• The Korean Journal of Physiology and Pharmacology
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• 제26권4호
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• pp.255-262
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• 2022

Oxytocin is a neuropeptide produced primarily in the hypothalamus and plays an important role in the regulation of mammalian birth and lactation. It has been shown that oxytocin has important cardiovascular protective effects. Here we investigated the effects of oxytocin on vascular reactivity and underlying the mechanisms in human umbilical vein endothelial cells (HUVECs) in vitro and in rat aorta ex vivo. Oxytocin increased phospho-eNOS (Ser 1177) and phospho-Akt (Ser 473) expression in HUVECs in vitro and the aorta of rat ex vivo. Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), inhibited oxytocin-induced Akt and eNOS phosphorylation. In the rat aortic rings, oxytocin induced a biphasic vascular reactivity: oxytocin at low dose (10^-9-10^-8 M) initiated a vasorelaxation followed by a vasoconstriction at high dose (10^-7 M). L-NAME (a nitric oxide synthase inhibitor), endothelium removal or wortmannin abolished oxytocin-induced vasorelaxation, and slightly enhanced oxytocin-induced vasoconstriction. Atosiban, an oxytocin/vasopressin 1a receptor inhibitor, totally blocked oxytocin-induced relaxation and vasoconstriction. PD98059 (ERK1/2 inhibitor) partially inhibited oxytocin-induced vasoconstriction. Oxytocin also increased aortic phospho-ERK1/2 expression, which was reduced by either atosiban or PD98059, suggesting that oxytocin-induced vasoconstriction was partially mediated by oxytocin/V1aR activation of ERK1/2. The present study demonstrates that oxytocin can activate different signaling pathways to cause vasorelaxation or vasoconstriction. Oxytocin stimulation of PI3K/eNOS-derived nitric oxide may participate in maintenance of cardiovascular homeostasis, and different vascular reactivities to low or high dose of oxytocin suggest that oxytocin may have different regulatory effects on vascular tone under physiological or pathophysiological conditions.

• The Korean Journal of Physiology and Pharmacology
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• 제20권5호
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• pp.441-447
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• 2016

Despite the complex vascular effects of dexmedetomidine (DEX), its actions on human pulmonary resistance arteries remain unknown. The present study tested the hypothesis that DEX inhibits vascular tension in human pulmonary arteries through the endothelial nitric oxide synthase (eNOS) mediated production of nitric oxide (NO). Pulmonary artery segments were obtained from 62 patients who underwent lung resection. The direct effects of DEX on human pulmonary artery tension and changes in vascular tension were determined by isometric force measurements recorded on a myograph. Arterial contractions caused by increasing concentrations of serotonin with DEX in the presence or absence of L-NAME (endothelial nitric oxide synthase inhibitor), yohimbine (${\alpha}_2$-adrenoceptor antagonist) and indomethacin (cyclooxygenase inhibitor) as antagonists were also measured. DEX had no effect on endothelium-intact pulmonary arteries, whereas at concentrations of $10^{-8}{\sim}10^{-6}mol/L$, it elicited contractions in endothelium-denuded pulmonary arteries. DEX (0.3, 1, or $3{\times}10^{-9}mmol/L$) inhibited serotonin-induced contraction in arteries with intact endothelium in a dose-dependent manner. L-NAME and yohimbine abolished DEX-induced inhibition, whereas indomethacin had no effect. No inhibitory effect was observed in endothelium-denuded pulmonary arteries. DEX-induced inhibition of vasoconstriction in human pulmonary arteries is mediated by NO production induced by the activation of endothelial ${\alpha}_2$-adrenoceptor and nitric oxide synthase.

• 동의생리병리학회지
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• 제27권6호
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• pp.809-817
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• 2013

The aim of this study was to evaluate the mechanism of vasodilation of Lespedezea cuneata(LC) in rabbit common carotid artery and cavernosal smooth muscle. LC relaxed arterial strips precontracted with norepinephrine and cavernosal strips precontracted with phenylephrine. The arterial relaxation effects of LC was endothelium-dependent. $N{\omega}$-nitro-L-arginine(L-NNA), NOS inhibitor, methylene blue(MB), cGMP inhibitor, indomethacin(IM), cyclo-oxygenase inhibitor and tetraethylammonium chloride(TEA), KCa-channel blocker attenuate the relaxation responses of LC in arterial strips. In $Ca^{2+}$-free krebs-ringer solution, pretreatment of LC extract significantly reduced the contraction induced by addition $Ca^{2+}$. L-NNA reduced LC extract-induced relaxation in cavernosal strips, but IM, TEA and MB didn't affect LC extract-induced relaxation. When LC extract was applicated on human umbilical vein endothelial cell, the nitric oxide concentration was increased. We conclude that in rabbit common carotid artery, LC may suppress influx of extra-cellular $Ca^{2+}$ through the release of endothelium derived relaxing factor including nitric oxide, prostacyclin, endothelium derived hyperpolarizing factor. And LC exerts a relaxing effect on corpus cavernosum through activating the NO.

• 약학회지
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• 제42권5호
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• pp.519-526
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• 1998

This study was performed in order to investigate the effect of renal function of NG-nitro-L-arginine (L-NOARG), inhibitor of nitric oxide (NO) synthase, in dog and ra bbit. L-NOARG, when given intravenously in dogs, exhibited the decrease in urine flow (vol), renal plasma flow (RPF), osmolar clearance ($C_{osm}$) and amounts of sodium and potassium excreted in urine($E_{Na},\;E_K$). These renal functions of L-NOARG showed the same aspect in rabbit, too. L-NOARG, when administered into a renal artery, showed the same pattern as was obtained when given intravenously in both experimental and control kidney in dog. L-NOARG administered into the carotid artery showed the decrease in Vol, RPF, $E_{Na}$, in a low doses that did not show any effect when given intravenously. Above results suggest that L-NOARG produces antidiuretic action in dog and rabbit, and these antidiuretic actions may be mediated by central action.

• The Korean Journal of Physiology and Pharmacology
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• 제5권1호
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• pp.93-98
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• 2001

The precise mechanism of set-point regulation in hypothalamus was not elucidated. Nitric oxide synthases(NOS) were detected in hypothalamus, however, the roles of NO in hypothalamus was not fully studied. So, we tested the effects of NO on body temperature because preoptic-anterior hypothalamus was known as the presumptive primary fever-producing site. NO donor sodium nitroprusside (SNP, 4 nmol, i.c.v.) elicited marked febrile response, and this febrile response was completely blocked by indomethacin (a cyclooxygenase inhibitor). But, ODQ (selective guanylate cyclase inhibitor, $50\;{\mu}g,$ i.c.v.) did not inhibit fever induced by SNP. The cyclic GMP analogue dibutyryl-cGMP $(100\;{\mu}g,\;i.c.v.)$ induced significant pyreses, which is blocked by indomethacin. $N^G-nitro-L-arginine$ methyl ester (L-NAME, non selective NOS inhibitor) inhibited fever induced by $interleukin-1{\beta}\;(IL-1{\bata},\;10\;ng,\;i.c.v.),$ one of endogenous pyrogens. These results indicate that NO may have an important role, not related to stimulation of soluble guanylate cyclase, in the signal pathway of thermoregulation in hypothalamus.

• 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.141-141
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• 1998

In order to study the effect of nitric oxide on the regulation of mouse cyplal expression, 5' flanking DNA of mouse cytochrome P450 lal was cloned into pGL3 basic vector encoding luciferase gene. pcyplal-Luc was transfected into Hepa I cells and various chemicals were treated. Luciferase activity was stimulated 1000 folds over that of control by TCDD (2,3,7,8-tetrachloro-p-dioxin) treatment and this stimulation was dose dependent. When SNP (sodium nitroprusside) which donates nitric oxide was administrated, this stimulatory effect of TCDD on luciferase activity was decreased. And LPS (lipopolysaccharide) which is an iNOS (inducible nitric oxide synthase) inducer also decreased the stimulatory effect of TCDD on luciferase. And iNOS inhibitor N$\^$G/-nitro-ι-arginine + TCDD treatment increased the stimulation effect of TCDD and this effect was abolished when ι-arginine was added to N$\^$G/-nitro-ι-arginine + TCDD treatment. When N$\^$G/-nitro-ι-arginine was concomitantly administrated with SNP or LPS to confirm the effect of nitric oxide, the inhibitory effect of SNP or LPS was abolished. These data strongly suggest that nitric oxide might be an inhibitory regulator on the cytochrome P450 lal gene expression in Hepa cells.

• Journal of Microbiology and Biotechnology
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• 제17권10호
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• pp.1717-1720
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• 2007

In the course of screening for nitric oxide inhibitors in activated microglial BV-2 cells, cyclo(dehydrohistidyl-L-tryptophyl) was isolated from solid-state fermentation cultures of an unidentified fungal strain, Fb956. Its structure was determined by spectroscopic methods including 2D NMR and chiral TLC analyses. Cyclo(dehydrohistidyl-L-tryptophyl) was found to have an inhibitory activity on nitric oxide production with an $IC_{50}$ of $6.5\;{\mu}M$ in activated BV-2 cells. The structure determination and biological activity of cyclo(dehydrohistidyl-L-tryptophyl) was reported for the first time in this study.

• Archives of Pharmacal Research
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• 제26권4호
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• pp.301-305
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• 2003

Nitric oxide (NO) is an important bioactive agent that mediates a wide variety of physiological and pathophysiological events. NO overproduction by inducible nitric oxide synthase (iNOS) results in severe hypotension and inflammation. This investigation is part of a study to discover new iNOS inhibitors from medicinal plants using a macrophage cell culture system. Two sesquiterpenes (1 and 2) were isolated from Artemisia iwayomogi (Compositae) and were found to inhibit NO synthesis ($IC_{50} 3.64 \mu g/mL and 2.81 \mu$g/mL, respectively) in lipopolysaccharide (LPS)-activated RAW 264.7 cells. Their structures were identified as 3-Ο-methyl-iso-secotanapartholide (1) and iso-secotanapartholide (2). Compounds 1 and 2 inhibited the LPS-induced expression of the iNOS enzyme in the RAW 264.7 cells. The inhibition of NO production via the down regulation of iNOS expression may substantially modulate the inflammatory responses.

• Natural Product Sciences
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• 제16권3호
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• pp.143-147
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• 2010

The chromatographic separation of a methanol extract of Artemisia princes led to the isolation of two sesquiterpene lactones, artecanin (1) and canin (2), together with a flavonoid, eupatilin (3). Their structures were determined by 1D, 2D-NMR and MS data analysis. All of the isolates were evaluated for their potential to inhibit the LPS-induced production of nitric oxide in murine macrophage RAW 264.7 cells. Compounds 1 - 3 inhibited nitric oxide production with $IC_{50}$ values of 19.5, 20.4 and 25.1 ${\mu}M$, respectively.

• Biomolecules & Therapeutics
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• 제7권3호
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• pp.210-215
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• 1999

Nitric oxide (NO) can mediate numerous physiological processes, including vasodilation, neurotransmission, cytotoxicity, secretion and inflammatory response. The regulation of NO production by inducible NO synthase (iNOS) is considered to be the possible target of the development of anti-inflammatory agent, based on the observation that NO can activate cyclooxygenase, which results in the synthesis of prostaglandins. In an effort to screen new inhibitor of NO production from about 352 species of herbal extracts, we found 9 species with 50% or more inhibitory effect on NO production. Especially, the dose-dependent inhibition of NO production in lipopolysaccharide-treated macrophages by two of the herbal extracts (Artemisiae asiaticae Herba and Saussureae Radix) was due to the decrease in the expression of iNOS.