Inhibitory Effects of Olmesartan on Catecholamine Secretion from the Perfused Rat Adrenal Medulla

Hyo-Jeong Lim; Sang-Yong Kim; Dong-Yoon Lim

doi:10.4196/kjpp.2010.14.4.241

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Lim, Kim, and Lim: Inhibitory Effects of Olmesartan on Catecholamine Secretion from the Perfused Rat Adrenal Medulla

Original Article

Korean J Physiol Pharmacol 2010;14(4):241-248.

Published online: 18 February 2010

DOI: https://doi.org/10.4196/kjpp.2010.14.4.241

Inhibitory Effects of Olmesartan on Catecholamine Secretion from the Perfused Rat Adrenal Medulla

Hyo-Jeong Lim¹, Sang-Yong Kim², Dong-Yoon Lim^3,

¹Department of Internal Medicine, School of Medicine, Seoul National University, Seoul 710-744, College of Medicine, Chosun University, Gwangju 501-759, Korea

²Division of Endocrinology, Department of Internal Medicine, College of Medicine, Chosun University, Gwangju 501-759, Korea

³Department of Pharmacology, College of Medicine, Chosun University, Gwangju 501-759, Korea

Corresponding to: Dong-Yoon Lim, Department of Pharmacology, College of Medicine, Chosun University, 375, Seoseok-dong, Dong-gu, Gwangju 501-759, Korea. (Tel) 82-62-230-6335, (Fax) 82-62-227-4693, (E-mail) dylim@chosun.ac.kr

This paper was presented at the Annual Scientific Meeting of the Korean Society of Hypertension, Seoul, Korea, May 15–16, 2010.

Received 2 August 2010 Revised 16 August 2010 Accepted 19 August 2010

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The present sutdy aimed to determine whether olmesartan, an angiotensin II (Ang II) type 1 (AT1) receptor blocker, can influence the CA release from the isolated perfused model of the rat adrenal medulla. Olmesartan (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). Olmesartan did not affect basal CA secretion. Also, in adrenal glands loaded with olmesartan (15 μM), the CA secretory responses evoked by Bay-K-8644 (10 μM, an activator of voltage-dependent L-type Ca²⁺ channels), cyclopiazonic acid (10 μM, an inhibitor of cytoplasmic Ca²⁺-ATPase), veratridine (100 μM, an activator of voltage-dependent Na⁺ channels), and Ang II (100 nM) were markedly inhibited. However, at high concentrations (150 ∼ 300 μM), olmesartan rather enhanced the ACh-evoked CA secretion. Taken together, these results show that olmesartan at low concentrations inhibits the CA secretion evoked by cholinergic stimulation (both nicotininc and muscarinic receptors) as well as by direct membrane depolarization from the rat adrenal medulla, but at high concentrations it rather potentiates the ACh-evoked CA secretion. It seems that olmesartan has a dual action, acting as both agonist and antagonist at nicotinic receptors of the isolated perfused rat adrenal medulla, which might be dependent on the concentration. It is also thought that this inhibitory effect of olmesartan may be mediated by blocking the influx of both Na⁺ and Ca²⁺ into the rat adrenomedullary chromaffin cells as well as by inhibiting the Ca²⁺ release from the cytoplasmic calcium store, which is thought to be relevant to the AT1 receptor blockade, in addition to its enhancement on the CA secreton.

Keywords: Olmesartan, Catecholamine secretion, Adrenal medulla, AT1 receptor blockade

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Fig. 1.

Dose-dependent effects of olmesartan on the secretory responses of catecholamines (CA) evoked by acetylcholine (ACh, upper) and high potassium (lower) from the perfused rat adrenal medullas. The CA secretion by a single injection of ACh (5.32 mM) and K⁺ (56 mM) in a volume of 0.05 ml was evoked at 15 min intervals after preloading with 5, 15 and 50 μM of olmesartan for 90 min as indicated at an arrow mark, respectively. Numbers in the parenthesis indicate number of rat adrenal glands. Vertical bars on the columns represent the standard error of the mean (S.E.M.). Ordinate: the amounts of CA secreted from the adrenal gland (% of control). Abscissa: collection time of perfusate (min). Statistical difference was obtained by comparing the corresponding control (CONTROL) with each concentration-pretreated group of olmesartan. ACh- and high K⁺-induced perfusates were collected for 4 minutes, respectively. ^∗p<0.05, ^∗∗p<0.01. ns: Statistically not significant.

Fig. 2.

Dose-dependent effects of losartan on the CA secretory responses evoked by DMPP (upper) and McN-A-343 (lower) from the perfused rat adrenal medullas. The CA secretion by perfusion of DMPP (100 μM) and McN-A-343 (100 μM) for 2 min and 4 min was induced at 20 and 15 min intervals after preloading with 5, 15 and 50 μM of olmesartan for 90 min, respectively. Statistical difference was obtained by comparing the corresponding control (CONTROL) with each concentration-pretreated group of olmesartan. DMPP- and McN-A-343-induced perfusates were collected for 8 and 4 minutes, respectively. Other legends are the same as in Fig. 1. ^∗p<0.05, ^∗∗p<0.01. ns: Statistically not significant.

Fig. 3.

Time-course effects of olmesartan on the CA release evoked by Bay-K-8644 (upper) and cyclopiazonic acid (lower) from the perfused rat adrenal medullas. Bay-K-8644 (10 μM) and cyclopiazonic acid (10 μM) were perfused into an adrenal vein for 4 min at 15 min intervals after preloading with olmesartan (15 μM) for 90 min, respectively. Other legends are the same as in Fig. 1. ^∗p<0.05, ^∗∗p<0.01. ns: Statistically not significant.

Fig. 4.

Time-course effects of olmesartan on the CA release evoked by veratridine (upper) and angiotensin II (lower) from the perfused rat adrenal medullas. Veratridine (100 μM) and angiotensin II (100 nM) was perfused into an adrenal vein for 4 min and 1 min at 15 min intervals after preloading with olmesartan (15 μM) for 90 min, respectively. Other legends are the same as in Fig. 1. ^∗∗p<0.01.

Fig. 5.

High dose-effects of olmesartan on the ACh-evoked CA secretory responses from the perfused rat adrenal medullas. The CA secretion by a single injection of ACh (5.32 mM) in a volume of 0.05 ml was evoked at 15 min intervals after preloading with 150 and 300 μM of olmesartan for 90 min as indicated at an arrow mark. ACh-induced perfusate was collected for 4 minutes. Other legends are the same as in Fig. 1. ^∗∗p<0.01. ns; Statistically not significant.

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