Although the role of
angiotensin II (Ang II) in the pathogenesis and progression of the failing heart is uncertain, previous reports have suggested that myocyte injury may be a component in this process. In this study, we investigated this possibility in more detail. Cardiotoxic effects of nonacutely hypertensive doses of Ang II were examined in 90 rats, including those receiving an
angiotensin infusion (200 ng/min i.p.) and those with
renovascular hypertension, where endogenous stimulation of Ang II occurred. Myocyte injury and wound healing resulting from these treatments were evaluated by 1) immunofluorescence after in vivo
monoclonal antibody labeling of
myosin to detect abnormal sarcolemmal permeability, 2) [3H]
thymidine incorporation into
DNA, to detect fibroblast proliferation, and 3) light microscopic evidence of myocytolysis and subsequent
scar formation. We found that exogenous Ang II produced multifocal antimyosin labeling of cardiac myocytes and myocytolysis, which were maximal on days 1-2 of the infusion. Subsequently,
DNA synthesis rates were increased, with fibroblast proliferation reaching peak levels on day 2 (Ang II-treated rats, 90.0 +/- 18.6 cpm/micrograms
DNA; control rats, 11.4 +/- 2.3 cpm/micrograms
DNA; p less than 0.05); microscopic
scarring was found on day 14 and represented 0.12 +/- 0.02% of the myocardium. Concurrent treatment with both
propranolol (30 mg/kg/day s.c.) and
phenoxybenzamine (5 mg/kg/day i.m.) did not attenuate Ang II-induced antimyosin labeling. Increased endogenous Ang II, resulting from renal
ischemia after abdominal aortic constriction, produced both antimyosin labeling and increased rates of
DNA synthesis like that observed with Ang II infusion. Both myocyte injury and fibroplasia were prevented with
captopril (65 mg/day p.o.), but this protective effect was not seen with
reserpine pretreatment. Infrarenal aortic banding without renal
ischemia, on the other hand, produced
hypertension without
necrosis. We conclude that pathophysiological levels of endogenous as well as low-dose exogenous Ang II were associated with altered sarcolemmal permeability and myocytolysis with subsequent fibroblast proliferation and
scar formation. Myocyte injury was unrelated to the hypertensive or enhanced
adrenergic effects of Ang II or to
hypertension per se.
Captopril was effective in preventing myocyte injury in
renovascular hypertension. The mechanism(s) responsible for Ang II-induced
necrosis will require further study.