Effects of Losartan on Catecholamine Release in the Isolated Rat Adrenal Gland

Abstract

The aim of this study was to determine whether losartan, an angiotensin II (Ang II) type 1 (AT1) receptor could influence the CA release from the isolated perfused model of the rat adrenal medulla. Losartan (5∼ 50 μM) perfused into an adrenal vein for 90 min produced dose-and time-dependent inhibition of the CA secretory responses evoked by ACh (5.32 mM), high K ＋ (56 mM, a direct membrane depolarizer), DMPP (100 μM) and McN-A-343 (100 μM). Losartan failed to affect basal CA output. Furthermore, in adrenal glands loaded with losartan (15 μ M) for 90 min, the CA secretory responses evoked by Bay-K-8644 (10 μM, an activator of L-type Ca 2＋ channels), cyclopiazonic acid (10 μM, an inhibitor of cytoplasmic Ca 2＋ -ATPase), veratridine (100 μM, an activator of Na ＋ channels), and Ang II (100 nM) were markedly inhibited. However, at high concentrations (150∼ 300 μM), losartan rather enhanced the CA secretion evoked by ACh. Collectively, these experimental results suggest that losartan at low concentrations inhibits the CA secretion evoked by cholinergic stimulation (both nicotininc and muscarinic receptors) as well as by membrane depolarization from the rat adrenal medulla, but at high concentration it rather inhibits ACh-evoked CA secretion. It seems that losartan has a dual action, acting as both agonist and antagonist to nicotinic receptors of the rat adrenal medulla, which might be dependent on the concentration. It is also thought that this inhibitory effect of losartan may be mediated by blocking the influx of both Na ＋ and Ca 2＋ into the rat adrenomedullary chromaffin cells as well as by inhibiting the Ca 2＋ release from the cytoplasmic calcium store, which is thought to be relevant to the AT1 receptor blockade, in addition to its enhancement of the CA release.

Interactions between angiotensin AT1 receptor antagonists and second‐generation antiepileptic drugs in the test of maximal electroshock

“…It can be suggested that a specific losartan mechanism of action is involved in the enhancement of the anticonvulsant activity of LTG. It has been reported that losartan inhibits voltage‐dependent Na + channels in the rat adrenal medulla as in the presence of losartan, veratridine‐evoked (an activator of Na + channels) catecholamine secretion was greatly inhibited . On the other hand, telmisartan delays the inactivation of voltage‐gated Na + channels in cardiomyocytes .…”

Influence of Fimasartan (a Novel AT1Receptor Blocker) on Catecholamine Release in the Adrenal Medulla of Spontaneously Hypertensive Rats

“…These results indicate that chronic blockade of RAAS may decrease the excess sypatheic responses to stress in cardiovascular diseases and prevent the likely development of Type II diabetes mellitus [11]. Previously, we found that losartan inhibits significantly the CA secretion evoked by Ang II in the perfused rat adrenal medulla [12]. Armando and his colleagues [47] also found that pre-treatment with candesartan, an ARB, eliminated the increase in adrenal NE and EP concentrations induced by isolation stress.…”

“…Moreover, we found that other ARBs, such as losartan and olmesartan also inhibit the CA secretion from the perfused rat adrenal gland, which is mediaited through blockade of AT 1 recptors [12,13]. In spontaneously hypertensive rats (SHRs), oral administration of AT 1 antagonist (candesartan) can effectively block central actions of Ang II, regulating blood pressure and reaction to stress, and selectively and differentially modulating sympathoadrenal responses [14].…”