• 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.

• Archives of Pharmacal Research
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• v.24 no.1
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• pp.64-68
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• 2001

Endothelin-1 (ET-1 ), a novel and potent vasoconstrictor in blood vessel, is known to have some functions in the rat central nervous system (CNS), In order to investigate the central functions of ET-1 , ET-1 was administered to the periaqueductal gray area (PAC) of anesthetized rats to induce barrel rolling and increase the arterial blood pressure (ABP). ET-1 had a modulatory effect on central cardiovascular and behavioral control. The selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (3${u}m/ol/kg$, i.p.) blocked the ET-1 induced responses, and both the nitric oxide synthase (NOS) inhibitor L-NAME (N-nitro-L-arginine mIThyl-ester 1 nmol/rat) and the nitric oxide (NO) scavenger hemoglobin (15 nmol/rat) had similar effects in redtAcing the IT-1 (10 pmol/rat)-induced behavioral changes and ABP elevation. However, NO donor sodium nitroprusside (SNP 10${u}g$, 1${u}g/rat$) decreased the ET-1 induced ABP elevation, and recovered the ET-1 -induced barrel rolling effect that was reduced by MK-801. These results suggest that ET-1 might have neuromodulatory functions such as ABP elevation and barrel rolling induction in the PAG of the rats via the NMDA receptor and NO.

• Tuberculosis and Respiratory Diseases
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• v.50 no.3
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• pp.300-309
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• 2001

Background : Sepsis is a clinical syndrome characterized by a systemic inflammatory and hemodynamic response to severe bacterial infections that involve various mediators. Endothelin (ET)-1, a potent vasoconstrictor is associated with mu1tiple organ failure, and interleukin (IL)-8, a proinflammtory cytokine, plays a major role in neurophil activation. Both have been reported to be useful parameters in the clinical assessment of sepsis. The levels of ET-1 and IL-8 in the blood were measured in patients with sepsis, and the correlation of both parameters and their relationship with the clinical data was assessed. Methods : 19 sepsis patients and 17 controls were studied. Blood samples of the sepsis patients were drawn in day 1, 3, 7, and 14. The APACHE III scores were calculated in concurrent days. The ET-1 and IL-8 levels were measured using immunoassay methods. Results : The ET-1 levels of patients with sepsis were significantly higher than in the controls. In patients with sepsis, non-survivors had higher ET-1 levels than survivors on day 1 and 7, and patients with shock also had higher ET-1 levels than normotensive patients on admission. The ET-1 levels were significantly correlated with the creatinine levels on day 1, 7, and 14. The IL-8 levels showed a significant correlation with the ET-1 levels on day 14. Conclusion : ET-1 was found to be closely related with the clinical outcome, shock, and renal failure, and showed a correlation with IL-8. These mediators can be considered not only to play pathophysiologic roles but also as useful parameters in the clinical assessment of sepsis.

• Applied Biological Chemistry
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• v.49 no.4
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• pp.293-297
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• 2006

Angiotensin converting enzyme(ACE) is a zinc-containing dipeptidase widely distributed in mammalian tissues and is thought to play a significant role in blood pressure regulation by hydrolyzing angiotensin I to the potent vasoconstrictor, angiotensin II. Recently, the presence of ACE in pig ovary was reported and the ACE from pig kidney was isolated and characterized. However no nucleotide sequence of the ACE gene from pig is yet known. We report here the cloning of the ACE cDNA from pig kidney by using the reverse transcriptase-polymerase chain reaction. The complete amino acid sequence deduced from the cDNA contains 1309 residues with a molecular mass of 150 kDa, beginning with a signal peptide of 33 amino acids. Amino acid sequence analysis showed that pig kidney ACE is also probably anchored by a short transmembrane domain located near the C-terminus. This protein contains a tandem duplication of the two homologous amino acid peptidase domain. Each of these two domains bears a putative metal-binding site (His-Glu-Met-Gly-His) identified in mammalian somatic ACE. The alignment of pig ACE amino acid sequence with human, rabbit, and mouse reveals that both two domains have been highly conserved during evolution.

• The Journal of Internal Korean Medicine
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• v.26 no.1
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• pp.182-198
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• 2005

Object : This study was designed to research whether the protection and inhibitory effects of cardiovascular diseases in L-NAME induced rat or ECV 304 cell lines through the Cell morphological pattern, Tunel assay, LDH activity, heart rate, blood pressure and immunohistochemistric analysis by Boonsimgieum water extract Methods : Nitric oxide(NO) play an important role in normal and pathophysiological cells including as a messenger molecule, neurotransmitter, microbiocidal agent, or dilator of blood vessels and artheriosclerosis, hypertension, myocardial infarction, respectively. Endothelial cell products can modulate the magnitude of a response to a vasoconstrictor, as evinced by the greater constriction after endothelium removal or NO synthesis blockade. To investigate that Boonsimgieum in the potential contribution of the levels of nitric oxide generated by endothelial nitric oxide synthase (eNOS) and the mechanisms of protection against NG-nitro-L-arginine methyl ester (L-NAME), human ECV 304 cells, which normally do not express eNOS, were expressed by L-NAME. L-NAME stimulated rat or cells were found to be resistant to injury and delayed death following the Boonsimgieum. Inhibition of nitric oxide synthesis abolished the protective effect against L-NAME, thrombin and collagen exposure. Interestingly, such effects have been observed during stimulation with agents such as phenylephrine and KCl on L-NAME mediate rats, were damaged by the NOS inhibitor L-NAME. Result : As the result of this study, In group, the anti-apoptosis and necrosis in the cardiovascular system have a potential capacity for prevented, protected and treating the diseases of cardiovascular system, against the necrosis of rat and ECV 304 cells with Caspase 3 and calpain expression by L-NAME is promoted. Conclusion : these results demonstrate neuroprotective and memory enhancing effects of ZIBU, suggesting its beneficial actions for the treatment of AD.

• Korean Journal of Fisheries and Aquatic Sciences
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• v.26 no.4
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• pp.321-329
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• 1993

The present study was conducted to elucidate the body modulating function of fermented seafood products. Angiotensin converting enzyme (ACE) acts in blood pressure regulation, converting angiotensin I to the potent vasoconstrictor angiotensin II and inactivating the vasodilator bradykinin to raise blood pressure. Salted and fermented anchovy which is one of the traditional fermented seafood in Korea was tested for inhibitory activity against ACE. ACE inhibitory activity of salted anchovy during the period of fermentation was increased with the elapse of fermentation days until fermentation of 60 days, but thereafter decreased inversely. When the fermented product was extracted with $50\%$ ethanol, the ACE inhibitory activity was the highest. And the ACE inhibitory activity was proportion to the content of $50\%$ ethanol soluble peptide-nitrogen of the fermented product. From the profiles of gel permeation chromatography on a Bio-Gel P-2 of $50\%$ ethanol soluble fraction obtained from salted and fermented anchovy fermented for 60 days at an ambient temperature, the higher activity fractions were C'($IC_{50}=97{\mu}g\;protein/ml$) and D'($IC_{50}=65{\mu}g\;protein/ml$). Amino acid analysis showed that the large quantify of threonine, glutamic acid, lysine for C' and serine, proline for D', respectively.

• Tuberculosis and Respiratory Diseases
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• v.45 no.2
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• pp.360-368
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• 1998

Background: Endothelin(ET), a potent vasoconstrictor peptide produced by endothelial cells and degraded predominantly in the pulmonary vasculature, have been implicated in the development of various organ dysfunctions. Plasma concentrations of ET-1 are reported to be elevated in patients with diffuse interstitial lung disease(DILD). But, there is no study to establish the exact source and mechanisms involved in the increased plasma ET-1 concentrations in DILD patients. Methods: 12 patients with IPF, 2 patients with sarcoidosis, 2 patients with scleroderma, 1 patient with SLE and 11 healthy volunteers were studied. ET was detected by radioimmunoassay in plasma and bronchoalveolar lavage fluid(BALF) as well as in 24-hr urine specimens. For each subjects, arterial/venous(A/V) ET ratio and renal ET clearance were calculated. Results: Elevated plasma, urine and BALF ET concentrations were found in patients with DILD compared with controls. But, no significant difference was observed in ET A/V ratio and ET renal clearance between patients with DILD and controls. Conclusion: We observed that plasma ET concentrations were elevated in patients with DILD, and that the main site of ET production may be lung parenchyme.

• Tuberculosis and Respiratory Diseases
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• v.48 no.2
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• pp.210-222
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• 2000

Background: Endothelin(ET) is the most potent vasoconstrictor and bronchoconstrictor. The plasma ET-1 level is elevated in patients with acute pulmonary thromboembolism(APTE). This finding suggest that ET-1 may be an important mediator in the cardiopulmonary derangement of APTE. But whether ET-1 is a pathogenic mediator or a simple marker of APTE is not known. The role of ET-1 in the pathogenesis of cardiopulmonary dysfunction in APTE(delete) was investigated through an evaluation of the effects of $ET_A$-receptor antagonist on APTE. The increase in local levels of preproET-1 mRNA and ET-1 peptide in the embolized lung was also demonstrated. Methods: In a canine autologous blood clot pulmonary embolism model, $ET_A$-receptor antagonist(10 mg/kg intravenously, n=6) was administered one hour after the onset of the embolism. Hemodynamic measurements, blood gas tensions and plasma levels of ET-1 immunoreactivity in this treatment group were compared with those in the control group(n=5). After the experiment., preproET-1 mRNA expression(using Northern blot analysis) and the distribution of ET-1(by immunohistochemical analysis) in the lung tissues were examined. Results: The increases in pulmonary arterial pressure and pulmonary vascular resistance of the treatment group were less than those of the control group. Decrease in cardiac output was also less in the treatment group. Complications such as systemic arterial hypotension and hypoxemia did not occur with the administration of $ET_A$-receptor antagonist The plasma level of ET-1 like(ED: what does 'like' mean?) immunoreactivity was increased after embolization in both groups but was significantly higher in the treatment group. The preproET-1 mRNA and ET-1 peptide expressions were increased in the embolized lung. Conclusion: ET-1 synthesis increases with embolization in the lung and may plays play an important role in the pathophysiology of cardiopulmonary derangement of APTE. Furthermore, $ET_A$-receptor antagonist attenuates cardiopulmonary alterations seen in APTE, suggesting a potential benefit of this therapy.

• Journal of Chest Surgery
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• v.37 no.6
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• pp.504-510
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• 2004

Background: Vasodilatory shock after cardiac surgery may result from the vasopressin deficiency following cardio-pulmonary bypass and sepsis, which did not respond to usual intravenous inotropes. In contrast to the adult patients, the effectiveness of vasopressin for vasodilatory shock in children has not been known well and so we reviewed our experience of vasopressin therapy in the small babies with a cardiac disease. Material and Method: Between February and August 2003, intravenous vasopressin was administrated in 6 patients for vasodilatory shock despite being supported on intravenous inotropes after cardiac surgery. Median age at operation was 25 days old (ranges; 2∼41 days) and median body weight was 2,870 grams (ranges; 900∼3,530 grams). Preoperative diag-noses were complete transposition of the great arteries in 2 patients, hypoplastic left heart syndrome in 1, Fallot type double-outlet right ventricle in 1, aortic coarctation with severe atrioventricular valve regurgitation in 1, and total anomalous pulmonary venous return in 1. Total repair and palliative repair were undertaken in each 3 patient. Result: Most patients showed vasodilatory shock not responding to the inotropes and required the vasopressin therapy within 24 hours after cardiac surgery and its readministration for septic shock. The dosing range for vasopressin was 0.0002∼0.008 unit/kg/minute with a median total time of its administration of 59 hours (ranges; 26∼140 hours). Systolic blood pressure before, 1 hour, and 6 hours after its administration were 42.7$\pm$7.4 mmHg, 53.7$\pm$11.4 mmHg, and 56.3$\pm$13.4 mmHg, respectively, which shows a significant increase in systolic blood pressure (systolic pressure 1hour and 6 hours after the administration compared to before the administration; p=0.042 in all). Inotropic indexes before, 6 hour, and 12 hours after its administration were 32.3$\pm$7.2, 21.0$\pm$8.4, and 21.2$\pm$8.9, respectively, which reveals a significant decrease in inotropic index (inotropic indexes 6 hour and 12 hours after the administration compared to before the administration; p=0.027 in all). Significant metabolic acidosis and decreased urine output related to systemic hypoperfusion were not found after vasopressin admin- istration. Conclusion: In young children suffering from vasodilatory shock not responding to common inotropes despite normal ventricular contractility, intravenous vasopressin reveals to be an effective vasoconstrictor to increase systolic blood pressure and to mitigate the complications related to higher doses of inotropes.

• The Korean Journal of Pharmacology
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• v.24 no.2
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• pp.221-232
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• 1988

Studies were conducted to determine whether reduced renal blood flow (RBF) exhibited by rats with uncontrolled, streptozotocin (STZ)-induced diabetes is attributable to diabetes-associated, enhanced renal vasoconstrictor influence of endogenous thromboxane $(TX)A_2$. Rats which were injected with STZ after pretreatment with 3-O-methyl glucose (3OMG), an agent which prevents STZ-induced hyperglycemia, were also studied. Basal values of total RBF (RBF; ml $min^{-1}$ $gKw^{-1}$; electromagnetic flow probe), systemic arterial pressure (BP; mm Hg) and renal vascular resistance (RVR;BP $RBF^{-1})$in pentobarbital-anesthetized rats during a control period were $5.9{\pm}0.3$(P<0.1_{VS}. CR), $115{\pm}3$ and $20.3{\pm}1.0$(P<0.1_{VS}. CR) for STZR (n=15), and $8.4{\pm}0.4$, $123{\pm}3$ and $15.1{\pm}0.8$ for age-matched control rats (CR; n= 15), respectively. Basal values of RBF, BP and RVR in 3OMG pretreated STZR were identical to CR. In preparations shown capable of renal vasodilatation, OKY 1581 (1 mg/kg, i.v. followed by 0.4 mg/kg min infusion) abolished arachidonate-induced $(TX)A_2$ synthesis, but did not alter basal BP, RBF or RVR in either STZR or CR (n=4/group). Similarly, i.r.a. infusion of SQ29548 (100 ng/ml RBF) abolished renal vasoconstriction induced by a TX/prostaglandin endoperoxide mimic, U46619, but had no discern able affect on RVR in either STZR (n=8) or CR (n=8). The data indicates that $TXA_2$ does not participate in the elevated basal RVR of STZR which are associated with the diabetic state.