• The Korean Journal of Physiology and Pharmacology
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• v.17 no.1
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• pp.99-109
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• 2013

The aim of this study was to determine whether fimasartan, a newly developed $AT_1$ receptor blocker, can affect the CA release in the isolated perfused model of the adrenal medulla of spontaneously hypertensive rats (SHRs). Fimasartan (5~50 ${\mu}M$) 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 ${\mu}M$) and McN-A-343 (100 ${\mu}M$). Fimasartan failed to affect basal CA output. Furthermore, in adrenal glands loaded with fimasartan (15 ${\mu}M$), the CA secretory responses evoked by Bay-K-8644 (10 ${\mu}M$, an activator of L-type $Ca^{2+}$ channels), cyclopiazonic acid (10 ${\mu}M$, an inhibitor of cytoplasmic $Ca^{2+}$-ATPase), and veratridine (100 ${\mu}M$, an activator of $Na^+$ channels) as well as by angiotensin II (Ang II, 100 nM), were markedly inhibited. In simultaneous presence of fimasartan (15 ${\mu}M$) and L-NAME (30 ${\mu}M$, 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 ${\mu}M$) alone. Also there was no difference in NO release between before and after treatment with fimasartan (15 ${\mu}M$). 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 $Ca^{2+}$ through their ion channels into the rat adrenomedullary chromaffin cells as well as by inhibiting the $Ca^{2+}$ release from the cytoplasmic calcium store, which is relevant to $AT_1$ receptor blockade without NO release.

• The Korean Journal of Pharmacology
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• v.32 no.1
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• pp.83-91
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• 1996

The present study was designed to determine the effect of hydrocortisone on CA secretion evoked by histamine from the isolated perfused rat adrenal glands. Histamine (150 ug) given into an adrenal vein produced significantly CA secretion from the rat adrenal medulla. This histamine-evoked CA secretion was enhanced markedly by the pretreatment with the natural glucocorticoid hydrocortisone (30 uM) or the synthetic glucocorticoid dexamethasone 30 (uM) for 20 min, respectively. Hydrocortisone-induced potentiation of CA secretion evoked by histamine was inhibited by preloading with heparin (3.56 U/ml), an $IP_3$ receptor antagonist while more enhanced by forskolin (0.2 uM), a potent stimulator of adenylate cyclase. From the experiment result taken together, it is thought that hydrocortisone (glucocorticoids) can enhance the releasing effect of CA evoked by histamine from the isolated perfused rat adrenal medulla, which seems to be associated to accumulation of inositol phosphate as well as cyclic AMP in the rat adrenomedullary chromaffin cells.

• BMB Reports
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• v.29 no.5
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• pp.393-397
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• 1996

Sprague-Dawley male rats (150 g) were chronically treated with 5 v/v % ethanol admixed with nutritionally complete liquid diet and fed ad libitum for 3 weeks. Controls were pair fed with the isocaloric sucrose liquid diet. One half of each group was exposed to cold stress at $4^{\circ}C$ either for 24 h (for determination of mRNA by in situ hybridization) or for 48 h (for determination of enzyme activity). Chronic ethanol treatment (ethanol) did not affect tyrosine hydroxylase (TH) mRNA level in locus coeruleus (LC) of brain and adrenal medulla (AM) compared to controls. Cold stress showed strong increase of TH mRNA level in LC and AM compared to controls. Pretreated ethanol reduced the increased TH mRNA level by cold stress in LC and AM. Ethanol did not affect TH activity in LC and adrenal glands (adrenals). Cold stress increased TH activity in LC but not in adrenals. Pretreated ethanol did not reduce the increased TH activity by cold stress in LC but this result was not shown in adrenals. It is suggested that ethanol does not affect the message level and enzyme protein level for TH in LC and AM in normal rat. It is also hypothesized that pretreated ethanol reduces the magnitude of acute cold stress response, that is induction of TH mRNA in LC and AM, and does not reduce the increased TH enzyme protein that is also acute cold stress response in LC.

• Korean Journal of Pharmacognosy
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• v.10 no.2
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• pp.61-67
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• 1979

Two pure saponin components, Panax saponin C (protopanaxatriol derivative, ginsenoside Re) and Panax saponin E (protopanaxadiol derivative, ginsenoside $Rb_l$) were isolated from Panax ginseng root and their acute toxicities in mice and antistress effects in rats were investigated. Average lethal doses $(LD_{50})$ of ginsenoside Re were 130mg/kg (i.v.), more than 1,000mg/kg (i.p.) and more than 1,500mg/kg (s.c.), respectively. Average lethal dose of ginsenoside $Rb_{1}$ was 243mg/kg intravenously. Adrenal ascorbic acid and cholesterol contents were significantly decreased when normal rats were exposed to heat $(40^{\circ}C)$ for 30 min. The reduction of the adrenal ascorbic acid and cholesterol contents in rats was partially prevented when the rats received the ginseng saponins prior to exposure to heat stress and most pronounced effects were observed in rats received ginsenoside Re. However, it was found that administration of ginseng alone, without stress, did not significantly change the ascorbic acid and cholesterol contents in adrenal glands. Eosinophil counts in the blood of the rats were elevated when the rats were exposed to the heat stress, and the elevation of the eosinophil counts were prevented with the ginseng saponins under the stress, but the changes were all insignificant statistically.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2001.11a
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• pp.95-95
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• 2001

Ciinidipine (FRC-8635) is a newly synthesized novel DHP type of organic Ca$\_$2＋/channel blockers that have been developed so far in Japan (Yoshimoto et al., 1991 : Hosono et at., 1992). It also has a blocking action on L-type voltage-dependent Ca$\^$2＋/channel (VDCCs) in the rabbit basilar artery (Oike et al., 1990) and a slow-onset and long-lasting hypotensive action in clinical and experimental studies (Ikeda et al., 1992 ; Tominaga et al., 1997). Recent electrophysiological data indicate that cilnidipine might be a dual-channel antagonist for peripheral neuronal N-type and vascular L-type Ca$\^$2＋/channels (Oike et al., 1990 ; Fujii et al., 1997; Uneyama et at., 1997). However, little is known about the involvement of N-type VDCCs in contributing to the muscarinic receptor-mediated CA secretion. Therefore, the present study was attempted to investigate the effect of cilinidipine on secretion of catecholamines (CA) evoked by ACh, high K$\^$＋/, DMPP and McN-A-343 from the isolated perfused rat adrenal gland. Cilnidipine (1-10 ${\mu}$M) perfused into an adrenal vein for 60 min produced dose- and time-dependent inhibition in CA secretory responses evoked by ACh (5.32${\times}$10$\^$-3/M), DMPP (10$\^$-4/ M for 2 min) and McN-A-343 (10$\^$-4/ M for 2 min). However, lower dose of lobeline did not affect CA secretion by high K$\^$＋/(5.6${\times}$10$\^$-2/ M), higher dose of it reduced greatly CA secretion of high K$\^$＋/. Cilnidipine itself did also fail to affect basal catecholamine output. Furthermore, in adrenal glands loaded with cilnidipine (10 ${\mu}$M), CA secretory response evoked by Bay-K-8644 (10 ${\mu}$M), an activator of L-type Ca$\^$2＋/channels was markedly inhibited while CA secretion by cyclopiazonic acid (10 ${\mu}$M), an inhibitor of cytoplasmic Ca$\^$2＋/-ATPase was no affected. Moreover, $\omega$-conotoxin GVIA (1 ${\mu}$M), given into the adrenal gland for 60 min, also inhibited time-dependently CA secretory responses evoked by ACh and high K$\^$＋/.

• The Korean Journal of Physiology and Pharmacology
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• v.4 no.2
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• pp.149-158
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• 2000

The present study was attempted to examine the effect of staurosporine (STS) on secretion of catecholamines (CA) evoked by cholinergic stimulation and membrane depolarization from the isolated perfused rat adrenal gland and to establish its mechanism of action. The perfusion of STS $(3{\times}10^{-7}{\sim}3{\times}10^{-8}\;M)$ into an adrenal vein for 20 min produced a dose-dependent inhibition in CA secretion evoked by ACh $(5.32{\times}10^{-3}\;M),$ high $K^+\;(5.6{\times}10^{-2}\;M),$ DMPP $(10^{-4}\;M\;for\;2\;min),$ McN-A-343 $(10^{-4}\;M\;for\;2\;min),$ cyclopiazonic acid $(10^{-5}\;M\;for\;4\;min)$ and Bay-K-8644 $(10^{-5}\;M\;for\;4\;min).$ Also, in the presence of tamoxifen $(2{\times}10^{-6}\;M),$ which is known to be a protein kinase inhibitor, CA secretory responses evoked by ACh, high $K^+,$ DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid were also significantly depressed. However, in adrenal glands preloaded with STS $(10^{-7}\;M)$ under the presence of phorbol-12, 13-dibutyrate $(10^{-7}\;M),$ a specific activator of protein kinases (for 20 min), the inhibitory effect of STS on CA secretory responses evoked by ACh, high $K^+,$ DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid was greatly recovered to the extent of the control release as compared to those in the presence of STS only. These results demonstrate that STS causes the marked inhibition of CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors as well as by membrane depolarization, indicating strongly that this effect may be mediated by inhibiting influx of extracellular calcium and release in intracellular calcium in the rat adrenomedullary chromaffin cells through preventing activation of protein kinases. Furthermore, these findings also suggest that these STS-sensitive protein kinases play a modulatory role partly in regulating the rat adrenomedullary CA secretion.

• Development and Reproduction
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• v.22 no.1
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• pp.19-27
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• 2018

In the present study, we employed Hershberger assay to determine possible androgenic or antiandrogenic activities of three di-2-ethylhexyl phthalate (DEHP) substitute candidates. The assay was carried out using immature castrated Sprague-Dawley male rats. After 7 days of the surgery, testosterone propionate (TP, 0.4 mg/kg/day) and test materials (low dose, 40 mg/kg/day; high dose, 400 mg/kg/day) were administered for 10 consecutive days by subcutaneous (s.c.) injection and oral gavage, respectively. Test materials were DEHP, 2-ethylhexyl oleate (IOO), 2-ethylhexyl stearate (IOS) and triethyl 2-acetylcitrate (ATEC). The rats were necropsied, and then the weights of five androgen-dependent tissues [ventral prostate, seminal vesicle, coagulating glands, levator ani-bulbocavernosus (LABC) muscle, paired Cowper's glands, and glans penis] and four androgen-insensitive tissues (kidney, adrenal glands, spleen and liver) were measured. All test materials including DEHP did not exhibit any androgenic activity in the assay. On the contrary, antiandrogen-like activities were found in all test groups, and the order of the intensity was ATEC < DEHP < ISO < IOO in the five androgen-sensitive tissues. There was no statistical difference between low dose treatment and high dose treatment of all replacement candidate groups. In DEHP groups, high dose treatment exhibited significant weight gains in LABC and Glan Penis. There was no statistical difference in androgen-insensitive tissue measurements. Since the effects of ATEC treatment on the accessory sex organs were much less or not present at all when compared to those of DEHP, ATEC could be a strong candidate to replace DEHP. IOO treatment brought most severe weight reduction in all of androgen-sensitive tissues, so this material should be excluded for further screening of DEHP substitute selection.

• Proceedings of the Korea Society of Environmental Toocicology Conference
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• 2002.10a
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• pp.168-168
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• 2002

To establish a test protocol for the rodent 20-day thyroid/pubertal assay, flutamide and diethylstilbestrol (DES) were administered to intact male Sprague-Dawley rats from postnatal day 33 for 20 days. Flutamide (1, 5, and 25 mg/kg/day) or DES (10, 20, and 40 ug/kg/day) was given once daily by oral gavage to immature male rats. Prepuce separation was significantly delayed in flutamide group and in DES group. One day after the last dose, the rats were killed and pituitary, thyroid, and reproductive organs were removed and weighed. Flutamide treatment resulted in a significant reduction in the weights of epididymides, ventral prostate, seminal vesicles plus coagulating glands and fluid (SVCGF), levator ani. bulbocarvenus muscles (LABC), Cowper's glands, and glans penis. The weight of adrenal glands decreased at % mg/kg/day, while testes and any other organ weights were unaffected. No microscopic changes were observed in the thyroid glands. Serum levels of testosterone wert significantly increased in the flutamide-treated groups and serum levels of estradiol were also increased. A significant reduction in the weights of testes, epididymides, ventral prostate, SVCGF, LABC, Cowpers glands, and glans penis of DES treated group. Serum testosterone and LH decreased significantly in DES group. Decrease of estradiol was observed, but not significant. These results indicate that flutamide and DES delay puberty in the male rat and its mode of action appears to be via altered secretion of steroids, which subsequently affect the development of the reproductive tract. (Supported by the grant from NITR/Korea FDA for Endocrine Disrupter Research.)

• Toxicological Research
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• v.14 no.2
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• pp.227-235
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• 1998

KH-502 (Flupyrazofos), a new organophosphorus insecticide synthesized by Korea Re-search Institute of Chemical Technology, was found to be effective against diamond-back moth(Plutella xylostella). This study was carried out to determine the acute toxicity of KH-502 in Sprague-Dawley rats and ICR mice. The test article was orally or dermally administered to the animals. Death, tremors, salivation, lacrimation, abnormal gait and corneal opacity were observed. Decrease in body weight gain was observed in all treatment groups. At necropsy, dark red coloration of lung, enlargement of adrenal glands and atrophy of spleen were observed. The oral $LD_{50}$ value was 372 mg/kg in male rats, 605 mg/kg in female rats, 186 mg/kg in male mice, and 115 mg/kg in female mice. And the dermal $LD_{50}$ was 4086 mg/kg in male and 3881 mg/kg in female rats.

• Biomolecules & Therapeutics
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• v.3 no.1
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• pp.12-20
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• 1995

Clofibrate, a peroxisome proliferator, is hepatocarcinogenic in rats in a dose-dependent manner. A total of 70 male and female F344 rats, 5-week-old, were divided into three groups. Rats were fed clofibrate at 0, 0.25, or 0.5% in diet for 30 days. All rats were anesthetized with $CO_2$, blood samples were taken by cardiac puncture for hematology and clinical chemistry, and the rats were killed by exsanguination. Livers, kidenys, pancreas, adrenal glands, spleen, heart, lungs, thyroid gland, reproductive organs, and digestive organs were removed, weighed, later processed, and embedded with paraplast for histological examination. The relative liver and kidney weights with respect to final body weight in the clofibrate-treated group were significantly increased compared with those of control group at all dose levels (p<0.01). It has been suggested that clofibrate may influence on hepatotoxicity by increases in peroxisomal proliferation.