J Korean Soc Hypertens.  2013 Mar;19(1):23-38. 10.5646/jksh.2013.19.1.23.

Influence of PD 123319 (AT2-Receptor Antagonist) on Catecholamine Secretion in the Perfused Rat Adrenal Medulla

• Hong SP
• Bidur B
• Choi MS
• Seo YH
• Lim DY

• KMID: 2196654
• DOI: http://doi.org/10.5646/jksh.2013.19.1.23

Abstract

BACKGROUND
The aim of this study was to examine whether PD 123319 (an angiotensin II type 2 [AT2] receptor antagonist) can influence the release of catecholamines (CA) from the perfused model of the rat adrenal medulla.
METHODS
The adrenal gland was isolated by the modification of Wakade method, and perfused with normal Krebs-bicarbonate solution. The content of CA was measured using the fluorospectrophotometer.
RESULTS
During perfusion of PD 123319 (range, 5 to 50 nM) into an adrenal vein for 90 minutes the CA secretory responses evoked by acetylcholine (ACh), high K+, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), and McN-A-343 was dose- and time-dependently inhibited. Furthermore, loading with PD 123319 for 90 minutes also markedly inhibited the CA secretory responses evoked by 4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoro-methyl-phenyl)-pyridine-5-carboxylate (Bay-K-8644), cyclopiazonic acid, veratridine, and angiotensin II (Ang II). PD 123319 did not affect basal CA output. Simultaneous perfusion of PD 123319 and CGP 42112 perfused into an adrenal vein for 90 minutes rather more potently inhibited the CA seretory responses evoked by Ach, high K+, DMPP, Bay-K-8644, veratridine, and Ang II compared to the inhibitory effect by PD123319-treated alone.
CONCLUSIONS
Taken together, these results show that PD 123319 inhibits the CA secretion evoked by both cholinergic and Ang II receptor stimulation from the perfused rat adrenal medulla. This inhibitory effect of PD 123319 seems to be exerted by blocking the influx of both Na+ and Ca2+ through their voltage-dependent channels into the rat adrenomedullary chromaffin cells as well as by reducing the Ca2+ release from its cytoplasmic calcium store, which may be relevant to AT2 receptor blockade. Based on these present data, it is thought that PD 123319 has different activity from previously known AT2 antagonist activity in the perfused adrenal medulla, and that AT2 receptors may be involved in the rat adrenomedullary CA secretion.

Keyword

PD 123319; Angiotensin II type 2 receptor blockers; Catecholamine secretion; Adrenal medulla

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
Acetylcholine
Adrenal Glands
Adrenal Medulla
Angiotensin II
Angiotensin II Type 2 Receptor Blockers
Animals
Calcium
Catecholamines
Chromaffin Cells
Cytoplasm
Dimethylphenylpiperazinium Iodide
Imidazoles
Indoles
Oligopeptides
Perfusion
Pyridines
Rats
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
Acetylcholine
Angiotensin II
Angiotensin II Type 2 Receptor Blockers
Calcium
Catecholamines
Dimethylphenylpiperazinium Iodide
Imidazoles
Indoles
Oligopeptides
Pyridines
Veratridine

Figure

• 

  Fig. 1. Dose-dependent effects of PD 123319 on the secretory responses of catecholamines (CA) evoked by acetylcholine (ACh) (A) and high potassium (B) from the perfused rat adrenal medullas. The CA secretion by a single injection of ACh (5.32 mM) or high K+ (56 mM) in a volume of 0.05 mL was evoked at 15 intervals during loading with 5, 15, and 50 nM of PD 123319 for 90 minutes 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. 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-treated group of PD 123319. ACh- and high K+-induced perfusates were collected for 4 minutes, respectively. NS, statistically not significant. *p < 0.05, **p < 0.01.

• 

  Fig. 2. DDose-dependent effects of PD 123319 on the catecholamines (CA) secretory responses evoked by 1,1-dimethyl-4 -phenylpiperazinium iodide (DMPP) (A) and McN-A-343 (B) from the perfused rat adrenal medullas. The CA secretion by perfusion of DMPP (100 μM) for 1 minute and 3-(m-chloro-phenyl-carbamoyl-oxy)-2-butynyltrimethyl ammonium chloride (McN-A-343, 100 μM) for 4 minutes was induced at 20 and 15 intervals during loading with 5, 15, and 50 nM of PD 123319 for 90 minutes, respectively. DMPP- and McN-A-343-induced perfusates were collected for 8 and 4 minutes, respectively. NS, statistically not significant. *p < 0.05, **p < 0.01.

• 

  Fig. 3. Time-course effects of PD 123319 on the catecholamines (CA) release evoked by 4-dihydro-2,6-dimethyl-3-nitro -4-(2-trifluoro-methyl-phenyl)-pyridine-5-carboxylate (Bay-K-8644) (A) and cyclopiazonic acid (B) from the perfused rat adrenal medullas. Bay-K-8644 (10 μM) and cyclopiazonic acid (10 μM) were perfused into an adrenal vein for 4 minutes at 15-minute intervals during loading with PD 123319 (15 nM) for 90 minutes, respectively. NS, statistically not significant. *p < 0.05, **p < 0.01.

• 

  Fig. 4. Time-course effects of PD 123319 on the catecholamines (CA) release evoked by veratridine (A) and angiotensin II (B) from the perfused rat adrenal medullas. Veratridine (100 μM) for 4 minutes and angiotensin II (100 nM) for 1 minute were perfused into an adrenal vein and at 15-minute intervals during loading with PD 123319 (15 nM) for 90 minutes, respectively. **p < 0.01.

• 

  Fig. 5. Influence of PD 123319 (or PD) plus CGP 42112 (CGP) on the catecholamines (CA) secretory responses evoked by acetylcholine (A) and high potassium (B) from the perfused rat adrenal medulla. The CA secretion by a single injection of acetylcholine (Ach) (5.32 mM) or high K+ (56 mM) in a volume of 0.05 mL was evoked at 15 intervals during simultaneous loading with PD (15 nM) plus CGP (15 nM) for 90 minutes. Statistical difference was obtained by comparing the corresponding control (control) with group of PD 123319-treated alone or group treated with PD + CGP. NS, statistically not significant. *p < 0.05, **p < 0.01.

• 

  Fig. 6. Effects of PD 123319 plus CGP 42112 on the catecholamines (CA) secretory responses evoked by 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) (A) and angiotensin II (B) from the perfused rat adrenal medulla. The CA secretion by perfusion of DMPP (100 μM) and angiotensin II for 1 minute was induced at 20- and 15-minute intervals during simultaneous loading with PD (15 nM) plus CGP (15 nM) for 90 minutes, respectively. **p < 0.01.

• 

  Fig. 7. Effects of PD 123319 plus CGP 42112 on the catecholamines (CA) secretory responses evoked by 4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoro-methyl-phenyl)-pyridine-5-carboxylate (Bay-K-8644) (A) and veratridine (B) from the perfused rat adrenal medulla. Bay-K-8644 (10 μM) and veratridine (100 μM) were perfused into an adrenal vein for 4 minutes at 15-minute intervals during simultaneous loading with PD (15 nM) plus CGP (15 nM) for 90 minutes. NS, not statistically significant. **p < 0.01.

Reference

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