• The Korean Journal of Physiology and Pharmacology
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• v.14 no.4
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• pp.241-248
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• 2010

The present sutdy aimed to determine whether olmesartan, an angiotensin II (Ang II) type 1 ($AT_1$) receptor blocker, can influence the CA release from the isolated perfused model of the rat adrenal medulla. Olmesartan ($5{\sim}50{\mu}M$) perfused into an adrenal vein for 90 min produced dose- and time-dependent inhibition of 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 ${\mu}M$). Olmesartan did not affect basal CA secretion. Also, in adrenal glands loaded with olmesartan (15 ${\mu}M$), the CA secretory responses evoked by Bay-K-8644 (10 ${\mu}M$, an activator of voltage-dependent L-type $Ca^{2+}$ channels), cyclopiazonic acid (10 ${\mu}M$, an inhibitor of cytoplasmic $Ca^{2+}$-ATPase), veratridine (100 ${\mu}M$, an activator of voltage-dependent $Na^+$ channels), and Ang II (100 nM) were markedly inhibited. However, at high concentrations ($150{\sim}300{\mu}M$), olmesartan rather enhanced the ACh-evoked CA secretion. Taken together, these results show that olmesartan at low concentrations inhibits the CA secretion evoked by cholinergic stimulation (both nicotininc and muscarinic receptors) as well as by direct membrane depolarization from the rat adrenal medulla, but at high concentrations it rather potentiates the ACh-evoked CA secretion. It seems that olmesartan has a dual action, acting as both agonist and antagonist at nicotinic receptors of the isolated perfused rat adrenal medulla, which might be dependent on the concentration. It is also thought that this inhibitory effect of olmesartan may be mediated by blocking the influx of both $Na^+$ and $Ca^{2+}$ into the rat adrenomedullary chromaffin cells as well as by inhibiting the $Ca^{2+}$ release from the cytoplasmic calcium store, which is thought to be relevant to the $AT_1$ receptor blockade, in addition to its enhancement on the CA secreton.

• Biomolecules & Therapeutics
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• v.11 no.2
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• pp.119-125
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• 2003

The present study was conducted to investigate the effects of bornyl acetate on arterial blood pressure and vascular contractile responses in the normotensive rats and to establish the mechanism of action. Both phenylephrine (an adrenergi$\alpha$-receptor agonist) and high potassium (a membrane-depolarizing agent) caused greatly contractile responses in the isolated aortic strips. These phenylephrine (10$^{-5}$ M)-induced contractile responses were depressed in the presence of high concentrations of bornyl acetate (10∼20 $\mu\textrm{g}$/ml), but not affected in low concentrations of bornyl acetate (2.5∼5$\mu\textrm{g}$/ml). High potassium (5.6 ${\times}$ 10$^{-2}$ M)-induced contractile responses were also greatly inhibited in the presence of bornyl acetate (2.5∼20 $\mu\textrm{g}$/ml) in a dose-dependent fashion. Bornyl acetate (1∼10 mg/kg) given into a femoral vein of the normotensive rat produced a dose-dependent depressor response, which is transient (data not shown). Interestingly, the infusion of a moderate dose of bornyl acetate (3mg/kg/30 min) made a significant reduction in pressor responses induced by intravenous norepinephrine. Collectively, these results obtained from the present study demonstrate that intravenous bornyl acetate causes a dose-dependent depressor action in the anesthetized rat at least partly through the blockade of adrenergic $\alpha$$_1$-receptors. bornyl acetate also causes vascular relaxation in the isolated aortic strips of the rat via the blockade of adrenergic $\alpha$$_1$-receptors, in addition to the unknown mechanism of direct vasorelaxation.

• The Korean Journal of Pain
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• v.23 no.4
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• pp.236-241
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• 2010

Background: Selective inhibitors of cycloosygenase (COX)-2 are commonly used analgesics in various pain conditions. Although their actions are largely thought to be mediated by the blockade of prostaglandin (PG) biosynthesis, evidences suggesting endogenous opioid peptide link in spinal antinociception of COX inhibitor have been reported. We investigated the roles of opioid receptor subtypes in the spinal antionociception of selective COX-2 inhibitor. Methods: To examine the antionociception of a selective COX-2 inhibitor, DUP-697 was delivered through an intrathecal catheter, 10 minutes before the formalin test in male Sprague-Dawley rats. Then, the effect of intrathecal pretreatment with CTOP, naltrindole and GNTI, which are ${\mu}$, $\delta$, and k opioid receptor antagonist, respectively, on the analgesia induced by DUP-697 was assessed. Results: Intrathecal DUP-697 reduced the flinching response evoked by formalin injection during phase 1 and 2 Naltrindole and GNTI attenuated the antinociceptive effect of intrathecal DUP-697 during both phases of the formalin test, CTOP reversed the antinociception of DUP-697 during phase 2, but not during phase 1, Conclusions: Intrathecal DUP-697, a selective COX-2 inhibitor, effectively relieved inflammatory pain in rats. The $\delta$ and $\kappa$ opioid receptors are involved in the activity of COX-2 inhibitor on the facilitated state as well as acute pain at the spinal level, whereas the ${\mu}$ opioid receptor is related only to facilitated pain.

• YAKHAK HOEJI
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• v.44 no.1
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• pp.52-59
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• 2000

An exceptionally conserved sequence that is shared among most G protein-coupled neurotransmitter receptors is an aspartate-arginine-tyrosine triplet that is located at the second cytoplasmic domain. Using the ml subtype of muscarinic acetylcholine receptors as an example, a point mutation of the arginine residue at position 123 into asparagine was induced. This mutation resulted in a complete blockade of the carbachol-induced increases of PI hydrolysis and intracellular $Ca^2$$^{+}$ level, in spite of the expression of the wild-type and mutant receptors at similar concentrations in Chinese hamster ovary cells. In marked contrast, the muscarinic agonist carbachol induced concentration-dependent enhancement of the activity of NO synthase at mutant ml receptors although the enhancement was significantly smaller than at wild-type ml receptors. These data suggest that this highly conserved arginine residue plays an important role in coupling of muscarinic receptors to the second messenger systems and the presence of alternate mechanisms of activation of neuronal NO synthase which might be operative in the absence of large changes in the concentration of cellular $Ca^{2+}$.2+/.

• The Korean Journal of Physiology and Pharmacology
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• v.18 no.1
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• pp.41-46
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• 2014

The possible roles of spinal histamine receptors in the regulation of the blood glucose level were studied in ICR mice. Mice were intrathecally (i.t.) treated with histamine 1 (H1) receptor agonist (2-pyridylethylamine) or antagonist (cetirizine), histamine 2 (H2) receptor agonist (dimaprit) or antagonist (ranitidine), histamine 3 (H3) receptor agonist (${\alpha}$-methylhistamine) or antagonist (carcinine) and histamine 4 (H4) receptor agonist (VUF 8430) or antagonist (JNJ 7777120), and the blood glucose level was measured at 30, 60 and 120 min after i.t. administration. The i.t. injection with ${\alpha}$-methylhistamine, but not carcinine slightly caused an elevation of the blood glucose level. In addition, histamine H1, H2, and H4 receptor agonists and antagonists did not affect the blood glucose level. In D-glucose-fed model, i.t. pretreatment with cetirizine enhanced the blood glucose level, whereas 2-pyridylethylamine did not affect. The i.t. pretreatment with dimaprit, but not ranitidine, enhanced the blood glucose level in D-glucose-fed model. In addition, ${\alpha}$-methylhistamine, but not carcinine, slightly but significantly enhanced the blood glucose level D-glucose-fed model. Finally, i.t. pretreatment with JNJ 7777120, but not VUF 8430, slightly but significantly increased the blood glucose level. Although histamine receptors themselves located at the spinal cord do not exert any effect on the regulation of the blood glucose level, our results suggest that the activation of spinal histamine H2 receptors and the blockade of spinal histamine H1 or H3 receptors may play modulatory roles for up-regulation and down-regulation, respectively, of the blood glucose level in D-glucose fed model.

• Experimental and Molecular Medicine
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• v.50 no.11
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• pp.6.1-6.12
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• 2018

Morphine tolerance remains a challenge in the management of chronic pain in the clinic. As shown in our previous study, the dopamine D2 receptor (D2DR) expressed in spinal cord neurons might be involved in morphine tolerance, but the underlying mechanisms remain to be elucidated. In the present study, selective spinal D2DR blockade attenuated morphine tolerance in mice by inhibiting phosphatidylinositol 3 kinase (PI3K)/serine-threonine kinase (Akt)-mitogen activated protein kinase (MAPK) signaling in a ${\mu}$ opioid receptor (MOR)-dependent manner. Levo-corydalmine (l-CDL), which exhibited micromolar affinity for D2DR in D2/CHO-K1 cell lines in this report and effectively alleviated bone cancer pain in our previous study, attenuated morphine tolerance in rats with chronic bone cancer pain at nonanalgesic doses. Furthermore, the intrathecal administration of l-CDL obviously attenuated morphine tolerance, and the effect was reversed by a D2DR agonist in mice. Spinal D2DR inhibition and l-CDL also inhibited tolerance induced by the MOR agonist DAMGO. l-CDL and a D2DR small interfering RNA (siRNA) decreased the increase in levels of phosphorylated Akt and MAPK in the spinal cord; these changes were abolished by a PI3K inhibitor. In addition, the activated Akt and MAPK proteins in mice exhibiting morphine tolerance were inhibited by a MOR antagonist. Intrathecal administration of a PI3K inhibitor also attenuated DAMGO-induced tolerance. Based on these results, l-CDL antagonized spinal D2DR to attenuate morphine tolerance by inhibiting PI3K/Akt-dependent MAPK phosphorylation through MOR. These findings provide insights into a more versatile treatment for morphine tolerance.

• YAKHAK HOEJI
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• v.48 no.6
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• pp.352-357
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• 2004

Atrial myocytes have two functionally separate groups of ryanodine receptors (RyRs): those at the periphery colocalized with L-type $Ca^{2+}$channels (DHPRS) and those a t the cell interior not associated with DHPRs. $Ca^{2+}$ current ($I_{ca}$) directly gates peripheral RyRs on action potential and the subsequent peripheral $Ca^{2+}$ release propagates into the center of atrial myocytes. The mechanisms that regulate the $Ca^{2+}$+ propagation wave remain Poorly understood. Using 2-D confocal$Ca^{2+}$ imaging, we examined the role of inositol 1,4,5-trisphosphate receptor (IP $_3R$) and mitochondria on ($I_{ca}$)- gated local $Ca^{2+}$ signaling in rat atrial myocytes. Blockade of IP $_3R$ by xestospongin C (XeC) partially suppressed the magnitudes of I ca-gated central and peripheral $Ca^{2+}$ releases with no effect on $I_{ca}$. Mitochondrial staining revealed that mitochondria were aligned with ${\thickapprox}2-{\mu}m$ separations in the entire cytoplasm of ventricular and atrial myocytes. Membrane depolarization induced rapid mitochondrial $Ca^{2+}$ rise and decay in the cell periphery with slower rise in the center, suggesting that mitochondria may immediately uptake cytosolic $Ca^{2+}$, released from the peripheral SR on depolarization, and re-release the $Ca^{2+}$ into the cytosol to activate neighboring central RyRs. Our data suggest that the activation of IP $_3R$ and mitochondrial $Ca^{2+}$ handing on action potential may serve as a cofactor for the $Ca^{2+}$ propagation from the DHPR-coupled RyRs to the DHPR-uncoupled RyRs with large gaps between them.

• Integrative Medicine Research
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• v.3 no.1
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• pp.4-10
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• 2014

Green tea and coffee consumption have been widely popular worldwide. These beverages contain caffeine to activate the central nervous system by adenosine receptor blockade, and due to the caffeine, addiction or tolerance may occur. In addition to this caffeine effect, green tea and coffee consumption have always been at the center of discussions about human health, disease, and longevity. In particular, green tea catechins are involved in many biological activities such as antioxidation and modulation of various cellular lipid and proteins. Thus, they are beneficial against degenerative diseases, including obesity, cancer, cardiovascular diseases, and various inflammatory diseases. Some reports also suggest that daily consumption of tea catechins may help in controlling type 2 diabetes. However, other studies have reported that chronic consumption of green tea may result in hepatic failure, neuronal damage, and exacerbation of diabetes, suggesting that interindividual variations in the green tea effect are large. This review will focus on the effect of green tea catechins extracted from the Camellia sinensis plant on type 2 diabetes and obesity, and the possible mechanistic explanation for the experimental results mainly from our laboratory. It is hoped that green tea can be consumed in a suitable manner as a supplement to prevent the development of type 2 diabetes and obesity.

• Korean Journal of Biological Psychiatry
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• v.4 no.2
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• pp.198-210
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• 1997

To examine the double-faced thymoleptic(antidepressant and antimanic) effects of risperidone in mood disorders, this article reviews the psychotropic-induced mania, thymoleptic effects of antipsychotics, therapeutic effects of risperidone and risperidone(RIS)-induced mania(RIM) in mood disorders, risk factors of RIM, possible neurochemical mechanism of these thymoleptic effects, pathophysiological and clinical significance of thymoleptic effects, and suggestive clinical guideline of RIS in mood disorders. RIS appeared effective for bipolar disorder at a lower dose than that recommended for schizophrenia, especially in the cases of maintenance of mood stabilizers, and gradual titration from low doses. Manic induction/exacerbation can occur by chance during RIS treatment in mood disorders, schizoaffective disorders, and schizophrenias. The possible risk factors for RIM are refractory mood disorder, especially in bipolar I disorder with poor initial response ; refractory schizoaffective disorders, especially in bipolar type with poor initial response ; refractory chronic schizophrenias, especially with initial responses ; psychotic features ; higher initial doses ; rapid titration ; combined therapy with antidepressants in refractory depression ; and RIS monotherapy in mania/hypomania. RIS is a drug that preferentially block 5-HT2 receptors. The effects of low dose are due mainly to the blockade of 5-HT2 receptors. There are more gradual increase in D2 blockade with increasing dose and this D2 blocking properties become apparent at higher doses. This may be related to a modulation of dopaminergic transmission by 5-HT2 antagonism at lower doses with the direct action of RIS on DA receptors coming into play at higher dose. The serotonergic antagonistic effect may be important for its effects on depressive symptoms. This, together with adequate blo-ckade of D2 receptors, may not necessarily lead to destabilization of mood disorder, but rather to more therapeutic effects. Therefore, this dose-receptor affinity relationship with both antidepressant and antimanic effects according to treatment duration can explain a continuum of antidepressant effect, antimanic effect, behavioral stimulation, and manic/hypomanic induction/exacerbation. It was the recognition of a useful psychiatric side effects by a thoughtful observer with fertile minds that led to their ultimate utilization as psychotropic drugs, i.e., phenothiazine, MAOI, TCA, and lithium. And, in vivo pharmacological challenge by novel psychotropics, as a neurochemical probe, with more specific actions is a useful tool to select pharmacologically homogeneous subgroup of the same phenotypical(clinical) condition, to further study the unknown underlying pathogenesis of various mental illnesses. Finally, RIS may be a useful alternative or adjunctive drug for patients with mood disorders without psychotic features or refractory to treatment with standard antipsychotic drugs. The more conservative doses(tirated slowly from 1-3 mg/d) of RIS, and maintenance of mood stabilizer in the cases with risk factors of RIM are recommended in mood disorder.

• Tuberculosis and Respiratory Diseases
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• v.54 no.1
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• pp.91-103
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• 2003

Background : Histamine is widely distributed in the lung. It increases capillary permeability and the P-selectin expression on vascular endothelial cell surfaces. We studied the role of endogenous histamine on the pathogenesis of endotoxin-induced acute lung injury (ALI) in rats. Methods: We instilled either normal saline (control group) or lipopolysaccharide (3 mg/Kg, LPS group) to tracheas of Sprague-Dawley rats. H1-receptor blocker (mepyramine, 10 mg/Kg, H1RB group), H2-receptor blocker (ranitidine, 10 mg/Kg, H2RB group), and H3-receptor blocker (thioperamide, 2 mg/Kg, H3RB group) were administered through vein or peritoneum along with intratracheal LPS administration. Statistical significance was accepted at p<0.05. Results : LPS increases the histamine level in BAL fluid significantly at 2 h after the treatment compared with control group. LPS significantly increases protein concentration, PMN cell count in bronchoalveolar lavage (BAL) fluid, and myeloperoxidase (MPO) activity in the lung tissue at 6 h compared to control group. PMN cell count in BAL fluid and MPO activity in lung tissue were significantly lower in H2RB-group compared to LPS-group. However, protein concentration in BAL fluid showed no significant differences between the LPS alone and LPS with histamine receptor blockade. Conclusions : Endogenous histamine might be involved in the recruitment of PMNs in LPS-induced ALI via H2 receptor. However, its role in ALI would not be significant in this model.