Korean J Physiol Pharmacol.  2010 Aug;14(4):241-248. 10.4196/kjpp.2010.14.4.241.

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

• Lim HJ
• Kim SY
• Lim DY

• KMID: 2285409
• DOI: http://doi.org/10.4196/kjpp.2010.14.4.241

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 micrometer) 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 micrometer) and McN-A-343 (100 micrometer). Olmesartan did not affect basal CA secretion. Also, in adrenal glands loaded with olmesartan (15 micrometer), the CA secretory responses evoked by Bay-K-8644 (10 micrometer, an activator of voltage-dependent L-type Ca2+ channels), cyclopiazonic acid (10 micrometer, an inhibitor of cytoplasmic Ca2+ -ATPase), veratridine (100 micrometer, an activator of voltage-dependent Na+ channels), and Ang II (100 nM) were markedly inhibited. However, at high concentrations (150~300 micrometer), 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.

Keyword

Olmesartan; Catecholamine secretion; Adrenal medulla; AT(1) receptor blockade

MeSH Terms

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
Adrenal Glands
Adrenal Medulla
Angiotensin II
Animals
Calcium
Chromaffin Cells
Cytoplasm
Dimethylphenylpiperazinium Iodide
Imidazoles
Indoles
Membranes
Rats
Receptors, Nicotinic
Tetrazoles
Veins
Veratridine
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
Angiotensin II
Calcium
Dimethylphenylpiperazinium Iodide
Imidazoles
Indoles
Receptors, Nicotinic
Tetrazoles
Veratridine

Figure

• 

  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.

Reference

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