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Masashi Yanagisawa - One of the best experts on this subject based on the ideXlab platform.
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<B>EndothelinB> B Receptor is not required But necessary for finite regulation of ovulation
Life Sciences, 2012Co-Authors: Jongki Cho, Heyyoung Kim, Dong Wook Kang, Masashi YanagisawaAbstract:Aims In the ovary, <B>EndothelinB>s regulate a variety of ovarian functions that include But not limited to folliculogenesis, steroidogenesis, oocyte maturation, ovulation and corpus luteum (CL) function. Two cognate Receptors, EDNRA and EDNRB are constitutively expressed in the ovary, and mediate the regulatory <B>EndothelinB> actions. However, the physiological significance of the presence of the two Receptors that often elicit opposite responses upon activation By an <B>EndothelinB> is yet to Be determined. This study was proposed to test the hypothesis that Both Receptors are present in the ovary to lend an <B>EndothelinB> a finite regulation of ovulation.
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acid regulation of nadc 1 requires a functional <B>EndothelinB> B Receptor
Kidney International, 2010Co-Authors: Liping Liu, Masashi Yanagisawa, Miriam Zacchia, Xuefei Tian, Laxiang Wan, Aiji Sakamoto, Robert J Alpern, Patricia A PreisigAbstract:MetaBolically generated acid is the major physiological stimulus for increasing proximal tuBule citrate reaBsorption, which leads to a decrease in citrate excretion. The activity of the Na-citrate cotransporter, NaDC-1, is increased in vivo By acid ingestion and in vitro By an acidic pH medium. In opossum kidney cells the acid stimulatory effect and the aBility of <B>EndothelinB>-1 (ET-1) to stimulate NaDC-1 activity are Both Blocked By the <B>EndothelinB> B (ETB) Receptor antagonist, BQ788. Acid feeding had no effect on Brush Border memBrane NaDC-1 activity in mice in which ETB Receptor expression was knocked out, whereas a stimulatory effect was found in wild-type mice. Using ETA/ETB chimeric and ETB C-terminal tail truncated constructs, ET-1 stimulation of NaDC-1 required a Receptor C-terminal tail from either ETA or ETB. The ET-1 effect was greatest when either the ETB transmemBrane domain and C-terminal tail were present or the ETB C-terminal tail was linked to the ETA transmemBrane domain. This effect was smaller when the ETB transmemBrane domain was linked to the ETA C-terminal tail. Thus, the acid-activated pathway mediating stimulation of NaDC-1 activity requires a functional ETB Receptor in vivo and in vitro, as does acid stimulation of NHE3 activity. Since increased NaDC-1 and NHE3 activities constitute part of the proximal tuBule adaptation to an acid load, these studies indicate that there are similarities in the signaling pathway mediating these responses.
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vascular <B>EndothelinB> B Receptor system in vivo plays a favoraBle inhiBitory role in vascular remodeling after injury revealed By <B>EndothelinB> B Receptor knockout mice
Circulation, 2002Co-Authors: Nobuyuki Murakoshi, Masashi Yanagisawa, Takashi Ohuchi, Takashi Miyauchi, Yoshihiko Kakinuma, Katsutoshi Goto, Iwao YamaguchiAbstract:Background— Two suBtypes of <B>EndothelinB> (ET) Receptors, ETA and ETB, are distriButed in vascular smooth muscle cells to cause contraction and proliferation. Vascular endothelial cells express only ETB Receptors, which cause NO release. Although ETA Receptor Blockade is reported to Be effective in ameliorating vascular remodeling, there is no report on the long-term effect of ETB Receptor Blockade on vascular remodeling after injury. Methods and Results— ETB Receptor–knockout (KO) mice, which were genetically rescued from lethal intestinal aganglionosis, and wild-type (WT) mice underwent complete ligation of the right common carotid artery, ie, a Blood flow cessation model of vascular remodeling. Fourteen days after ligation, the intimal area, the ratio of intimal to medial areas, and the stenotic ratio in the ligated artery of KO mice were significantly increased compared with those of WT mice. The expression level of ET-1 mRNA in the ligated artery of KO mice was increased similarly to that of WT mice, wh...
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exaggerated hypoxic pulmonary hypertension in <B>EndothelinB> B Receptor deficient rats
American Journal of Physiology-lung Cellular and Molecular Physiology, 2002Co-Authors: Dunbar D Ivy, Masashi Yanagisawa, Cheryl E Gariepy, Sarah A Gebb, Kelley L Colvin, Ivan F McmurtryAbstract:Mechanisms By which <B>EndothelinB> (ET)-1 mediates chronic pulmonary hypertension remain incompletely understood. Although activation of the ET type A (ETA) Receptor causes vasoconstriction, stimulatio...
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<B>EndothelinB> B Receptor deficiency potentiates et 1 and hypoxic pulmonary vasoconstriction
American Journal of Physiology-lung Cellular and Molecular Physiology, 2001Co-Authors: Ivan F Mcmurtry, Masashi Yanagisawa, Cheryl E Gariepy, Sarah A Gebb, Timothy Le D Cras, Kenneth G Morris, Richard C Wiseman, Steven H AbmanAbstract:<B>EndothelinB> (ET)-1 contriButes to the regulation of pulmonary vascular tone By stimulation of the ETA and ETB Receptors. Although activation of the ETA Receptor causes vasoconstriction, stimulation ...
Markus Hecker - One of the best experts on this subject based on the ideXlab platform.
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decoy oligodeoxynucleotide characterization of transcription factors controlling <B>EndothelinB> B Receptor expression in vascular smooth muscle cells
Molecular Pharmacology, 2000Co-Authors: Andreas H Wagner, Marco Cattaruzza, Robert Krzesz, Dingcheng Gao, Christian Schroeder, Markus HeckerAbstract:<B>EndothelinB>-1 is not only a powerful vasoconstrictor But also a potent mitogen for vascular smooth muscle cells (SMC), acting through Both the <B>EndothelinB>-A and <B>EndothelinB>-B Receptor (ET(B)-R). Although vascular SMC are known to express the ET(B)-R, its transcriptional regulation has not Been studied thus far. Here we demonstrate that the potent inhiBitor of nuclear factor kappaB activation, pyrrolidine dithiocarBamate (PDTC; 30-100 microM), induces de novo ET(B)-R expression in rat aortic and mesenteric cultured SMC. Electrophoretic moBility shift analyses revealed that Besides inhiBition of nuclear factor kappaB, PDTC enhances activator protein-1 (AP-1), CCAAT/enhancer-Binding protein (C/EBP), and GATA-2 activity in these cells. PreincuBation of PDTC-stimulated cells with appropriate decoy oligodeoxynucleotides confirmed the involvement of these three transcription factors, namely that of AP-1, in ET(B)-R expression. The stimulatory effect of PDTC on ET(B)-R expression was also confirmed functionally By monitoring an enhanced ET-1-induced apoptosis in PDTC-treated cells that was sensitive to the ET(B)-R antagonist, BQ788. Taken together, these findings demonstrate that C/EBP, GATA-2, and in particular AP-1 can control ET(B)-R expression in vascular SMC. They further support the notion that ET(B)-R expression in these cells may play an important role in cardiovascular complications, such as restenosis following angioplasty that in the early phase is characterized By prominent SMC apoptosis.
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stretch induced <B>EndothelinB> B Receptor mediated apoptosis in vascular smooth muscle cells
The FASEB Journal, 2000Co-Authors: Marco Cattaruzza, Hannelore Ehrenreich, Caroline Dimigen, Markus HeckerAbstract:Growing evidence suggests that a pressure-induced increase in the synthesis of <B>EndothelinB> (ET-1) is involved in arterial remodeling and, as a consequence, in the manifestation of chronic hypertension. To study potential stretch-induced changes in gene expression and their functional consequences, we have cultured rat aortic smooth muscle cells (raSMC) and porcine aortic endothelial cells (PAEC) on flexiBle elastomer memBranes. The cells were periodically stretched (up to 20% elongation, 0.5 Hz, 6 h) and the expression of prepro-ET-1 and that of the <B>EndothelinB> A and B Receptors (ETA-R and ETB-R) were analyzed By semi-quantitative RT-PCR analysis and ELISA (ET-1). In contrast to PAEC where ET-1 synthesis was up-regulated up to eightfold on exposure to cyclic stretch, ET-1 synthesis in raSMC was decreased By more than 80% under these conditions. ETA R -mRNA expression in stretched raSMC declined to 50% whereas ETB R -mRNA levels were increased up to 10-fold. One functional consequence of this apparent shift ...
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pressure induced upregulation of prepro<B>EndothelinB> 1 and <B>EndothelinB> B Receptor expression in raBBit jugular vein in situ implications for vein graft failure
Arteriosclerosis Thrombosis and Vascular Biology, 2000Co-Authors: Manfred Lauth, Marco Cattaruzza, Marcmoritz Berger, Markus HeckerAbstract:ABstract —Upregulation of <B>EndothelinB>-1 (ET-1) synthesis in venous Bypass grafts in response to arterial levels of Blood pressure may play a major role in graft failure. To investigate this hypothesis, isolated segments of the raBBit jugular vein were perfused at physiological (0 to 5 mm Hg) and nonphysiological (20 mm Hg) levels of intraluminal pressure. As judged By reverse transcription–polymerase chain reaction analysis (mRNA level), neither <B>EndothelinB>-converting enzyme nor <B>EndothelinB> A Receptor expression appeared to Be pressure sensitive. In contrast, there was a profound and time-dependent increase in endothelial prepro-ET-1 mRNA and intravascular ET-1 aBundance (By ELISA) as well as in smooth muscle <B>EndothelinB> B Receptor mRNA and functional protein (By superfusion Bioassay) on raising the perfusion pressure from 5 to 20 mm Hg, But not from 0 to 5 mm Hg, for up to 12 hours. Video microscopy analysis revealed that the segments were distended By 75% at 5 mm Hg and near maximally at 20 mm Hg compared with the resting diameter at 0 to 1 mm Hg. Treatment of the segments with actinomycin D (1 μmol/L), the specific protein kinase C inhiBitor, Ro 31–8220 (0.1 μmol/L), or the c-Src family–specific tyrosine kinase inhiBitor, herBimycin A (0.1 μmol/L), demonstrated that the pressure-induced expression of these gene products occurs at the level of transcription and requires activation of protein kinase C, But not c-Src. In venous Bypass grafts such deformation-induced changes in gene expression may contriBute not only to acute graft failure through ET-1–induced vasospasm But also to <B>EndothelinB> A Receptor– and/or <B>EndothelinB> B Receptor–mediated smooth muscle cell hyperplasia and graft occlusion.
Anil Gulati - One of the best experts on this subject based on the ideXlab platform.
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selective <B>EndothelinB> B Receptor stimulation increases vascular endothelial growth factor in the rat Brain during postnatal development
Drug Research, 2015Co-Authors: Mary G Leonard, Preetha Prazad, Bhagya L Puppala, Anil GulatiAbstract:<B>EndothelinB>, vascular endothelial growth factor and nerve growth factor play important roles in development of the central nervous system. ET(B) Receptors have Been shown to promote neurovascular remodeling in the adult ischemic Brain through an increase in VEGF and NGF. It is possiBle that ET(B) Receptors may Be involved in postnatal development of the Brain through VEGF and NGF. In the present study, the Brains of male rat pups on postnatal days 1, 7, 14 and 28 were analyzed for expression of ET(B) Receptors, VEGF and NGF. In order to determine the effect of ET(B) Receptor stimulation, a separate group of pups were administered saline or ET(B) Receptor agonist, IRL-1620, on day 21, and their Brains were analyzed on day 28. The intensity of ET(B) Receptor and VEGF staining in the vasculature as well as the numBer of Blood vessels of normal pups increased with age and was significantly higher on postnatal day 14 compared to day 1 and day 7. In contrast, Both ET(B) and NGF staining intensity in the cortex and suBventricular zones decreased (P<0.01) at postnatal day 14 compared to earlier time points. Stimulation of ET(B) Receptors resulted in a significant increase in VEGF and ET(B) intensity Both in the vasculature and the Brain (P<0.05), however, IRL-1620 did not produce any change in NGF expression. Results indicate that ET(B) Receptors appear to play a role in the development of the CNS and selective stimulation of ET(B) Receptors enhances VEGF But not NGF in the postnatal rat Brain.
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<B>EndothelinB> B Receptor agonist irl 1620 enhances angiogenesis and neurogenesis following cereBral ischemia in rats
Brain Research, 2013Co-Authors: Mary G Leonard, Anil GulatiAbstract:<B>EndothelinB> B Receptor agonist, IRL-1620, has Been shown in previous studies, conducted in our laB, to provide significant neuroprotection at Both 24h and 1 week following permanent cereBral ischemia. It is possiBle that IRL-1620 may Be neuroprotective due to angiogenesis and neurogenesis. However, the effect of IRL-1620 on neurovascular remodeling following cereBral ischemia has not Been estaBlished. The present study was conducted to determine the effect of IRL-1620 [Suc-[Glu9,Ala11,15]-<B>EndothelinB>-1(8-12)] on astrocytes, neurons, and vascular endothelial cells after induction of cereBral ischemia. Male Sprague-Dawley rats undergoing permanent middle cereBral artery occlusion (MCAO) received three intravenous injections of either vehicle or IRL-1620 at 2, 4, and 6h post occlusion. At 24h post occlusion, IRL-1620 treatment preserved neuronal numBers in the cortex, striatum and suBventricular zone (SVZ) of the ischemic rat Brain, while simultaneously enhancing the numBer of Blood vessels laBeled with vascular endothelial growth factor (VEGF) compared to vehicle treatment. By 1 week following MCAO, VEGF-positive vessels/30 µm Brain slice in the IRL-1620 group numBered 11.33±2.13 versus 4.19±0.79 in the vehicle group (P<0.01). Additionally, animals receiving IRL-1620 displayed increased numBer of proliferating cells (P<0.0001) and cells positively staining for nerve growth factor (NGF; P<0.0001) in the infarcted Brain. VEGF and NGF protein expression significantly increased at 1 week post MCAO in the infarcted hemisphere of IRL-1620 treated rats as compared to sham (P<0.01). Pretreatment with BQ788 Blocked the effects of IRL-1620, thus confirming the role of ETB Receptors in the neurovascular remodeling actions of IRL-1620. Results of the present study indicate that IRL-1620, administered on the day of infarct, is neuroprotective and enhances angiogenic and neurogenic remodeling following cereBral ischemia.
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<B>EndothelinB> B Receptor agonist irl 1620 provides long term neuroprotection in cereBral ischemia in rats
Brain Research, 2012Co-Authors: Mary G Leonard, Seema Briyal, Anil GulatiAbstract:ABstract We have earlier shown that stimulation of <B>EndothelinB> B Receptors By IRL-1620 provides significant neuroprotection at 24 h following cereBral ischemia. However, the effect of IRL-1620 is not known in the suBacute phase of cereBral ischemia, where development of cereBral edema further contriButes towards Brain damage. This study was designed to determine the effect of IRL-1620 on neurological functions, infarct volume, oxidative stress, and <B>EndothelinB> Receptors following permanent middle cereBral artery occlusion for 7 days. Rats received three intravenous injections of either vehicle or IRL-1620 [Suc-[Glu9,Ala11,15]-<B>EndothelinB>-1(8–12)] at 2, 4, and 6 h post occlusion. Treatment with IRL-1620 reduced infarct volume (54.06 ± 14.12 mm 3 vs. 177.06 ± 13.21 mm 3 ), prevented cereBral edema and significantly improved all neurological and motor function parameters when compared to the vehicle-treated group. Vehicle-treated middle cereBral artery occluded rats demonstrated high levels of malondialdehyde and low levels of reduced glutathione and superoxide dismutase; these effects were reversed in IRL-1620 treated rats. No change in expression of <B>EndothelinB> A Receptor was oBserved 7 days after induction of cereBral ischemia in vehicle or IRL-1620 treated rats. Rats receiving IRL-1620 demonstrated an upregulation of <B>EndothelinB> B Receptor only in the infarcted hemisphere 7 days following occlusion. All effects of IRL-1620 were Blocked By <B>EndothelinB> B Receptor antagonist, BQ788. Results of the present study demonstrate that IRL-1620, administered on day 1, provides significant neuroprotection till 7 days after the induction of cereBral ischemia in rats. Selective <B>EndothelinB> B Receptor activation may prove to Be a novel therapeutic target in the treatment of cereBral ischemia.
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<B>EndothelinB> B Receptor agonist, IRL 1620, enhances the anti-tumor efficacy of paclitaxel in Breast tumor rats
Breast Cancer Research and Treatment, 2005Co-Authors: N.v. Rajeshkumar, Anil GulatiAbstract:Pharmacological agents that increase tumor Blood flow could Be utilized to promote the delivery of anti-cancer drugs. We have demonstrated that administration of <B>EndothelinB>-1 (ET-1) to Breast tumor Bearing rats transiently increased tumor Blood flow By stimulating <B>EndothelinB> B (ET_B) Receptors. The present study evaluated the effect of ET_B Receptor agonist, IRL 1620, on Breast tumor perfusion, concentration of [^3H]paclitaxel in tumor and tissues, and efficacy of paclitaxel in N -methyl nitrosourea induced Breast tumor Bearing rats. Administration of IRL 1620 (3 and 9 nmol/kg) significantly increased (203 and 140%, respectively) Breast tumor perfusion. BQ 788, an ET_B Receptor antagonist, pretreatment completely aBolished IRL 1620 induced increase in tumor perfusion. Tumor [^3H]paclitaxel concentration was increased By 308% when [^3H]paclitaxel was administered 15 min after IRL 1620 (3 nmol/kg) compared to vehicle treated rats. However, IRL 1620 did not increase [^3H]paclitaxel concentrations in other organs. Efficacy study showed that paclitaxel (5 mg/kg) administration on every third day for a total of five doses produced 60.0, 4.5 and 0% reduction in tumor volume, tumor progression and complete tumor remission, respectively, compared to saline treated rats. However, paclitaxel (5 mg/kg) when administered 15 min after IRL 1620 (3 nmol/kg) produced 268.9, 210.3 and 20% reduction in tumor volume, tumor progression and complete remission of tumors, respectively, compared to saline treated rats. In conclusion, IRL 1620 significantly enhanced delivery and effectiveness of paclitaxel in an animal model of Breast cancer.
David J. Webb - One of the best experts on this subject based on the ideXlab platform.
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collecting duct specific knockout of the <B>EndothelinB> B Receptor causes hypertension and sodium retention
American Journal of Physiology-renal Physiology, 2006Co-Authors: Alan Bagnall, David J. Webb, Peter K Stricklett, Kevin A Strait, Yuri Kotelevtsev, Donald E KohanAbstract:Collecting duct (CD)-derived <B>EndothelinB>-1 (ET-1) inhiBits renal Na reaBsorption and its deficiency increases Blood pressure (BP). The role of CD <B>EndothelinB> B (ETB) Receptors in mediating these effects is unknown. CD-specific knockout of the ETB Receptor was achieved using an aquaporin-2 promoter-Cre recomBinase transgene and the loxP-flanked ETB Receptor gene (CD ETB KO). Systolic BP in mice with CD-specific knockout of the ETB Receptor, ETA Receptor (CD ETA KO) and ET-1 (CD ET-1 KO), and their respective controls were compared during normal- and high-salt diet. On a normal-sodium diet, CD ETB KO mice had elevated BP, which increased further during high salt feeding. However, the degree of hypertension in CD ETB KO mice and the further increase in BP during salt feeding were lower than that of CD ET-1 KO mice, whereas CD ETA KO mice were normotensive. CD ETB KO mice had impaired sodium excretion following acute sodium loading. Aldosterone and plasma renin activity were decreased in CD ETB KO mice on normal- and high-sodium diets, while plasma and urinary ET-1 levels did not differ from controls. In conclusion, the CD ETB Receptor partially mediates the antihypertensive and natriuretic effects of ET-1. CD ETA and ETB Receptors do not fully account for the antihypertensive and natriuretic effects of CD-derived ET-1, suggesting paracrine effects of this peptide.
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Selective <B>EndothelinB> B Receptor Blockade does not influence BNP-induced natriuresis in man
Kidney International, 2006Co-Authors: Kim Van Der Zander, Bas L.j.h. Kietselaer, Leonard Hofstra, Alexander J. P. Houben, David J. Webb, P. W. De LeeuwAbstract:Brain natriuretic peptide (BNP) and <B>EndothelinB>-1 (ET-1) Both exhiBit natriuretic activity within the human kidney. Furthermore, they Both act partly through activation of the endothelial nitric oxide pathway. Since ET-1 may cause vasodilation and natriuresis via stimulation of the ET-B Receptor, the aim of the present study was to investigate whether renal ET-B Receptors participate in the renal actions of BNP. In this placeBo-controlled, crossover study, we infused BNP (4 pmol/kg/min) or placeBo (i.v.) for 1 h, with or without co-infusion of the ET-B Receptor antagonist BQ-788 (50 nmol/min) for 15 min on 4 separate days, in 10 healthy suBjects (mean age 54±6 years.). During infusion, we measured effective renal plasma flow (ERPF), and glomerular filtration rate (GFR) using PAH/inulin clearance. Cardiac output was measured Before and after infusion, using echocardiography. Blood pressure and heart rate (HR) were monitored as well. Urine and plasma samples were taken every hour to measure diuresis, natriuresis, cyclic 3′,5′ guanosine monophosphate, and ET-1 levels. BNP with or without ET-B Receptor Blockade increased natriuresis and diuresis. In addition, BNP alone increased GFR and filtered load, without changing ERPF. BQ-788 infusion did not affect renal hemodynamics or natriuresis. Neither BNP nor BQ-788 altered cardiac output, Blood pressure, and heart rate. In conclusion, the present study shows that selective ET-B Receptor Blockade has no effect on the BNP-induced natriuresis and glomerular filtration rate.
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Systemic Blockade of the <B>EndothelinB>-B Receptor Increases Peripheral Vascular Resistance in Healthy Men
Hypertension, 1999Co-Authors: Fiona E. Strachan, Ian B Wilkinson, James C Spratt, Neil R. Johnston, Gillian A. Gray, David J. WebbAbstract:ABstract —<B>EndothelinB>-1 (ET-1) is an important mediator of vascular tone in humans, and a numBer of <B>EndothelinB> Receptor antagonists are currently in clinical development as vasodilator agents. While the vasoconstrictor role of the ETA Receptor is undisputed, the role of the ETB Receptor remains unclear. Hemodynamic effects of systemic doses of the ETB-selective antagonist BQ-788 were investigated in 5 healthy male volunteers (age range, 33 to 48 years) in a placeBo-controlled, four-way crossover study. After a 15-minute infusion of BQ-788 (3, 30, or 300 nmol/min) or placeBo, plasma ET-1 and Big ET-1, Blood pressure, heart rate, cardiac index, and stroke index were measured. Total peripheral vascular resistance was calculated from cardiac index and mean arterial pressure. Hemodynamic data are expressed as maximum, placeBo-corrected, percentage change from Baseline following BQ-788 (300 nmol/min) and were examined By ANOVA. Plasma ET-1 increased By 3.7±1.2 pg/mL (maximum at 15 minutes, P =0.02), whereas there was no significant change in plasma Big ET-1. Although BQ-788 had no effect on mean arterial pressure, there was a reduction in heart rate (13±7% at 50 minutes; P =0.002), cardiac index (17±5% at 40 minutes; P
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systemic Blockade of the <B>EndothelinB> B Receptor increases peripheral vascular resistance in healthy men
Hypertension, 1999Co-Authors: Fiona E. Strachan, Ian B Wilkinson, James C Spratt, Neil R. Johnston, Gillian A. Gray, David J. WebbAbstract:ABstract —<B>EndothelinB>-1 (ET-1) is an important mediator of vascular tone in humans, and a numBer of <B>EndothelinB> Receptor antagonists are currently in clinical development as vasodilator agents. While the vasoconstrictor role of the ETA Receptor is undisputed, the role of the ETB Receptor remains unclear. Hemodynamic effects of systemic doses of the ETB-selective antagonist BQ-788 were investigated in 5 healthy male volunteers (age range, 33 to 48 years) in a placeBo-controlled, four-way crossover study. After a 15-minute infusion of BQ-788 (3, 30, or 300 nmol/min) or placeBo, plasma ET-1 and Big ET-1, Blood pressure, heart rate, cardiac index, and stroke index were measured. Total peripheral vascular resistance was calculated from cardiac index and mean arterial pressure. Hemodynamic data are expressed as maximum, placeBo-corrected, percentage change from Baseline following BQ-788 (300 nmol/min) and were examined By ANOVA. Plasma ET-1 increased By 3.7±1.2 pg/mL (maximum at 15 minutes, P =0.02), whereas there was no significant change in plasma Big ET-1. Although BQ-788 had no effect on mean arterial pressure, there was a reduction in heart rate (13±7% at 50 minutes; P =0.002), cardiac index (17±5% at 40 minutes; P <0.0001), and stroke index (8±4% at 40 minutes; P =0.002) and an increase in total peripheral vascular resistance (24±5% at 40 minutes; P <0.0001). The selective ETB Receptor antagonist BQ-788 causes peripheral vasoconstriction in healthy volunteers, suggesting that the overall Balance of effects of endogenous ET-1 at the vascular ETB Receptor favors vasodilatation. Further investigation is now clearly required to address whether selective ETA or comBined ETA/ETB Receptor Blockade will Be more effective in the clinical setting.
Jasper Rine - One of the best experts on this subject based on the ideXlab platform.
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Exclusion of EDNRB and KIT as the Basis for white spotting in Border Collies
Genome Biology, 2000Co-Authors: Danika Metallinos, Jasper RineAbstract:Background White spotting patterns in mammals can Be caused By mutations in the genes for the <B>EndothelinB> B Receptor and c-Kit, whose protein products are necessary for proper migration, differentiation or survival of the melanoBlast population of cells. Although there are many different dog Breeds that segregate white spotting patterns, no genes have Been identified that are linked to these phenotypes. Results An intercross was generated from a female Newfoundland and a male Border Collie and the white spotting phenotypes of the intercross progeny were evaluated By measuring percentage surface area of white in the puppies. The Border Collie markings segregated as a simple autosomal recessive (7/25 intercross progeny had the phenotype). Two candidate genes, for the <B>EndothelinB> B Receptor ( EDNRB ) and c-Kit ( KIT ), were evaluated for segregation with the white spotting pattern. Polymorphisms Between the Border Collie and Newfoundland were identified for EDNRB using Southern analysis after a portion of the canine gene had Been cloned. Polymorphisms for KIT were identified using a microsatellite developed from a Bacterial artificial chromosome containing the canine gene. Conclusions Both EDNRB and KIT were excluded as a cause of the white spotting pattern in at least two of the intercross progeny. Although these genes have Been implicated in white spotting in other mammals, including horses, pigs, cows, mice and rats, they do not appear to Be responsiBle for the white spotting pattern found in the Border Collie Breed of dog.
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a missense mutation in the <B>EndothelinB> B Receptor gene is associated with lethal white foal syndrome an equine version of hirschsprung disease
Mammalian Genome, 1998Co-Authors: D L Metallinos, A T Bowling, Jasper RineAbstract:Lethal White Foal Syndrome is a disease associated with horse Breeds that register white coat spotting patterns. Breedings Between particular spotted horses, generally descriBed as frame overo, produce some foals that, in contrast to their parents, are all white or nearly all white and die shortly after Birth of severe intestinal Blockage. These foals have aganglionosis characterized By a lack of suBmucosal and myenteric ganglia from the distal small intestine to the large intestine, similar to human Hirschsprung Disease. Some sporadic and familial cases of Hirschsprung Disease are due to mutations in the <B>EndothelinB> B Receptor gene (EDNRB). In this study, we investigate the role of EDNRB in Lethal White Foal Syndrome. A cDNA for the wild-type horse <B>EndothelinB>-B Receptor gene was cloned and sequenced. In three unrelated lethal white foals, the EDNRB gene contained a 2-Bp nucleotide change leading to a missense mutation (I118K) in the first transmemBrane domain of the Receptor, a highly conserved region of this protein among different species. Seven additional unrelated lethal white foal samples were found to Be homozygous for this mutation. No other homozygotes were identified in 138 samples analyzed, suggesting that homozygosity was restricted to lethal white foals. All (40/40) horses with the frame overo pattern (a distinct coat color pattern that is a suBset of overo horses) that were tested were heterozygous for this allele, defining a heterozygous coat color phenotype for this mutation. Horses with toBiano markings included some carriers, indicating that toBiano is epistatic to frame overo. In addition, horses were identified that were carriers But had no recognized overo coat pattern phenotype, demonstrating the variaBle penetrance of the mutation. The test for this mutant allele can Be utilized in all Breeds where heterozygous animals may Be unknowingly Bred to each other including the Paint Horse, Pinto horse, Quarter Horse, Miniature Horse, and ThoroughBred.