BACKGROUND: Monocyte chemoattractant protein- 1 (MCP-1) is an important mediator for monocyte/ macrophage infiltration in various inflammatory renal diseases and is produced by renal cells. In the process of renal diseases, endothelin-1 (ET-1) is known to play an active role in cell growth, inflammation and fibrosis. The aim of this study was to investigate whether three isoforms of endothelin regulate MCP-1 expression in cultured mesangial cells. METHODS: Mesangial cells were incubated with or without various doses of ET-1, ET-2 or ET-3. To determine the monocyte chemotactic activity, chemotaxis assay was performed in modified Boyden chambers using freshly isolated human monocytes. MCP-1 mRNA expression in mesangial cells was measured by Northern blot analysis. RESULTS: ET-1, ET-2 and ET-3 stimulated monocyte chemotactic activity released from mesangial cells in a dose-dependent manner. ET-1, ET-2 and ET-3 also stimulated MCP-1 mRNA expression in a time-dependent manner, which was seen as early as 4 hours and was maintained up to 24 hours. CONCLUSION: These data suggest that ET-1, ET- 2 and ET-3 stimulate MCP-1 expression in mesangial cells and may contribute to the monocyte/ macrophage infiltration in inflammatory renal diseases.
Animals ; Blotting, Northern ; Chemokine CCL2* ; Chemotaxis ; Endothelin-1* ; Endothelin-2* ; Endothelin-3* ; Endothelins ; Fibrosis ; Humans ; Inflammation ; Macrophages ; Mesangial Cells* ; Monocytes* ; Protein Isoforms ; Rats* ; RNA, Messenger

In the freshly isolated rat nephron, the effect of endothelin-1, -2 and -3 (ET-1, -2 and -3) on cytosolic free calcium concentration ((Ca2+)i) was determined using the fluorescent indicator Fura-2/AM. (Ca2+)i increase was investigated in 9 parts of the single nephron including glomerulus (Glm), S1, S2, S3, Cortical and medullary thick ascending limb and cortical (CCT) and outer medullary collecting tubule (OMCT). Endothelins increased (Ca2+)i in Glm (ET-1; 127+/-17%, ET-2; 93+/-5%, ET-3; 169+/-17%), CCT (ET-1; 30+/-6%, ET-2; 38+/- 19%, ET-3; 158+/-18%) and OMCT (ET-1; 197+/- 11%, ET-2; 195+/- 11%, ET-3; 215+ 37%) at 10(-7) M. In OMCT, ET-1 and ET-2 increased (Ca2+)i in a dose-dependent manner (10(-10) ~ 10(-6) M). To the contrary, ET-3-induced (Ca2+)i rise was begun from 10(-12) M. BQ-123Na, an antagonist of ETA receptor, at 10(-4) M inhibited about 30% of (Ca2+)i rise induced by ET-1 and -3. Binding experiments using (125I)ET-3 showed the existence of ETB 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.
Angiotensin II ; Animals ; Calcium* ; Cytosol ; Endothelin-1 ; Endothelin-2 ; Endothelins* ; Extremities ; Nephrons* ; Rats* ; Vasopressins

No abstract available.
Endothelin-1* ; Endothelins*

No abstract available.
Endothelin-1* ; Endothelins*

Endothelin (ET) is a potent vasoconstrictive 21-amino acid peptide hormone released from vascular endothelium The effects of ET-1 on coronary and systemic hemodynamics in comparison with Bay K 8644, a Ca2+ agonist, were studied in halothane-anesthetized dogs. The modification of ET-1 effects by nicardipine, a voltage-dependent Ca2+ antagonist, was also investigated. Single bolus ET-1 (100 ng/ kg) and Bay K 8644 (30 ug) were administered consecutively into left circumflex coronary artery during intracoronary infusion of either 0.9% saline (0.5 ml/kg/h, n=11) or nicardipine (1 ug/kg/min, n=10). Coronary and systemic hemodynamic parameters were measured just prior to (baseline), during saline or nicardipine infusion and 1, 5, 10, 20, 30, 45, and 60 min after ET-1 injection. Also electrocardiographic changes were observed continuously. The results are as follows: 1) Both ET-1 and Ray K 8644 produced a marked and immediate reduction in coronary blood flow and an increase in coronary vascular resistance. 2) ET-1 evoked coronary vasoconstrictions were long-lasting as compared with transient actions of Bay K 8644. 3) ET-1 reduced peak systolic intramyocardial pressure (IMP), mean aortic pressure (MAP), and cardiac index (CI), in contrast Bay K 8644 increased IMP without any changes in MAP and CL 4) Nicardipine (1 ug/kg/min, i.c) produced a significant increase (2-fold) in coronary blood flow and a reduction (46%) in coronary vascular resistance, whereas other hemodynamic parameters remained unchanged. 5) Nicardipine partially attenuated coronary vascular and systemic effects of ET-1, but it completely prevented those of Bay K 8644. 6) ET-1 (100 ng/kg, i.c.) produced a significant ST segment elevation in electrocardiogram in all cases of the saline group, but in none of the nicardipine group. These findings suggest that ET-1 is a potent and long-lasting coronary vasoconstrictor and that its vasoconstrictive effect is mediated in part by promoting Ca2+ influx through a voltage-dependant Ca2+ channel since nicardipine only partially attenuated ET-1 induced cardiovascular effects.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester ; Animals ; Arterial Pressure ; Coronary Vessels ; Dogs* ; Electrocardiography ; Endothelin-1* ; Endothelins ; Endothelium, Vascular ; Hemodynamics* ; Nicardipine* ; Vascular Resistance ; Vasoconstriction

OBJECTIVE: We examined the vasoconstricting poperties of endothelin (ET) on isolated arteries from pregnant as well as non-pregnant uterus. METHODS: Arteries of the uterus were obtained from both hysterectomized uterus and during pregnany hysterectomy for control group and cesarean section for pregnant group. Rings of uterine artery were suspended on muscle chambers at their optimal length for generating tension and contractile properties were examined. RESULTS: ET-1 and ET-2 induced concentration-dependent constriction of both isolated arterial strips from non-pregnant and pregnant uterus. The contraction to ET-1 and ET-2 were more enhanced in full-term pregnancy. Furthermore, in pregnant group, sarafotoxin S6c and IRL 1620, ET. agonists, induced a dose-dependent contraction, which was not shown in those from non-pregnant human. Pretreatment of human uterine arterial strips from pregnant uterus with BQ610, an ET. antagonist, for 10 min resulted in a dose-related rightward shift of ET-1 response curve with diminution of maximal response. Schild plot analysis yielded a pA value of 7.29 with a slope of 0.98. However, BQ788, an ET antagonist, did not produce any rightward shift. The contraction to lower concentration (10-8~3*10-7 M) of sarafotoxin S6c was not affected by BQ788, whereas that to higher concentration (10-s-8*10-7 M) was marked diminished. However, BQ610 did not exnt any efFect on sarafotoxin S6c-induced contraction in arterial staips from pregnant uterus. When the bath solution was replaced with Ca-free physiological salt solution (PSS) containing 1 mM EGTA for 10 min prior to adding sarafotoxin S6c, sarafotoxin S6c-induced contraction was completely abolished. Sarafotoxin S6c (10 nM)-induced contraction was prefetentially blocked by a protein kinase C antagonist, H-7, whereas it was less sensitive to a calmodulin antagonist, calmidazolium, CONCLUSION: Based on above results, we concluded that ET plays an important role in regulating uterine blood flow through the activation of ETa and ETB receptors. Furthermote, ETB receptors may predominantly contribute to the modulation of human uterine circulation in full-term pregnancy.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ; Arteries* ; Baths ; Calmodulin ; Cesarean Section ; Constriction ; Egtazic Acid ; Endothelin-2 ; Endothelins* ; Female ; Humans* ; Hysterectomy ; Pregnancy ; Protein Kinase C ; Receptors, Endothelin ; Uterine Artery ; Uterus*

PURPOSE: The enhanced expression of the cyclooxygenase-2 (COX-2), prostaglandin E2 receptor (EPs) and endothelin-1 (ET-1) axis is known to play a significant role in the development and progression of several malignancies. To date, little work has been done to investigate the relationships between the COX-2, EPs and ET-1 axis in prostate cancer (PC) cells. The aim of this study is to investigate the expression of preproET-1 (PPET-1), ET-1 receptor A (ET(A)R), and endothelin converting enzyme-1 (ECE-1) in the PC cell lines and to evaluate the effects of COX-2 and EPs on the expression of PPET-1, ET(A)R, and ECE-1. MATERIALS AND METHODS: Two PC cell lines, PC-3 and DU-145 cells were used for this study. By performing reverse transcription polymerase chain reaction (RT-PCR), the mRNA expressions of PPET-1, ET(A)R and ECE-1 were detected, and then the mRNA expressions of PPET-1, ET(A)R and ECE-1 were detected after being treating the cells with selective COX-2 inhibitor (NS-398), or EP2 (butaprost) and EP4 (misoprostol), which are both agonist of 10(-10), 10(-8) and 10(-6)M. RESULTS: PPET-1, ET(A)R and ECE-1 mRNA were expressed in both cell lines. After NS-398 treatment, only the PPET-1 mRNA expression was decreased at 4, 8 and 12 hours in the PC-3 cells. EP2 and EP4 agonist induced an increase for the PPET-1, ET(A)R and ECE-1 mRNA expressions, compared with the NS-398 treated group (control), in the PC-3 cells. CONCLUSIONS: ET-1/ET(A)R and ECE-1, whose expressions are increased by EP2 and EP4, may play key roles in the development and progression of PC via COX-2. A combination treatment with selective inhibitors for COX-2, EPs and ET(A)R would be novel approach to prostate cancer therapy.
Axis, Cervical Vertebra* ; Cell Line ; Cyclooxygenase 2* ; Dinoprostone* ; Endothelin-1 ; Endothelins* ; Polymerase Chain Reaction ; Prostate* ; Prostatic Neoplasms* ; Receptors, Prostaglandin E ; Reverse Transcription ; RNA, Messenger

BACKGROUND: Recent studies have documented increased release of endothelin(ET) during acute attack of asthma. The purpose of this study is to observe the link between plasma level and urinary excretion of each and changes during acute exacerbation. METHOD: Plasma and 24 hour urine were collected from sixteen asthmatics during acute exacerbation, twice ; first day of symptomatic exacerbation and two weeks after treatment. Controls were ten healthy normal subjects. All patients were treated with corticosteroid and beta-2 adrenergic agonist on admission. ET was determined by radioimmmunoassay and had 100% cross reactivity with ET-1, 67% with ET-2, 84% with ET-3, and 8% with Big-ET. RESULTS: Plasma ETs were significantly elevated during acute attack of asthma compared with those in remission and controls. However, there was no significant changes in urine ET concentrations or total ET amounts in 24 hour urine during exacerbation upto two weeks. Those levels of urine ET in asthmatics were still higher than controls. ET concentrations in plasma or urine were not correlated with pulmonary functional parameters and hypoxemia. CONCLUSION: The findings suggests that increased plasma ETs are related with exaggerated release during acute asthma. Urinary ET excretion is increased in asthma. However, urine ET changes during exacerbation should be observed in a larger and longer scale.
Adrenergic Agonists ; Anoxia ; Asthma* ; Endothelin-2 ; Endothelins* ; Humans ; Plasma*

Endothelin can affect the contractile properties of cardiacmyocyte, stimulate myocyte growth and myofibrillogenesis, and increase resistance to apoptosis by intracellular signaling pathways. This article briefly reviews the regulative effects of these signaling pathways including protein kinase C, mitogen activated protein kinase, and phosphoinositide 3'-OH kinase/protein kinase B.
Animals ; Endothelin-1 ; physiology ; Endothelins ; physiology ; Humans ; Mitogen-Activated Protein Kinases ; metabolism ; Myocardial Contraction ; drug effects ; Myocytes, Cardiac ; metabolism ; Phosphatidylinositol 3-Kinases ; metabolism ; Protein Kinase C ; metabolism ; Signal Transduction

Endothelin(ET) is known as a family of potent hydrophobic, vasoactive peptide. We investigated the effect according to the concentrations of ET on intraocular pressure(IOP), aqueous outflow facility, pupillary diameter and light reflex and iris vessels. Twenty-four hours after injection of 2.5 microgram and 10 microgram of ET-1 into the anteriorvitreous of rabbit eyes, the IOP was reduced by 69% and 80%, respectively and did not return to the level of prefreatment until at least 14 days and 20 days, respectively. But the decrease of IOP was not due to the increased aqueous outflow. The pupillary diameter of ET-1 treated eyes was 1 to 2mm larger than the pretreatment. The time course of the pupillary effects generally ran paralled with the reduction of IOP. The iridial and conjunctival hyperemia was detectable during the pupillary dilatation. Endothelins are therefore potential participants in the local regulation of IOP, ocular blood vessel tone, and iris smooth muscle tone.
Blood Vessels ; Dilatation ; Endothelin-1* ; Endothelins ; Humans ; Hyperemia ; Intraocular Pressure ; Iris ; Muscle, Smooth ; Reflex