Adriamycin-induced changes to the myocardial beta-adrenergic system in the rabbit.
The functional integrity of the beta-adrenergic stimulatory pathway in a rabbit model of heart failure induced by long-term adriamycin treatment was investigated. Adriamycin-induced cardiomyopathy was produced in 46 rabbits by injecting 0.75 mg/kg of adriamycin, three times per week, for a period of 11 weeks. Biochemical studies performed on isolated membrane preparations revealed a 40 and 55% decrease in basal adenylyl cyclase activity in the left and right ventricles of the adriamycin treated rabbits, respectively. Furthermore, the Vmax of forskolin stimulation was significantly lower in both ventricles with no change in Kact. The Vmax of 5'-guanylylimidodiphosphate stimulation of the stimulatory guanylyl nucleotide binding protein Gs and beta-adrenergic receptor stimulation by isoproterenol were also significantly decreased (42%) in both ventricles of the adriamycin-treated rabbits with no change in Kact. Despite the decrease in receptor-mediated cyclic AMP production, no decrease in beta-adrenergic receptor population was found. Mechanical studies on the isolated right ventricular papillary muscle revealed a decrease in baseline total tension (3.1 +/- 0.4 g/mm2 to 1.8 +/- 0.2 g/mm2) and dT/dt (15.1 +/- 1.6 g/mm2 s to 7.9 +/- 0.8 g/mm2 s) in the adriamycin-treated rabbits. Furthermore, tension generation and dT/dt response to increasing concentrations of forskolin or isoproterenol were both significantly lower in the adriamycin-treated rabbits as compared to normal. We suggest that a decrease in the activity of the adenylyl cyclase component of the beta-adrenergic stimulatory pathway is largely responsible for the decrease in cyclic AMP generation in the adriamycin-treated rabbits. This defect may play an important role in the decrease of contractility in this model of heart failure.
Calderone
A
A
L'hopital du Sacré-Coeur et la Faculté de Médecine, Départment de Physiologie, Université de Montréal, Quebec, Canada.
de Champlain
J
J
Rouleau
J L
JL
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*
D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D004317:Doxorubicin; D000262:Adenylyl Cyclases; D007545:Isoproterenol