Using the whole-cell patch clamp technique, we found that anorectics inhibit potassium channels in the cell membrane of the smooth muscle cells of resistance pulmonary arteries, causing membrane depolarization and vasoconstriction (Figure 1). In isolated perfused rat lung, the dexfenfluramine-induced vasoconstriction is markedly potentiated by the inhibition of endogenous synthesis of nitric oxide, a vasodilator normally produced by the vascular endothelium (Figure 2). This suggests, that the reason why only some of the patients taking appetite suppressants suffer from primary pulmonary hypertension might be a preexisting pulmonary endothelial dysfunction.

Figure 1 : Appetite suppressants, aminorex and fenfluramine, reduce the whole-cell potassium current in isolated pulmonary resistance arteries. This is a result of a patch-clamp experiment where the composition of the patch pipette solution and the bathing solution ensured that the current was carried exclusively by potassium. The current inhibited by the appetite suppressants is sensitive to 4-aminopyridine (4-AP), but not to tetraethylammonium (TEA), indicating the channel affected is of the delayed rectifier, rather than of the calcium-sensitive, type. The data are the mean±SEM.

Figure 2: The vasoconstrictor effect of an appetite suppressant, dexfenfluramine in isolated perfused rat lungs is potentiated by inhibition of endogenous nitric oxide synthesis by NG-nitro-L-arginine methyl ester (L-NAME, 5x10-5M). The lungs were perfused at constant flow rate, so that the changes in pressure reflect changes in vascular resistance. The data are the averaged (±SEM) actual pressure tracings from 5 lungs/group.

The electrophysiological data in this study were acquired by Drs. H. Reeve, J. Huang and E. Michelakis.