubicin induced cardiomyopathy.
OBJECTIVE
The aim was to study the activity of receptors coupled to guanine nucleotide binding regulatory proteins (G proteins) in doxorubicin induced cardiomyopathy, with special attention to G proteins, beta adrenoceptors, muscarinic receptors, and adenylyl cyclase.


METHODS
Messenger RNA of G proteins, densities and high affinity agonist binding of beta adrenoceptors and muscarinic receptors, activity of adenylyl cyclase, calcium influx, and in vivo lipid peroxidation were determined before, in the early stage, and in the later stage of doxorubicin cardiomyopathic heart failure.


METHODS
Sprague-Dawley rats between 150-200 g were used. Doxorubicin was given intravenously at two doses of 4 mg.kg-1 and 6 mg.kg-1 every third week (1st, 4th, 7th week) for nine weeks. Doxorubicin treated rats plus corresponding controls were killed at 3 weeks (n = 7), 6 weeks (n = 7), and 9 weeks (n = 6), respectively.


RESULTS
Northern blot and dot blot hybridisations of the total RNA revealed that messenger RNA of both stimulatory and inhibitory G proteins were identical between doxorubicin treated rats and controls. No alterations in the densities of beta adrenoceptors and muscarinic receptors were observed, neither did the high affinity agonist binding of beta adrenoceptors and muscarinic receptors change. Furthermore, modulation of adenylyl cyclase was unimpaired. In contrast, Ca(2+)-ATPase and serum water soluble fluorescent substance, a product of in vivo lipid peroxidation, were shown to increase dramatically in doxorubicin treated rats (4 mg.kg-1 for 6 and 9 weeks, 6 mg.kg-1 for 3, 6 and 9 weeks) as compared with corresponding controls.


CONCLUSIONS
The findings suggest that, despite increased calcium influx and lipid peroxidation in doxorubicin induced cardiomyopathy, the activity of receptors coupled to G proteins remained normal.
Fu
L X
LX
Wallenberg Laboratory, Sahlgren's Hospital, Göteborg, Sweden.
Sjögren
K G
KG
Liang
Q M
QM
Waagstein
F
F
Hoebeke
J
J
Hjalmarson
A
A
D000262:Adenylyl Cyclases / Q000032:analysis; D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism*; D004317:Doxorubicin / Q000633:toxicity*; D019204:GTP-Binding Proteins / Q000032:analysis*; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000032:analysis*; D011976:Receptors, Muscarinic / Q000032:analysis*
D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D006165:Guanylyl Imidodiphosphate; D004317:Doxorubicin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D002118:Calcium