Amiodarone attenuates apoptosis, but induces phospholipidosis in rat alveolar epithelial cells.

Amiodarone-induced pulmonary toxicity is a serious side-effect, but the underlying molecular mechanisms remain unclear. We examined phospholipidosis and apoptosis in rat alveolar epithelial cells after medium-term oral amiodarone treatment. Amiodarone (30 mg/kg daily, a dosage corresponding to that used clinically) or vehicle was administered by gavage in 33 Wistar rats for two weeks. Apoptosis was assessed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labelling (TUNEL) and the expression of apoptosis- and phospholipidosis-related proteins was measured by immunohistochemistry. Amiodarone decreased phospholipase-C-γ1 and increased phosphatidylinositol-(4,5)-bisphosphate, resulting in phospholipidosis, evidenced by the appearance of intracellular inclusion bodies with a multi-lamellated interior. Amiodarone exerted two opposite effects on apoptosis; compared to controls, the expression of activated-caspase-8 was higher in treated rats, while the expression of apoptosis inhibitors survivin, Bcl-2 and c-Flip was lower. On the other hand, the expression of activated-caspase-3 was lower after treatment. Overall, amiodarone attenuated apoptosis, evidenced by fewer TUNEL-positive cells. Medium-term oral amiodarone administration induced phospholipidosis in rat alveolar epithelial cells. Although such treatment decreased anti-apoptotic proteins, apoptosis was attenuated via a decrease in the caspase-3 pathway. These findings improve current understanding on the mechanisms underlying amiodarone-induced pulmonary toxicity.

Randomised comparison of growth hormone versus IGF-1 on early post-myocardial infarction ventricular remodelling in rats.

OBJECTIVE: Growth hormone and insulin-like growth factor-1 participate in post-myocardial infarction healing, but their relative importance is unclear. We compared the treatment effects of these agents on left ventricular remodelling. DESIGN: Wistar rats were randomised into a single dose of either growth hormone (0.5microg, n=29), or insulin-like growth factor-1 (0.5microg, n=27), delivered by direct intramyocardial punctures, and were compared with controls (n=30). Five minutes after treatment, myocardial infarction was generated by permanent ligation of the left coronary artery. Twenty-four hours post-ligation, serum levels of catecholamines were measured using radioimmunoassay and infarct size as well as infarct expansion index were calculated. The expression of genes related to extracellular matrix and angiogenesis was measured using polymerase chain reaction. RESULTS: Infarct expansion index was lower in growth hormone-treated rats (0.28+/-0.03, p=0.007) and in insulin-like growth factor-1-treated rats (0.35+/-0.03, p=0.044) compared to controls (0.51+/-0.06). Infarct size was significantly (p=0.0076) lower in growth hormone-treated rats (32.2+/-2.0%) and marginally (p=0.094) lower in insulin-like growth factor-1-treated rats (36.2+/-2.3%) compared to controls (42.0+/-2.7%). Survival rates were comparable in the three groups. Epinephrine was lower in the growth hormone group (2.8+/-0.2microg/l) compared to either controls (5.0+/-0.6microg/l, p=0.007), or to insulin-like growth factor-1-treated rats (6.3+/-0.6microg/l, p=0.0001). Collagen I and III expression in the infarct zone was higher in the growth hormone group compared to either the insulin-like growth factor-1 group or to controls. CONCLUSIONS: Both growth hormone and insulin-like-growth factor-1 decrease early infarct expansion, but growth hormone results in more favourable extracellular matrix remodelling and sympathetic activation.