The aim of the present study was to examine the effect of leptin on CA release from the isolated perfused model of the rat adrenal gland, and to establish its mechanism of action. Leptin (1∼100 ng/ml), when perfused into an adrenal vein of the rat adrenal gland for 60 min, enhanced a dose-dependently the secretory responses of CA evoked by ACh (5.32⁓10⁣3 M), DMPP (10⁣4 M) and McN-A-343 (10⁣4 M), although it alone has weak effect on CA secretion. However, it did not affect the CA secretion evoked by excess K⁢ (5.6⁓10⁣2 M). Leptin alone produced a weak secretory response of the CA. Moreover, leptin (10 ng/ml) in to an adrenal vein for 60 min also augmented the CA release evoked by BAY-K-8644, an activator of the dihydropyridine L-type Ca2⁢ channels, and cyclopiazonic acid, an inhibitor of cytoplasmic Ca2⁢ ATPase. However, in the presence of U0126 (1μM), an inhibitor of mitogen-activated protein kinase (MAPK), leptin no longer enhanced the CA secretion evoked by ACh and DMPP. Furthermore, in the presence of anti-leptin (10 ng/ml), an antagonist of Ob receptor, leptin (10 ng/ml) also no longer potentiated the CA secretory responses evoked by DMPP and Bay-K-8644. Collectively, these experimental results suggest that leptin enhances the CA secretion from the rat adrenal medulla evoked by cholinergic stimulation (both nicotininc and muscarinic receptors), but does not that by membrane depolarization. It seems that this enhanced effect of leptin may be mediated by activation of U0126-sensitive MAPK through the leptin receptors, which is probably relevant to the activation of the dihydropyridine L-type Ca2⁢ channels located on the rat adrenomedullary chromaffin cells.