Korean J Physiol Pharmacol.  2013 Feb;17(1):99-109. 10.4196/kjpp.2013.17.1.99.

Influence of Fimasartan (a Novel AT1 Receptor Blocker) on Catecholamine Release in the Adrenal Medulla of Spontaneously Hypertensive Rats

• Lim HJ
• Lee SK
• Lim DY

• KMID: 1432769
• DOI: http://doi.org/10.4196/kjpp.2013.17.1.99

Abstract

The aim of this study was to determine whether fimasartan, a newly developed AT1 receptor blocker, can affect the CA release in the isolated perfused model of the adrenal medulla of spontaneously hypertensive rats (SHRs). Fimasartan (5~50 microM) perfused into an adrenal vein for 90 min produced dose- and time-dependently inhibited the CA secretory responses evoked by ACh (5.32 mM), high K+ (56 mM, a direct membrane depolarizer), DMPP (100 microM) and McN-A-343 (100 microM). Fimasartan failed to affect basal CA output. Furthermore, in adrenal glands loaded with fimasartan (15 microM), the CA secretory responses evoked by Bay-K-8644 (10 microM, an activator of L-type Ca2+ channels), cyclopiazonic acid (10 microM, an inhibitor of cytoplasmic Ca(2+)-ATPase), and veratridine (100 microM, an activator of Na+ channels) as well as by angiotensin II (Ang II, 100 nM), were markedly inhibited. In simultaneous presence of fimasartan (15 microM) and L-NAME (30 microM, an inhibitor of NO synthase), the CA secretory responses evoked by ACh, high K+, DMPP, Ang II, Bay-K-8644, and veratridine was not affected in comparison of data obtained from treatment with fimasartan (15 microM) alone. Also there was no difference in NO release between before and after treatment with fimasartan (15 microM). Collectively, these experimental results suggest that fimasartan inhibits the CA secretion evoked by Ang II, and cholinergic stimulation (both nicotininc and muscarinic receptors) as well as by membrane depolarization from the rat adrenal medulla. It seems that this inhibitory effect of fimasartan may be mediated by blocking the influx of both Na+ and Ca2+ through their ion channels into the rat adrenomedullary chromaffin cells as well as by inhibiting the Ca2+ release from the cytoplasmic calcium store, which is relevant to AT1 receptor blockade without NO release.

Keyword

Adrenal Medulla; AT1 receptor blockade; Catecholamine secretion; Fimasartan

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
Biphenyl Compounds
Calcium
Chromaffin Cells
Cytoplasm
Dimethylphenylpiperazinium Iodide
Indoles
Ion Channels
Membranes
NG-Nitroarginine Methyl Ester
Pyrimidines
Rats
Rats, Inbred SHR
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
Biphenyl Compounds
Calcium
Dimethylphenylpiperazinium Iodide
Indoles
Ion Channels
NG-Nitroarginine Methyl Ester
Pyrimidines
Tetrazoles
Veratridine

Figure

• 

  Fig. 1 Dose-dependent effects of fimasartan on the secretory responses of catecholamines (CA) evoked by acetylcholine (ACh, upper) and DMPP (lower) 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 and perfusion of DMPP (100 µM) for 1 min was evoked at 15 and 20 min intervals during simultaneous loading with 5, 15 and 50 µM of fimasartan 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 with each concentration-pretreated group of fimasartan. ACh- and DMPP-induced perfusates were collected for 4 and 8 minutes, respectively. *: p<0.05, **: p<0.01. ns: Statistically not significant.

• 

  Fig. 2 Dose-dependent effects of fimasartan on the CA secretory responses evoked by McN-A-343 (upper) and high potassium (lower) from the perfused rat adrenal medullas. The CA secretion by perfusion of McN-A-343 (100 µM) for 4 min and injection of high K+ (56 mM) in a volume of 0.05 mL was induced at 15 intervals during simultaneous loading with 5, 15 and 50 µM of fimasartan for 90 min, respectively. Statistical difference was obtained by comparing the corresponding control with each concentration-pretreated group of fimasartan. McN-A-343- and high K+-induced perfusates were collected for 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 fimasartan 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 during simultaneous loading with fimasartan (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 fimasartan on the CA release evoked by veratridine (upper) and angiotensin II (lower) from the perfused rat adrenal medullas. Veratridine (100 µM) for 4 min and angiotensin II (100 nM) for 1 min were perfused into an adrenal vein and at 15 min intervals during simultaneous loading with fimasartan (15 µM) for 90 min, respectively. Other legends are the same as in Fig. 1. **: p<0.01.

• 

  Fig. 5 Influence of fimasartan plus L-NAME on the CA secretory responses evoked by acetylcholine (upper) and DMPP (lower) from the perfused adrenal medulla of SHRs. The CA secretion by a single injection of ACh (5.32 mM) in a volume of 0.05 mL and perfusion of DMPP (100 µM) for 1 min was evoked at 15 or 20 min intervals during simultaneous loading with fimasartan (15 µM) plus L-NAME (30 µM) for 90 min. Statistical difference was obtained by comparing the corresponding control with group of fimasartan-treated alone or group treated with fimasartan+L-NAME. Other legends are the same as in Fig. 1. **: p<0.01.

• 

  Fig. 6 Effects of fimasartan plus L-NAME on the CA secretory responses evoked by high potassium (upper) and angiotensin II (lower) from the perfused adrenal medulla of SHRs. The CA secretion by injection of high K+ (56 mM) in a volume of 0.05 mL and perfusion of angiotensin II (100 nM) for 1 min was induced at 15 min intervals during simultaneous loading with fimasartan (15 µM) plus L-NAME (30 µM) for 90 min, respectively. Other legends are the same as in Fig. 1 and 5. **: p<0.01.

• 

  Fig. 7 Effects of fimasartan plus L-NAME on the CA secretory responses evoked by Bay-K-8644 (upper) and veratridine (lower) from the perfused adrenal medulla of SHRs. Bay-K-8644 (10 µM) and veratridine (100 µM) were perfused into an adrenal vein for 4 min at 15 min intervals during simultaneous loading with fimasartan (15 µM) plus L-NAME (30 µM) for 90 min. Other legends are the same as in Fig. 1 and 5. **: p<0.01. ns: Not statistically significant.

• 

  Fig. 8 Effects of of fimasartan on nitric oxide (NO) production in the perfused adrenal medulla of SHRs. Perfusate sample was taken for 8 min after loading the perfusion of fimasartan (15 µM) at a rate of 0.31 ml/min. Ordinate: the amounts of NO released from the adrenal medulla (% of control). Abscissa: Treatment (before and after fimasartan). Statistical difference was made by comparing the control with fimasartan-treated group. ns: not statistically significant.

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