Isoproterenol-induced myocardial fibrosis in relation to myocyte necrosis.
Treatment of rats with the beta-adrenergic agonist isoproterenol results in cardiac hypertrophy, myocyte necrosis, and interstitial cell fibrosis. Our objectives in this study have been to examine whether hypertrophy and fibrosis occur in a compensatory and reparative response to myocyte loss or whether either process may be occurring independently of myocyte loss and thus be a reactive response to adrenergic hormone stimulation. We have examined this question by evaluating each of these responses in rats treated with different doses and forms of isoproterenol administration. Myocyte necrosis was evaluated using in vivo labeling with monoclonal antimyosin for identification of myocytes with permeable sarcolemma, which was indicative of irreversible injury. Myocardial fibrosis was evaluated by morphometric point counting of Gomori-stained tissue sections and by assessment of the stimulation of fibroblast proliferation by determination of increased levels of DNA synthesis. Stimulation of fibroblast DNA synthesis was determined from DNA specific radioactivities and radioautography after pulse labeling with [3H]thymidine. The evidence provided by this study suggests that the degree and timing of myocardial hypertrophy does not follow the course of myocyte loss and, thus, appears to be either a response to altered cardiac loading or a reactive response to beta-adrenergic hormone stimulation rather than a compensation for myocyte loss. Myocardial fibrosis, on the other hand, appears to be more closely related to myocyte necrosis with respect to collagen accumulation in the same areas of the heart, its dose-response relation to the amount of isoproterenol administered, and the timing of increased DNA synthesis, or fibroblast proliferation, after myocyte loss.
Benjamin
I J
IJ
Cardiovascular Institute, Michael Reese Hospital, Chicago, Illinois.
Jalil
J E
JE
Tan
L B
LB
Cho
K
K
Weber
K T
KT
Clark
W A
WA
D000818:Animals; D000911:Antibodies, Monoclonal; D001345:Autoradiography / Q000379:methods; D006332:Cardiomegaly / Q000139:chemically induced / Q000473:pathology; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D005355:Fibrosis; D006321:Heart / Q000187:drug effects; D007545:Isoproterenol / Q000633:toxicity*; D008297:Male; D009206:Myocardium / Q000473:pathology*; D009218:Myosins / Q000032:analysis; D009336:Necrosis; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
D000911:Antibodies, Monoclonal; D014316:Tritium; D004247:DNA; D011433:Propranolol; D009218:Myosins; D007545:Isoproterenol; D013936:Thymidine