• Archives of Pharmacal Research
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• 제14권3호
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• pp.271-278
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• 1991

To investigate further whether the effects of the dihydropyridine (DHP) drugs on calcium channels are related to those of these drugs on muscarinic receptors, the binding characteristics of the DHP calcium channel agonist, Bay K 8644, on muscarinic receptors and calcium channels were compared to those of the DHP calcium channel antagonists, nicardipine and nimodipine in the dog cardiac sarcolemma. Bay K 8644, nicardipine and nimodipine inhibited the specific $[^3H]$QNB binding with $K_i$ values of 16.7\mu{M}$, 3.5\mu{M}$ and 15.5\mu{M}$ respectively. Saturation data of $[^3H]$QNB binding with $K_i$ VALUES OF 16.7\mu{M}$ 3.5\mu{M}$ and 15.5\mu{M}$ respectively. Saturation data of $[^3H]$QNB binding in the presence of these DHP drugs showed this inhibition to be competitive. Bay K 8644, like nicardipine and nimodipine, blocked the binding of $[^3H]$nitrendipine to the high affinity DHP binding sites, but atropine did not, indicating that the muscarinic receptors and the DHP binding sites m but atropine did not, indicating that the muscarinic receptors and the DHP bindings sites on calcium channels are distinct. The $K_i$ value of Bay K 8644 for the DHP binding sites was 4nM. Nicardipine and nimodipine $(K_i:0.1-0.2\;nM)$ were at least 20 times more potent than Bay K 8644 in inhibiting $[^3H]$ nitrendipine binding. Thus, the muscarinic receptors were about 4000 times less sensitive than thes high afinity DHP binding sites to Bay K 8644. These results suggest that the DHP calcium agonist Bay K 8644 binds directly to the muscarinic receptors but its interaction with the muscarinic receptors is not related to its binding to the DHP binding sites on calcium channels.

• The Korean Journal of Physiology
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• 제27권1호
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• pp.51-55
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• 1993

The effects of a calcium channel blocker and an activator on the release of atrial natriuretic peptide (ANP) were investigated in rats. They were volume expanded (VE) up to 5% of the body weight over 30min by being infused with iso-oncotic saline. Following VE, plasma ANP concentration markedly increased in association with increases in the right atrial pressure. Addition of either nifedipine ($0.4{\mu}m/min$) or Bay K 8644 ($0.4{\mu}m/min$) in the infusate potentiated the VE-induced release, although neither of them affected the right atrial pressure. The nifedipine added group showed a lower mean arterial pressure than the Bay K added group throughout the infusion period. VE decreased plasma renin concentration, the magnitude of which was attenuated by nifedipine but not by Bay K. It may be hypothesized that a decrease in cytoplasmic calcium is primary stimulus far the ANP release, and an increase plays o role in secondary liberation of the ANP accumulated in the interstitium into the lumen of the atria through myocardial contraction. further studies will be needed to confirm the hypothesis.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1996년도 춘계학술대회
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• pp.242-242
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• 1996

The influence of glucocorticoids on the secretory responses of catecholamines (CA) evoked by acetylcholine (ACh), DMPP, McN-A-343, excess K$\^$+/ and Bay-K-8644 from the isolated perfused rat adrenal gland and to clarify the mechanism of its action. The perfusion of the synthetic glucocorticoid dexamethasone (10-100 uM) into an adrenal vein for 20min produced relatively a dose-dependent inhibition in CA secretion evoked by ACh (5.32mM), excess K$\^$+/ (56mM), DMPP (a selective nicotinic receptor agonist, 100uM for 2min), McN-A-343 (a muscarinic receptor agonist, 100uM for 4min), Bay-K-8644 (a calcium channel activator, 10 uM for 4min) and cyclopiazonic acid (a releaser of intracellular Ca$\^$2+/, 10uM for 4min).

• 약학회지
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• 제54권6호
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• pp.461-465
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• 2010

We investigated the role of L-type $Ca^{2+}$ channel in receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast formation. BayK 8644, a L-type $Ca^{2+}$ channel agonist, was shown to increase the RANKLinduced osteoclastogenesis and actin ring formation in mouse bone marrow-dereived macrophage (BMM) culture system. BayK 8644 stimulated RANKL-induced extracellular signal-regulated kinase (ERK) and p38 MAP kinase (MAPK) activation, which leads to increased nuclear factor of activated T cells (NFAT)c1 expression. Taken together, these data indicate that L-type $Ca^{2+}$ channel regulates osteoclast formation possibly through ERK- and p38-mediated NFATc1 expression.

• Biomolecules & Therapeutics
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• 제10권3호
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• pp.142-151
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• 2002

The present study was attempted to investigate the effect of apamin on catecholamine (CA) secretion evoked by ACh, high $K^+$, DMPP, McN-A-343, cyclopiazonic acid and Bay-K-8644 from the isolated perfused rat adrenal gland and to establish the mechanism of its action. The perfusion of apamin (1 nM) into an adrenal vein for 20 min produced greatly potentiation in CA secretion evoked by ACh (5.32 $ imes$ $10^{-3}$ M), high $K^+$, (5.6 $ imes$ $10^{-2}$), 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). However, apamin itself did fail to affect basal catecholamine output. Furthermore, in adrenal glands preloaded with apamin (1 nM) under the presence of glibenclamide ($10^{-6}$ M), an antidiabetic sulfonylurea that has been shown to be a specific blocker of ATP-regulated potassium channels (for 20 min), CA secretion evoked by DMPP and McN-A-343 was not affected. However, the perfusion of high concentration of apamin (100 nM) into an adrenal vein for 20 min rather inhibited significantly CA secretory responses evoked by ACh, high $K^+$, DMPP, McN-A-343, cyclopiazonic acid and Bay-K-8644. Taken together, these results suggest that the low concentration of apamin causes greatly the enhancement of CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors as well as by membrane depolarization. These findings suggests that apamin-sensitive SK ($Ca^{2+}$) channels located in rat adrenal medullary chromaffin cells may play an inhibitory role in the release of catecholamines mediated by stimulation of cholinergic nicotinic and muscarinic receptors as well as membrane depolarization. However, it is thought that high concentration of apamin cause the inhibitory responses in catecholamine secretion evoked by stimulation of cholinergic receptors as well as by membrane depolarization from the rat adrenal gland without relevance with the SK channel blockade.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1998년도 Proceedings of UNESCO-internetwork Cooperative Regional Seminar and Workshop on Bioassay Guided Isolation of Bioactive Substances from Natural Products and Microbial Products
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• pp.148-149
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• 1998

It has been known that potassium channel openers are a new class of molecules that have attracted general interest because of their potent antihypertensive activity in vivo and vasorelaxant activity in vitro (Hamilton and Weston, 1989). In the present study, it was attempted to examine the effect of the potassium channel opener on catecholamine (CA) secretion evoked by cholinergic stimulation, membrane depolarization and calcium mobilization from the isolated perfused rat adrenal gland. The perfusion of pinacidil (30-300 uM) into an adrenal vein for 20 min produced relatively dose-dependent inhibition in CA secretion evoked by ACh (5.32 mM), high $K^{+}$ (56 mM), DMPP (100 uM for 2 min), McN-A-343 (100 uM for 2 min), cyclopiazonic acid (10 uM for 4 min) and Bay-K-8644 (10 uM for 4 min). Also, under the presence of minoxidil (100 uM), which is also known to be a potassium channel activator, CA secretory responses evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid were also significantly depressed. However, in adrenal glands preloaded with pinacidil (100 uM) under the presence of glibenclamide (1 uM), an antidiabetic sulfonylurea that has been shown to be a specific blocker of ATP-regulated potassium channels (for 20 min), CA secretory responses evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid were considerably recovered to a considerable extent of the normal release as compared to that of pinacidil only. These results, taken together, suggest that pinacidil cause 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. Furthermore, these findings suggest strongly that these potassium channel openers-sensitive membrane potassium channels also play an important role in regulating CA secretion.

• Biomolecules & Therapeutics
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• 제8권4호
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• pp.338-348
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• 2000

The present study was attempted to determine the effect of 5'-(N'-ethylcarboxamido) adenosine (NECA), which is an potent $A_2$-adenosine receptor agonist, on catecholamine (CA) secretion evoked by cholinergic stimulation, membrane depolarization and calcium mobilization from the isolated perfused rat adrenal gland. NECA (20 nM) perfused into the adrenal vein for 60 min produced a time-related inhibition in CA secretion evoked by ACh (5.32x10$^{-3}$ M), high $K^{+}$(5.6x10$^{-2}$ 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 $\beta$,${\gamma}$-methylene adenosine-5'-triphosphate (MATP), which is also known to be a selective $P_{2x}$-purinergic receptor agonist, showed a similar inhibition elf CA release evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid. However, in adrenal glands preloaded with 20$\mu$M NECA for 20 min under the presence of 20$\mu$M 3-isobutyl-1-methyl-xanthine (IBMX), an adenosine receptors antagonist, CA secretory responses evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid were much recovered in comparison to the case of NECA-treatment only. Taken together, these results indicate that NECA causes the marked inhibition of CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors as well as by membrane depolarization. This inhibitory effect may be mediated by inhibiting influx of extracellular calcium and release in intracellular calcium in the rat adrenomedullary chromaffin cells through the adenosine receptor stimulation. Therefore, it is suggested that the inhibitory mechanism of adenosine receptor stimulation may play a modulatory role in regulating CA secretion.n.n.

• The Korean Journal of Physiology and Pharmacology
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• 제3권3호
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• pp.339-350
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• 1999

The present study was attempted to examine the effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on catecholamine (CA) secretion evoked by cholinergic stimulation, membrane depolarization and calcium mobilization from the isolated perfused rat adrenal gland. The perfusion of PACAP (10 nM) into an adrenal vein for 60 min produced a great 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 neuropeptide (NPY), which is known to be co-localized with norepinephrine in peripheral sympathetic nerves, CA secretory responses evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid were also significantly depressed. However, in adrenal glands preloaded with PACAP (10 nM) under the presence of VIP antagonist $[(Lys^1,\;Pro^{2.5},\;Arg^{3.4},\;Tyr^6)-VIP\;(3\;{\mu}M)]$ for 20 min, CA secretory responses evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid were not altered greatly in comparison to the case of PACAP-treatment only. Taken together, these results suggest that PACAP causes the marked inhibition of CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors as well as by membrane depolarization, indicating that this effect may be mediated by inhibiting influx of extracellular calcium and release in intracellular calcium in the rat adrenomedullary chromaffin cells.

• Archives of Pharmacal Research
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• 제24권3호
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• pp.240-248
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• 2001

The present study was attempted to investigate the effect of quinine on secretion of catecholamines (CA) etroked by cholinergic stimulation and membrane depolarization from the isolated perfused rat adrenal gland. The perfusion of quinine (15-150${\mu}$M) into an adrenal vein for 60 min produced dose- and time-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 ($10^{-5}$ for 4 min) and Bay-K-8644 ($10^{-5}$ M for 4 min). Also, under the presence of pinacidil ($10^{-4}$ M), which is also known to be a selective potassium channel activator, CA secretory responses evoked by ACh, high potassium, DMPP McN-A-343, Bay-K-8644 and cyclopiazonic acid were also greatly reduced. When preloaded along with quinine ($5{\times}10^{-5}M$) and glibenclamide ($10^{-6}$ M), a specific blocker of ATP-regulated potassium channels, CA secretory responses evoked by ACh, high potassium, DMPP McN-A-343, Bay-K-8644 and cyclopiazonic acid were recovered as compared to those of quinine-treatment only. taken together, these results demonstrate that quinine inhibits CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors as well as by membrane depolarization through inhibiting influx of extracellular calcium and release in intracellular calcium in the rat adrenmodullary chromaffin cells. These findings suggest that activation of potassium channels may be involved at least in inhibitory action of quinine on CA secretion from the rat adrenal gland.

• Archives of Pharmacal Research
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• 제25권4호
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• pp.511-521
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• 2002

The purpose of this study was to determine whether bromocriptine affects the catecholamines (CA) secretion evoked in isolated perfused rat adrenal glands, by cholinergic stimulation, membrane depolarization and calcium mobilization, and to establish the mechanism of its action. The perfusion of bromocriptine ($1~10{\;}{\mu}M$) into an adrenal vein, for 60 min, produced relatively dose-dependent inhibition in the secretion of catecholamines (CA) evoked by acetylcholine (ACh, 5.32 mM), DMPP ($100{\;}{\mu}M$ for 2 min), McN-A-343 ($100{\;}{\mu}M$ for 2 min), cyclopiazonic acid (CPA, $10{\;}{\mu}M$ for 4 min) and Bay-K-8644 ($10{\;}{\mu}M$ for 4 min). High $K^+$ (56 mM)-evoked CA release was also inhibited, although not in a dose-dependent fashion. Also, in the presence of apomorphine ($100{\;}{\mu}M$), which is also known to be a selective $D_2$-agonist, the CA secretory responses evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid were also significantly depressed. However, in adrenal glands preloaded with bromocriptine ($3{\;}{\mu}M$) in the presence of metoclopramide ($15{\;}{\mu}M$), a selective $D_2$-antagonist, the CA secretory responses evoked by ACh, high potassium, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid considerably recovered as compared to that of bromocriptine only. Taken together, these results suggest that bromocriptine can inhibit the CA secretion evoked by stimulation of cholinergic receptors, as well as by membrane depolarization, in the perfused rat adrenal medulla. It is thought this inhibitory effect of bromocriptine may be mediated by inhibiting the influx of extracellular calcium and the release from intracellular calcium stores, through the activation of dopaminergic $D_2$-receptors located in the rat adrenomedullary chromaffin cells. Furthermore, these findings also suggest that the dopaminergic $D_2$-receptors may play an important role in regulating adrenomedullary CA secretion.