276 COMPARISON OF INHIBITORY EFFECTS BETWEEN LOSARTAN, OLMESARTAN AND FIMASARTAN ON CATECHOLAMINE RELEASE IN THE PERFUSED ADRENAL MEDULLA

Abstract

Recently, we have found that both losartan (Noh et al. 2009) and olmesartan (Lim et al., 2010) inhibit the secretion of catecholamines (CA) from the perfused rat adrenal medulla. Therefore, the aim of the present study was to compare the inhibitory effects of three major ARBs (losartan, olmesartan and fimasartan) each other on the CA release from the isolated perfused model of the rat adrenal medulla. Losartan (LST, 15 μM), olmesartan (OST, 15 μM) and fimasartan (FST, 15 μM), perfused into an adrenal vein for 90 min, inhibited the CA secretory responses evoked by ACh (5.32 mM) and high K+ (56 mM, a direct membrane depolarizer), DMPP (100 μM, a selective neuronal nicotinic receptor agonist) and McN-A-343 (100 μM, a selective muscarinic M1 receptor agonist) in a time-dependent fashion, respectively. Also, in adrenal glands loaded with LST (15 μM), OST (15 μM) and FST (15 μM), the CA secretory responses evoked by Bay-K-8644 (10 μM, an activator of L-type Ca2+ channels), cyclopiazonic acid (10 μM, an inhibitor of cytoplasmic Ca2+-ATPase), and veratridine (100 μM, an activator of voltage-dependent Na+ channels) as well as by angiotensin ll (100 nM) were time-dependently reduced, respectively. Based on the same concentration (15 μM) of three ARBs, for the CA release evoked by Ach, high K+, DMPP, and McN-A-343, the following rank order of inhibitory potency was obtained: LST<OST<FST. Also, for the CA release evoked by Bay-K-8644, cyclopiazonic acid, and angiotensin ll, the following rank order of inhibitory potency was obtained: LST<OST<FST. However, for the CA release evoked by veratridine, the following rank order of inhibitory potency was obtained: LST<OST=FST. All three ARBs themselves did not affect basal CA output. Collectively, these experimental results suggest that all three ARBs inhibit the CA secretion evoked by cholinergic stimulation (both nicotininc and muscarinic receptors) as well as direct membrane depolarization from the perfused rat adrenal medulla. It seems that this inhibitory effect of all three ARBs may be mediated by blocking the influx of both Na+ and Ca2+ through their voltage-dependent ion channels into the adrenomedullary chromaffin cells as well as by inhibiting the Ca2+ release from its cytoplasmic calcium store. Based on the same concentration used in this study, it is also suggested that there is difference in potency of the inhibitory effects on the CA release between three ARBs, indicating that fimasartan seems to be more potent among three ARBs.