Chronic adriamycin treatment and its effect on the cardiac beta-adrenergic system in the rabbit.
Treatment of male rabbits with adriamycin at a cardiotoxic dose (1 mg/kg intravenously, i.v., twice a week for 9 weeks) caused cardiovascular disturbances characteristic of chronic heart failure. The severity of symptoms varied, indicating differences in the individual sensitivity of the animals to adriamycin. Thus, cardiac output (CO) was decreased by greater than 40% in only 4 of the 7 animals in which it was measurable at 9 weeks. Elevated levels of atrial natriuretic factor (ANF) and plasma renin activity (PRA), as well as pulmonary congestion, hydrothorax, and ascites were also evident. The baroreflex response to sodium nitroprusside (NPS) was blunted. The response to the inotropic drug dobutamine was depressed by 50% as compared with the control animals. Right ventricular beta-adrenoceptor density was significantly reduced in these animals (22.9 +/- 3.1 as compared with 31.8 +/- 1.0 fmol/mg protein in control animals) owing to a selective downregulation of the beta 1-adrenoceptor population. The loss of beta-adrenoceptors was highly correlated with severity of heart failure symptoms: i.e., baroreflex dysfunction as indicated by the NPS slope (r = 0.91), decrease in CO during the previous weeks (r = 0.88), and plasma norepinephrine (NE) levels (r = 0.96). However, when all adriamycin-treated animals were compared collectively regardless of the severity of heart failure, with the controls, no difference in the beta-adrenoceptor density was detectable, a finding in agreement with previous observations in this model. Chronic treatment of rabbits with adriamycin thus causes low-output failure, reflecting some of the findings reported for the human disease; however, individual sensitivity to adriamycin varies considerably between rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)
Bocherens-Gadient
S A
SA
Sandoz Pharma Ltd., Basel, Switzerland.
Quast
U
U
Nussberger
J
J
Brunner
H R
HR
Hof
R P
RP
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects*; D002303:Cardiac Output, Low / Q000139:chemically induced*; D004280:Dobutamine; D015536:Down-Regulation; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D011311:Pressoreceptors / Q000187:drug effects; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D012083:Renin / Q000097:blood
D011943:Receptors, Adrenergic, beta; D009599:Nitroprusside; D004280:Dobutamine; D004317:Doxorubicin; D009320:Atrial Natriuretic Factor; D012083:Renin