Alterations in Alveolar Type II Cell Metabolism Induced by Tetrandrine and Other Alkaloids

Abstract

Tetrandrine (TT) and other bisbenzylisoquinoline alkaloids have been used in China as a treatment for fibrotic lung diseases. Because of their potential use as pulmonary therapeutic agents, we studied the effects of some of these compounds on energy metabolism in isolated rat alveolar type II cells, i.e., cells which play a critical role in maintaining normal lung function. Incubation of type II cells with most of the alkaloids produces a reduction in cellular ATP content. However, there is no effect of the alkaloids on cellular oxygen consumption. All of the alkaloids which produce reductions in cell ATP levels cause increases in internal calcium levels of type II cells. Incubation of the cells with the calcium ionophore, 4-bromo A-23187, leads to increased amounts of intracellular calcium and reductions in ATP levels, but has no effect on oxygen consumption. Exposure of isolated lung mitochondria to calcium produces a concentration-dependent reduction in ATP synthesis with no effect on mitochondrial oxygen consumption. Direct exposure of mitochondria to TT has no effect on ATP synthesis. These results are consistent with the notion that the alkaloids produce an increase in type II cell internal calcium levels which, in turn, leads to reduced rates of mitochondrial ATP synthesis.