Korean J Physiol Pharmacol.  2009 Jun;13(3):229-239. 10.4196/kjpp.2009.13.3.229.

Provinol Inhibits Catecholamine Secretion from the Rat Adrenal Medulla

• Lee JH
• Seo YS
• Lim DY

• KMID: 2071676
• DOI: http://doi.org/10.4196/kjpp.2009.13.3.229

Abstract

The aim of the present study was to examine the effect of provinol, which is a mixture of polyphenolic compounds from red wine, on the secretion of catecholamines (CA) from isolated perfused rat adrenal medulla, and to elucidate its mechanism of action. Provinol (0.3~3 microgram/ml) perfused into an adrenal vein for 90 min dose- and time-dependently inhibited the CA secretory responses evoked by ACh (5.32 mM), high K+ (a direct membrane-depolarizer, 56 mM), DMPP (a selective neuronal nicotinic NN receptor agonist, 100 micrometer) and McN-A-343 (a selective muscarinic M1 receptor agonist, 100 micrometer). Provinol itself did not affect basal CA secretion. Also, in the presence of provinol (1 microgram/ml), the secretory responses of CA evoked by Bay-K-8644 (a voltage-dependent L-type dihydropyridine Ca2+ channel activator, 10 microgram), cyclopiazonic acid (a cytoplasmic Ca2+-ATPase inhibitor, 10 microgram) and veratridine (an activator of voltage-dependent Na+ channels, 10 microgram) were significantly reduced. Interestingly, in the simultaneous presence of provinol (1 microgram/ml) plus L-NAME (a selective inhibitor of NO synthase, 30 micrometer), the CA secretory responses evoked by ACh, high K+, DMPP, McN-A-343, Bay-K-8644 and cyclpiazonic acid recovered to the considerable extent of the corresponding control secretion in comparison with the inhibition of provinol-treatment alone. Under the same condition, the level of NO released from adrenal medulla after the treatment of provinol (3 microgram/ml) was greatly elevated in comparison to its basal release. Taken together, these data demonstrate that provinol inhibits the CA secretory responses evoked by stimulation of cholinergic (both muscarinic and nicotinic) receptors as well as by direct membrane-depolarization from the perfused rat adrenal medulla. This inhibitory effect of provinol seems to be exerted by inhibiting the influx of both calcium and sodium into the rat adrenal medullary cells along with the blockade of Ca2+ release from the cytoplasmic calcium store at least partly through the increased NO production due to the activation of nitric oxide synthase.

Keyword

Provinol; Catecholamine secretion; Adrenal medulla; Cholinergic receptors; Nitric oxide

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 Medulla
Animals
Calcium
Catecholamines
Cytoplasm
Dihydropyridines
Dimethylphenylpiperazinium Iodide
Indoles
Neurons
NG-Nitroarginine Methyl Ester
Nitric Oxide
Nitric Oxide Synthase
Rats
Receptor, Muscarinic M1
Receptors, Cholinergic
Sodium
Veins
Veratridine
Wine
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
Calcium
Catecholamines
Dihydropyridines
Dimethylphenylpiperazinium Iodide
Indoles
NG-Nitroarginine Methyl Ester
Nitric Oxide
Nitric Oxide Synthase
Receptor, Muscarinic M1
Receptors, Cholinergic
Sodium
Veratridine

Figure

• 

  Fig. 1. Dose-dependent effects of provinol on the secretory responses of catecholamines (CA) evoked by acetylcholine (left) and high potassium (right) from the perfused rat adrenal medulla. The CA secretion by a single injection of ACh (5.32×10−3 M) and K+ (5.6×10−2 M) in a volume of 0.05 ml was evoked at 15 min intervals during loading with 0.3, 1.0 and 3.0 μg/ml of provinol for 90 min as indicated by the arrow marks, respectively. The numbers in parentheses indicate the 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-treated group of provinol. ACh- and high K+-induced perfusates were collected for 4 minutes, respectively. ∗∗p<0.01.

• 

  Fig. 2. Dose-dependent effects of provinol on the CA secretory responses evoked by DMPP (left) and McN-A-343 (right) from the perfused rat adrenal medulla. The CA secretion by perfusion of DPPP (10−4 M) and McN-A-343 (10−4 M) for 2 min was induced at 15 and 20 min intervals during loading with 0.3, 1.0 and 3.0 μg/ml of provinol for 90 min, respectively. Statistical difference was obtained by comparing the corresponding control (CONTROL) with each concentration-pretreated group of provinol. 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: Not statistically significant.

• 

  Fig. 3. Time-course effects of provinol on the CA secretion evoked by Bay-K-8644 (left) and cyclopiazonic acid (right) from the perfused rat adrenal medulla. Bay-K-8644 (10−5 M) and cyclopiazonic acid (10−5 M) were perfused into an adrenal vein for 4 min at 15 min intervals during loading with provinol (1.0 μM) for 90 min. Other legends are the same as in Fig. 1. ∗∗p<0.01. ns: Not statistically significant.

• 

  Fig. 4. Time-course effects of provinol on the CA secretion evoked by veratridine from the perfused rat adrenal medulla. Veratridine (10−4 M) was perfused into an adrenal vein for 4 min at 15 min intervals during loading with provinol (1.0 μM) for 90 min. Other legends are the same as in Fig. 1. ∗∗p<0.01.

• 

  Fig. 5. Effects of provinol plus L-NAME on the CA secretory responses evoked by acetylcholine (left) and high potassium (right) from the perfused rat adrenal medulla. The CA secretion by a single injection of ACh (5.32×10−3 M) and K+ (5.6×10−2 M) in a volume of 0.05 ml was evoked at 15 min intervals during simultaneous loading with provinol (1.0 μM) plus L-NAME (30 μM) for 90 min. Statistical difference was obtained by comparing the corresponding control (CONTROL) with provinol-treated group or group treated with provinol+L-NAME. Other legends are the same as in Fig. 1. ∗p<0.05, ∗∗p<0.01. ns: Not statistically significant.

• 

  Fig. 6. Effects of provinol plus L-NAME on the CA secretory responses evoked by DMPP (left) and McN-A-343 (right) from the perfused rat adrenal medulla. The CA secretion by perfusion of DPPP (10−4 M) and McN-A-343 (10−4 M) for 2 min was induced at 15 and 20 min intervals after preloading with provinol (1.0 μM) plus L-NAME (30 μM) for 90 min, respectively. Other legends are the same as in Fig. 1 and 5. ∗p<0.05, ∗∗p<0.01. ns: Not statistically significant.

• 

  Fig. 7. Effects of provinol plus L-NAME on the CA secretory responses evoked by Bay-K-8644 (left) and cyclopiazonic acid (right) from the perfused rat adrenal medulla. Bay-K-8644 (10−5 M) and cyclopiazonic acid (10−5 M) were perfused into an adrenal vein for 4 min at 15 min intervals during simultaneous loading with provinol (1.0 μM) for 90 min. Other legends are the same as in Fig. 1 and 5. ∗p<0.05, ∗∗p<0.01. ns: Not statistically significant.

• 

  Fig. 8. Effects of provinol on nitric oxide (NO) production in the perfused rat adrenal medulla. Perfusate sample was taken for 8 min after loading the perfusion of provinol (3.0 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 provinol). Statistical difference was made by comparing the control with provinol-treated group. ∗∗p<0.01.

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