• Journal of Mechanical Science and Technology
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• v.15 no.12
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• pp.1822-1828
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• 2001

The experiment for the sympathetic detonation (Sudo et al., 1951) (Fukuyama et al., 1958) in water was conducted. Composition B (RDX: 64%, TNT: 36%, Detonation velocity: 7900m/s) was used for both donor (the thickness was 50mm, and the diameter was 31mm) and receptor charges. The distance between the donor and the receptor, and the thickness (5, 7.5, 10mm) of the receptor were varied in the experiments. In order to investigate the basic characteristics of the underwater sympathetic detonation of high explosive, the sympathetic detonation phenomena were visualized by a high-speed camera (HADLAND PHOTONICS, IMACON790) in forms of streak and framing photographs. The 200ns/mm streak velocity was 2㎲. Manganin gauges (KYOWA Electronic INSTRUMENTS CO. SKF-21725) were used for the pressure measurements. The gauges were set under the receptor. The pressures during the complete and incomplete explosions were measured.

• The Korean Journal of Physiology and Pharmacology
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• v.4 no.3
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• pp.185-195
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• 2000

Vascular diseases are significant complications of diabetes mellitus (DM), and the endothelial cells may play a pivotal role in the development of vascular disease in DM. Endothelin-1 (ET-1) released from endothelium is a potent vasoconstrictor peptide and circulating level of ET-1 is increased in a variety of disease states. The purpose of this study was to determine the changes of responsiveness to ET-1 in DM, and we experimented on the changes in the ET-1-induced contraction, levels of nitrite and lipid peroxidation, and ET-1 immunoreactivity in aorta from streptozotocin-induced DM rats. DM was induced by single injection of streptozotocin (55 mg/kg, i.p.). The immunoreactive ET-1 levels in endothelial layer of thoracic aorta were much higher in DM rats than control rats. Nitrite in tissue homogenate was decreased and plasma nitrite was increased in DM rats. Malondialdehyde (MDA) was significantly increased in DM rats and cGMP was not significantly different between control and DM rats. ET-1 produced concentration- dependent contractile responses that are significantly attenuated in DM rats compared to controls. In the presence of selective $ET_A$ receptor antagonist BQ610, the maximum contraction was decreased and the concentration ratios for BQ610 yielded $pA_2$ values of 7.3 (slope, 0.65) in control rats, whereas BQ610 had no antagonistic effect on ET-1-induced contraction in DM rats. However, pretreatment with BQ788, an $ET_B$ receptor antagonist, maximum response was decreased and the dose-response curves for ET-1 were shifted to the right in both groups and $pA_2$ values were 7.9 and 7.7 (slope, 1.05 in control and DM rats), respectively. IRL 1620 and sarafotoxin S6c, $ET_B$ agonists, induced relaxation in control rats but not in DM rats. These results indicate that endothelial cell dysfunction and enhanced immunoreactivity of ET-1 have been found in DM rat and ET-1-induced contraction was attenuated in DM rat. These attenuated responses might be at least in part caused by the alteration of $ET_A$ receptor properties (e.g. desensitization), and partly related with an alteration in intracellular mechanism for contraction to ET-1.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.5
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• pp.565-572
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• 1997

In the freshly isolated rat nephron, the effect of endothelin-1, -2 and -3 (ET-1, -2 and -3) on cytosolic free calcium concentration ($[Ca^{2+}]_i$) was determined using the fluorescent indicator Fura-2/AM. $[Ca^{2+}]_i$ increase was investigated in 9 parts of the single nephron including glomerulus (Glm), $S_1,\;S_2,\;S_3$, cortical and medullary thick ascending limb and cortical (CCT) and outer medullary collecting tubule (OMCT). Endothelins increased $[Ca^{2+}]_i$ in Glm (ET-1; $127{\pm}17%$, ET-2; $93{\pm}5%$, ET-3; $169{\pm}17%$), CCT (ET-1; $30{\pm}6%$, ET-2; $38{\pm}19%$, ET-3; $158{\pm}18%$) and OMCT (ET-1; $197{\pm}11%$, ET-2; $195{\pm}11%$, ET-3; $215{\pm}37%$) at 10-7 M. In OMCT, ET-1 and ET-2 increased $[Ca^{2+}]_i$ in a dose-dependent manner ($10^{-10}{\sim}10^{-6}$ M). To the contrary, ET-3-induced $[Ca^{2+}]_i$ rise was begun from $10^{-12}$ M. BQ-123Na, an antagonist of ETA receptor, at $10^{-4}$ M inhibited about 30% of $[Ca^{2+}]_i$ rise induced by ET-1 and -3. Binding experiments using $[^{125}I]ET-3$ showed the existence of $ET_B$ receptor in OMCT. This binding was replaced by ET-1, ET-2 or ET-3 by the almost same degree but not by angiotensin II or vasopressin.

• Biomolecules & Therapeutics
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• v.16 no.4
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• pp.306-311
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• 2008

Although hepatic microcirculatory dysfunction occurs during endotoxemia, the mechanism responsible for this remains unclear. Since Kupffer cells provide signals that regulate hepatic response in inflammation, this study was designed to investigate the role of Kupffer cells in the imbalance in the expression of vasoactive mediators. Endotoxemia was induced by intraperitoneal E. coli endotoxin (LPS, 1 mg/kg body weight). Kupffer cells were inactivated with gadolinium chloride ($GdCl_3$, 7.5 mg/kg body weight, intravenously) 2 days prior to LPS exposure. Liver samples were taken 6 h following LPS exposure for RT-PCR analysis of mRNA for genes of interest: endothelin (ET-1), its receptors $ET_A$ and $ET_B$, inducible nitric oxide synthase (iNOS), heme oxygenase (HO-1), and tumor necrosis factor-$\alpha$ (TNF-$\alpha$). mRNA levels for iNOS and TNF-$\alpha$ were significantly increased 31.8-fold and 26.7-fold in LPS-treated animals, respectively. This increase was markedly attenuated by $GdCl_3$, HO-1 expression significantly increased in LPS-treated animals, with no significant difference between saline and $GdCl_3$ groups. ET-1 was increased by LPS. mRNA levels for $ET_A$ receptor showed no change, whereas $ET_B$ transcripts increased in LPS-treated animals. The increase in $ET_B$ transcripts was potentiated by $GdCl_3$. We conclude that activation of Kupffer cells plays an important role in the imbalanced hepatic vasoregulatory gene expression induced by endotoxin.

• The Korean Journal of Physiology and Pharmacology
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• v.10 no.6
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• pp.343-347
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• 2006

The present study was designed to investigate the effects renin-angiotensin-aldosterone system (RAAS), endothelin (ET) and local natriuretic peptide (NP) system for glomerulopathy induced in the experimental bilateral ureteral obstructive rats. Sprague-Dawley male rats ($200{\sim}220g$ body weight) were bilaterally obstructed by ligation of the proximal ureters for 24 hours. Control rats were treated in the same ways, except that no ligature was made. The glomeruli were isolated from cortex by graded sieve methods, and the mRNA expressions of local renin-angiotensin system (RAS), aldosterone synthase (CYP11B2), endothelin-1 (ET-1) and NP system were determined by real-time polymerase chain reaction. Following the bilateral ureteral obstruction, the mRNA expressions of renin, angiotensin converting enzyme 1 as well as ET-1 were increased, while that of angiotensin converting enzyme 2 was not changed. The expressions of CYP11B2 and angiotensin II receptors were not changed. C-type natriuretic peptide (CNP) expression was increased, while its receptors (natriuretic peptide receptor-B) were not changed. We suggest that the upregulation of local RAS and ET playa role in the progressive glomerular injury, and that the enhanced CNP activity also plays a compensatory role in obstructive uropathy in the glomerulus.

• Tuberculosis and Respiratory Diseases
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• v.50 no.2
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• pp.182-195
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• 2001

Background : Idiopathic pulmonary fibrosis(IPF) is a devastating illness for which there is little effective treatment. The key cytokines currently implicated in the fibrotic process are the transforming growth factor-${\beta}_1$(TGF-${\beta}_1$), tumor necrosis factor-$\alpha$(TNF-$\alpha$), endothelin-1(ET-1) and interferon-$\gamma$(IFN-$\gamma$). The rat model for paraquat-induced pulmonary fibrosis was chosen to investigate the role of ET-1 in this disease. Both ET-1 and TGF-${\beta}_1$ expression in lung lesions were examined using immunohistochemical staining. After $Bosentan^{(R)}$ administration, an orally active ET-$l_A$ and ET-$1_B$ receptor antagonist, the degree of pulmonary fibrosis and ET-1 and TGF-${\beta}_1$ expression were analyzed. Method : Sprague-Dawley rats were divided into three groups, the control group, the fibrosis group, and the fibrosis-$Bosentan^{(R)}$-treated group. The animals were sacrificed periodically at 1, 3, 5, 7, 10, 14 days after administering saline or paraquat. The effects between groups were compared with the results of light microscopy and immunohistochemical staining for ET-1 and TGF-${\beta}_1$. The degree of fibrosis was evaluated by H&E and Masson's trichrome staining, which were graded by a computerized image analyzer. The degree of immunohistochemical staining was categorized by a semi-quantitative analysis method. Results : The lung collagen content had increased in the paraquat instillated animals by day 3, and continued to increase up to day 14. A daily treatment by gavage with $Bosentan^{(R)}$ (100mg/kg) did not prevent the increase in collagen deposition on the lung that was induced by paraquat instillation. There were increased immunohistochemical stains of ET-1 on the exudate, macrophages, vascular endothelial cells and pneumocytes in the paraquat instillated group. Furthermore, TGF-${\beta}_1$ expression was higher on the exudate, macrophages, some inflammatory cells, pneumocytes( type I, and II), vascular endothelium and the respiratory epithelial cells around the fibrotic area. After Bosentan treatment, there were no definite changes in ET-1 and TGF-${\beta}_1$ expression. Conclusion : Fibrosis of the Paraquat instillated group was more advanced when compared with the control group. In addition, there was increased ET-1 and TGF-${\beta}_1$ expression around the fibrotic area. ET-1 is associated with lung fibrosis but there was little effect of the ET-1 receptor blocker($Bosentan^{(R)}$) on antifibrosis.Background : Idiopathic pulmonary fibrosis(IPF) is a devastating illness for which there is little effective treatment. The key cytokines currently implicated in the fibrotic process are the transforming growth factor-${\beta}_1$(TGF-${\beta}_1$), tumor necrosis factor-$\alpha$(TNF-$\alpha$), endothelin-1(ET-1) and interferon-$\gamma$(IFN-$\gamma$). The rat model for paraquat-induced pulmonary fibrosis was chosen to investigate the role of ET-1 in this disease. Both ET-1 and TGF-${\beta}_1$ expression in lung lesions were examined using immunohistochemical staining. After $Bosentan^{(R)}$ administration, an orally active ET-$1_A$ and ET-$1_B$ receptor antagonist, the degree of pulmonary fibrosis and ET-1 and TGF-${\beta}_1$ expression were analyzed. Method : Sprague-Dawley rats were divided into three groups, the control group, the fibrosis group, and the fibrosis-$Bosentan^{(R)}$-treated group. The animals were sacrificed periodically at 1, 3, 5, 7, 10, 14 days after administering saline or paraquat. The effects between groups were compared with the results of light microscopy and immunohistochemical staining for ET-1 and TGF-${\beta}_1$. The degree of fibrosis was evaluated by H&E and Masson's trichrome staining, which were graded by a computerized image analyzer. The degree of immunohistochemical staining was categorized by a semi-quantitative analysis method. Results : The lung collagen content had increased in the paraquat instillated animals by day 3, and continued to increase up to day 14. A daily treatment by gavage with $Bosentan^{(R)}$ (100mg/kg) did not prevent the increase in collagen deposition on the lung that was induced by paraquat instillation. There were increased immunohistochemical stains of ET-1 on the exudate, macrophages, vascular endothelial cells and pneumocytes in the paraquat instillated group. Furthermore, TGF-${\beta}_1$ expression was higher on the exudate, macrophages, some inflammatory cells, pneumocytes( type I, and II), vascular endothelium and the respiratory epithelial cells around the fibrotic area. After Bosentan treatment, there were no definite changes in ET-1 and TGF-${\beta}_1$ expression. Conclusion : Fibrosis of the Paraquat instillated group was more advanced when compared with the control group. In addition, there was increased ET-1 and TGF-${\beta}_1$ expression around the fibrotic area. ET-1 is associated with lung fibrosis but there was little effect of the ET-1 receptor blocker($Bosentan^{(R)}$) on antifibrosis.

• The Journal of Korean Physical Therapy
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• v.20 no.3
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• pp.53-59
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• 2008

Purpose: The non-receptor-type protein tyrosine kinase Syk (636 amino acids, 72 kDa) is ubiquitously expressed in hematopoietic stem cells and has been widely studied as a regulator and effector of B cell receptor signaling that occurs in processes such as differentiation, proliferation and apoptosis. However, the mechanism relating Syk and p38 mitogen-activated protein kinases (p38MAPK) by endothelin-1 (ET-1, 21 amino acids) stimulation in muscle cells, especially in the volume-dependent hypertensive state, remains unclear. Methods: In this study, we investigated the relationship between Syk and p38MAPK for isometric contraction and enzymatic activity by ET-1 from rat aortic smooth muscle cells and aldosterone-analogue deoxycorticosterone acetate (DOCA) hypertensive state rats (ADHR). Results: The systolic blood pressure was significantly increased in ADHR than in a control group of animals. ET-1 induced isometric contraction and phosphorylation of p38MAPK, which was increased in muscle strips from ADHR. Increased vasoconstriction and phosphorylation of p38MAPK induced by treatment with 30 nM ET-1 were inhibited by the use of 10${\mu}M$ SB203580, an inhibitor of p38MAPK from ADHR. Furthermore, ET-1 induced isometric contraction and phosphorylation of Syk and p38MAPK, which were increased in the aortic smooth muscle cells. Increased tension and phosphorylation of Syk and p38MAPK induced by ET-1 were inhibited by SB203580 from rat aortic smooth muscle cells. Conclusion: These results, suggest that the Syk activity affects ET-1-induced contraction through p38MAPK in smooth muscle cells and that the same pathway directly or indirectly is associated with volume dependent hypertension. The findings suggest the need to develop cardiovascular disease-specialized physical therapy.

• Archives of Pharmacal Research
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• v.27 no.1
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• pp.111-117
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• 2004

Hepatic microcirculatory failure is a major component of reperfusion injury in the liver. Recent data provided some evidence that endothelium-derived vasoconstrictors and vasodilators may be functionally important to the control of the total hepatic blood flow under these conditions of circulatory failure. Since Kupffer cells provide signals that regulate the hepatic response in ischemia/reperfusion (I/R), the aim of this study was to investigate the role of Kupffer cells in the I/R-induced imbalance of vasoregulatory gene expression. Rats were subjected to 60 min hepatic ischemia, followed by 5 h of reperfusion. The Kupffer cells were inactivated by gadolinium chloride ($GdCl_3$, 7.5 mg/kg body weight, intravenously) 1 day prior to ischemia. Liver samples were obtained 5 hrs after reperfusion for RT-PCR analysis of the mRNA for genes of interest: endothelin-1 (ET-1), its receptors $ET_A and ET_B$, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1). ET-1 mRNA expression was increased by I/R. mRNA levels for $ET_A$ receptors showed no change, whereas $ET_B$ receptor transcripts increased in the I/R group. The increases in ET-1 and $ET_B$ mRNA were not prevented by the $GdCI_3$ pretreatment. The mRNA levels for iNOS and eNOS significantly increased within the I/R group with no significant difference between the I/R group and the $GdCl_3$-treated I/R group. HO-1 mRNA expression significantly increased in the I/R group and this increase was attenuated by $GdCI_3$. In conclusion, we have demonstrated that an imbalance in hepatic vasoregulatory gene expression occurs during I/R. Our findings suggest that the activation of Kupffer cells is not required for I/R-induced hepatic microvascular dysfunction.

• The Korean Journal of Physiology and Pharmacology
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• v.25 no.2
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• pp.159-166
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• 2021

Nicotinamide adenine dinucleotide phosphate oxidases (NOXs) are the major enzymatic source of reactive oxygen species (ROS). NOX2 and NOX4 are expressed in the heart but its role in hypoxia-induced atrial natriuretic peptide (ANP) secretion is unclear. This study investigated the effect of NOX on ANP secretion induced by hypoxia in isolated beating rat atria. The results showed that hypoxia significantly upregulated NOX4 but not NOX2 expression, which was completely abolished by endothelin-1 (ET-1) type A and B receptor antagonists BQ123 (0.3 μM) and BQ788 (0.3 μM). ET-1-upregulated NOX4 expression was also blocked by antagonists of secreted phospholipase A2 (sPLA2; varespladib, 5.0 μM) and cytosolic PLA2 (cPLA2; CAY10650, 120.0 nM), and ET-1-induced cPLA2 expression was inhibited by varespladib under normoxia. Moreover, hypoxia-increased ANP secretion was evidently attenuated by the NOX4 antagonist GLX351322 (35.0 μM) and inhibitor of ROS N-Acetyl-D-cysteine (NAC, 15.0 mM), and hypoxia-increased production of ROS was blocked by GLX351322. In addition, hypoxia markedly upregulated Src expression, which was blocked by ET receptors, NOX4, and ROS antagonists. ET-1-increased Src expression was also inhibited by NAC under normoxia. Furthermore, hypoxia-activated extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) were completely abolished by Src inhibitor 1 (1.0 μM), and hypoxia-increased GATA4 was inhibited by the ERK1/2 and Akt antagonists PD98059 (10.0 μM) and LY294002 (10.0 μM), respectively. However, hypoxia-induced ANP secretion was substantially inhibited by Src inhibitor. These results indicate that NOX4/Src modulated by ET-1 regulates ANP secretion by activating ERK1/2 and Akt/GATA4 signaling in isolated beating rat hypoxic atria.

• Archives of Pharmacal Research
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• v.27 no.7
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• pp.769-775
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• 2004

Hepatic ischemia and reperfusion (l/R) predisposes the liver to secondary stresses such as endotoxemia, possibly via dysregulation of the hepatic microcirculation secondary to an imbalanced regulation of the vascular stress genes. In this study, the effect of hepatic I/R on the hepatic vasoregulatory gene expression in response to endotoxin was determined. Rats were subjected to 90 min of hepatic ischemia and 6 h of reperfusion. Lipopolysaccharide (LPS, 1 mg/kg) was injected intraperitoneally after reperfusion. Plasma and liver samples were obtained 6 h after reperfusion for serum aminotransferase assays and RT-PCR analysis of the mRNA for the genes of interest： endothelin-1 (ET-1), its receptors $ET_A$ and $ET_B$, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1), cyciooxygenase-2 (COX-2), and tumor necrosis factor-a (TNF-${\alpha}$). The activities of serum aminotransferases were significantly increased in the I/R group. This increase was markedly potentiated by LPS treatment. The ET-1 mRNA was increased by LPS alone, and this increase was significantly greater in both the I/R alone and I/R ＋ LPS groups compared to the sham. There were no significant differences in ETA receptor mRNA levels among any of the experimental groups. $ET_B$ mRNA was increased by both LPS alone and I/R alone, with no significant difference between the I/R alone and I/R ＋ LPS groups. The eN OS and HO-1 transcripts were increased by I/R alone and further increased by I/R ＋ LPS. The iNOS mRNA levels were increased by I/R alone, but increased significantly more by both LPS alone and I/R ＋ LPS compared to I/R alone. The TNF-${\alpha}$ mRNA levels showed no change with I/R alone, but were increased by both LPS alone and I/R ＋ LPS. The COX-2 expression was increased significantly by I/R alone and significantly more by I/R ＋ LPS. Taken collectively, significantly greater induction of the vasodilator genes over the constriction forces was observed with I/R ＋ LPS. These results may partly explain the increased susceptibility of ischemic livers to injury as a result of endotoxemia.