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21. |
Characterization of Angiotensin II Receptor Subtpes in Rat Heart |
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Circulation Research,
Volume 71,
Issue 6,
1992,
Page 1482-1489
Leonardo Sechi,
Chandi Griffin,
Eileen Grady,
Judith Kalinyak,
Morris Schambelan,
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摘要:
Angiotensin II exerts positive inotropic and chronotropic effects on the mammalian heart by binding to specific membrane receptors. Recently, two subtypes of angiotensin II receptors (AT1and AT2) have been distinguished by using the nonpeptide antagonists losartan (previously known as DuP 753) and PD123177. To evaluate the tissue distribution and subtypes of angiotensin II receptors in rat heart, we performed a125I-[Sar1,Ile8] angiotensin II in situ binding assay on tissue sections obtained from adult Sprague-Dawley rats (10 and 14 weeks old). Binding specificity was verified by competition with unlabeled [Sar1] angiotensin II. Distribution of AT1and AT2receptors was determined by competition with losartan and PD123177, respectively, and the density of the receptors was quantified by emulsion autoradiography. Angiotensin II receptors were widely distributed throughout the heart, with each receptor subtype accounting for approximately 50% of the specific binding. Binding density was comparable in the atria, right and left ventricles, intraventricular septum, and sinoatrial node, whereas it was significantly greater in the atrioventricular node. The AT1receptor appears to interact with guanidine nucleotide regulatory proteins, because GTP-γ-S causes dissociation of the radioligand from this receptor. In contrast, the AT2receptor does not appear to directly interact with guanine nucleotide regulatory proteins, inasmuch as radioligand dissociation from this receptor subtype is not affected by GTP-γ-S. Because angiotensin II has been reported to have growth-potentiating effects in several tissues, we examined angiotensin II receptors in fetal (embryonic days 16 and 19) and neonatal (1-, 2-, 3-, and 10-day-old) rats. A twofold increase in the density of both receptor subtypes was found immediately after birth, reaching a maximum on day 2 and decreasing toward prenatal values thereafter. Thus, in rat heart, AT1and AT2receptors are equally distributed over the myocardium. The density of these angiotensin II receptors is developmentally regulated.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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22. |
Coronary Collateral Development in Swine After Coronary Artery Occlusion |
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Circulation Research,
Volume 71,
Issue 6,
1992,
Page 1490-1500
F. White,
S. Carroll,
A. Magnet,
C. Bloor,
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摘要:
We have quantified the development of the coronary collateral circulation in the pig. The collateral circulation was induced to grow by placing an ameroid occluder on the left circumflex coronary artery. Two to 16 weeks after ameroid placement, the coronary collateral circulation was identified after the injection of several colors of a silicone polymer into the coronary arteries and the aorta. We identified intercoronary and extracardiac collaterals and quantified their number, location, size, and wall thickness. Intercoronary collaterals grew to a level that represents a 14-fold increase in normal collateral blood flow under resting conditions compared with the values in an animal not subjected to coronary artery occlusion. Extracardiac collaterals could potentially supply approximately 30% of resting flow. The sources of the extracardiac collaterals were the bronchial and internal mammary arteries. Coronary collateral morphometry and DNA synthesis in the pig heart also were examined. Coronary collaterals had significantly less smooth muscle than did normal arterioles. This may account, in part, for the reduced response of the coronary collaterals to vasodilators. We observed intense DNA synthesis in endothelial and smooth muscle cells in the first 2 or 3 weeks of ischemia. However, DNA synthesis rapidly ceased after this time, coincident with coronary collateral reserve values (ischemic/nonischemic regional blood flow ratios during maximal vasodilation) reaching their maximum level. This suggests that failure of the vessels to continue proliferating accounts for the occurrence of the plateau in blood flow levels.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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23. |
Effect of Inhibition of Endopeptidase 24.11 on Responses to Angiotensin II in Human Volunteers |
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Circulation Research,
Volume 71,
Issue 6,
1992,
Page 1501-1507
A. Richards,
Gary Wittert,
Eric Espiner,
Timothy Yandle,
Hamid Ikram,
Chris Frampton,
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摘要:
The effects of endopeptidase 24.11 inhibition on angiotensin-induced changes in plasma angiotensin II, aldosterone, and atrial natriuretic factor concentrations and blood pressure were assessed in normal volunteers. Two groups, each consisting of eight normal volunteers, received stepwise infusions of angiotensin II (2, 4, and 8 ng/kg per minute) on day 5 of dose administration with 25 mg every 12 hours (group 1) or 100 mg every 12 hours (group 2) of an oral inhibitor of endopeptidase 24.11 (UK 79300, candoxatril) or placebo in balanced randomized, double-blind, placebo-controlled crossover studies. Both doses of candoxatril significantly enhanced achieved plasma angiotensin II concentrations during infusions (group 1,p<0.001; group 2,p<0.01; overall treatment effect for combined data,p<0.001). This effect was most pronounced at the highest dose of angiotensin II (treatment-time interaction, p< 0.0001 for combined data) and tended to be more marked with the higher dose of candoxatril (treatment-group interaction, p=0.08). The pressor response to angiotensin II was clearly enhanced by the lower dose of candoxatril; peak systolic and diastolic pressures exceeded placebo values by approximately 10 mm Hg (p<0.001 and p<0.05 for systolic and diastolic pressures, respectively). This effect of candoxatril was absent in group 2, which (unlike group 1) had exhibited a modest natriuretic response (sustained cumulative negative sodium balance, −70±21 mmol; p<0.01) to the higher dose of inhibitor. Baseline plasma aldosterone concentrations and the incremental aldosterone response to angiotensin II infusions were not significantly altered by low-dose (group 1) candoxatril. Basal aldosterone levels were slightly enhanced by the higher dose of inhibitor (p<0.05), but the incremental response to angiotensin II infusions was unchanged. Pretreatment with candoxatril caused plasma atrial natriuretic factor to rise above baseline values during angiotensin infusions (p<0.001, combined data). Inhibition of endopeptidase 24.11 significantly reduced clearance of infused angiotensin II in association with an enhanced pressor response to exogenous angiotensin when the inhibitor was given in doses below natriuresis. For cases in which a sufficient inhibitor was administered to elicit natriuresis, pressor responses did not change despite augmented plasma angiotensin II. These data carry implications for the potential therapeutic use of endopeptidase inhibitors in high and low renin states.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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24. |
Optimization of Retroviral Vector‐Mediated Gene Transfer Into Endothelial Cells In Vitro |
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Circulation Research,
Volume 71,
Issue 6,
1992,
Page 1508-1517
Mark Kahn,
Sung Lee,
David Dichek,
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摘要:
Retroviral vector-mediated gene transfer into endothelial cells is relatively inefficient with transduction rates as low as 1–2% in vitro and even lower in vivo. To increase the efficiency of gene transfer into endothelial cells, we used retroviral vectors expressing β-galactosidase and urokinase and measured endothelial cell transduction efficiencies with quantitative assays for β-galactosidase and urokinase protein. We evaluated several techniques reported to improve the efficiency of retroviral transduction in vitro, including 1) extended periods of exposure to vector, 2) repeated exposures to vector, 3) maximization of the ratio of vector particles to endothelial cells by increasing the volume and concentration of vector particles or by decreasing the number of endothelial cells exposed, 4) cocultivation of endothelial cells with vector-producing cells, and 5) variation of the type and concentration of polycation used with the retroviral vector. Only the use of more concentrated (higher titer) vector-containing supernatant and the use of the polycation DEAE-dextran improved the efficiency of gene transfer into endothelial cells in vitro. In an optimized transduction protocol, a 60-second exposure to 1 mg/ml DEAE-dextran followed by a single 6-hour exposure to supernatant of a titer of 105–106colony-forming units/ml resulted in transduction efficiencies of 50–90% with both vectors. Decreasing the time of the supernatant exposure to 15 minutes permitted transduction efficiencies of 15–20% while significantly minimizing the duration of the transduction. Therefore, the optimized protocol allows high efficiency in vitro gene transfer into endothelial cells within several hours. The briefer protocol may prove useful for in vivo gene transfer in which the time of exposure to the supernatant is limited.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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25. |
Kinetics of C5a Release in Cardiac Lymph of Dogs Experiencing Coronary Artery Ischemia‐Reperfusion Injury |
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Circulation Research,
Volume 71,
Issue 6,
1992,
Page 1518-1524
William Dreyer,
Lloyd Michael,
Thinh Nguyen,
C. Smith,
Donald Anderson,
Mark Entman,
Roger Rossen,
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摘要:
Previous studies of myocardial ischemia suggest that complement activation may play a central role in the inflammatory response during reperfusion. Our previous work has demonstrated neutrophil chemotactic activity to be present in reperfusion canine cardiac lymph after myocardial ischemia and infarction. To evaluate the contribution of the complement-dependent anaphylatoxin C5a to this neutrophil chemotactic activity, rabbit antiserum to canine C5a was prepared. At dilutions >1:500 but <1:2,000, the antiserum abolished the ability of zymosan-activated dog serum to induce a ruffled, bipolar morphology in isolated neutrophils used as a bioassay of chemotactic stimulation. This antiserum did not affect similar morphological changes in neutrophils exposed to platelet activating factor (10−7–10−6M) or recombinant human interleukin-8 (10−9–10−8M); thus, we deemed it functionally specific for canine C5a. In a pattern similar to what we previously reported, cardiac lymph collected before a 1-hour ligation of the left circumflex coronary artery had little ability to alter the morphology of canine neutrophils (shape change index, 11.3±4.6, mean±SEM; n=7), but by 1 hour of reperfusion, lymph activated neutrophils significantly in five of seven dogs (mean shape change index, 72.6±17.7; p<0.01). At 2 hours of reperfusion, neutrophil activation by lymph occurred in six of seven dogs (mean shape change index, 103.1±22.2). At 3 hours of reperfusion, cardiac lymph of only three of six dogs caused neutrophil activation, and at 4 hours of reperfusion, this activity was evident in lymph from only two of five dogs. In all cases, however, the neutrophil stimulatory activity of cardiac lymph was inhibited 85–90% by addition of anti-C5a (p<0.01). Preimmunization serum had no effect. Thus, these data indicate that C5a is the predominant chemotactic factor in the first 4 hours after reperfusion of ischemic myocardium in the dog.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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26. |
Platelet‐Derived Growth Factor‐BB‐Induced Suppression of Smooth Muscle Cell Differentiation |
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Circulation Research,
Volume 71,
Issue 6,
1992,
Page 1525-1532
Bethany Holycross,
Randal Blank,
Maria Thompson,
Michael Peach,
Gary Owens,
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摘要:
Previously, we demonstrated that treatment of postconfluent quiescent rat aortic smooth muscle cells (SMCs) with platelet-derived growth factor (PDGF)-BB dramatically reduced smooth muscle (SM) α-actin synthesis. In the present studies, we focused on the expression of two other SM-specific proteins, SM myosin heavy chain (SM-MHC) and SM α-tropomyosin (SM-αTM), to determine whether the actions of PDGF-BB were specific to SM α-actin or represented a global ability of PDGF-BB to inhibit expression of cell-specific proteins characteristic of differentiated SMCs. SM-MHC and SM-αTM expression were assessed by one- or two-dimensional gel electrophoretic analysis of proteins from cells labeled with [35S]methionine, as well as by Northern analysis of mRNA levels. Synthesis of both SM-specific proteins was decreased by 50–709% in PDGF-BB-treated cells as compared with cells treated with PDGF vehicle. Treatment of cells with 10% fetal bovine serum, which produced a mitogenic effect equivalent to that of PDGF-BB, decreased SM-MHC synthesis by 40% but increased SM-αTM synthesis. SM-MHC and SM-αTM mRNA expression was decreased by 80% at 24 hours in PDGF-BB-treated postconfluent SMCs, whereas treatment with 10% fetal bovine serum did not decrease the expression of SM-αTM mRNA but did inhibit SM-MHC mRNA expression by 36%. Consistent with the absence of detectable PDGF α-receptors on these cells, PDGF-AA had no effect on either mitogenesis or expression of SM-MHC or SM-αTM. These findings indicate that proliferation, per se, does not coordinately reduce SM-specific protein expression and suggest that circulating or locally produced PDGF-BB may play a generalized role in the modulation of the SMC phenotype to a less differentiated state, a characteristic of SMCs in atherosclerotic blood vessels.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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27. |
Nitric Oxide Synthase in Cardiac Nerve Fibers and Neurons of Rat and Guinea Pig Heart |
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Circulation Research,
Volume 71,
Issue 6,
1992,
Page 1533-1537
Lars Klimaschewski,
Wolfgang Kummer,
Bernd Mayer,
Jean Couraud,
Ulrike Preissler,
Bärbel Philippin,
Christine Heym,
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摘要:
Participation of nitric oxide (NO) in the autonomic innervation of rat and guinea pig hearts was investigated by applying the NADPH diaphorase technique and immunohistochemistry with NO synthase antiserum. We present evidence that NO synthase is localized in cardiac ganglion cells and nerve fibers innervating the sinuatrial and atrioventricular nodes, the myocardium, local neurons, coronary arteries, and pulmonary vessels, suggesting an involvement of NO in neurogenic heart rate regulation, myocardial cell function, neuronal transmission in cardiac ganglia, and coronary as well as pulmonary vasodilation.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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28. |
Differences in Cardiac Calcium Release Channel (Ryanodine Receptor) Expression in Myocardium from Patients with End‐Stage Heart Failure Due to Ischemic versus Dilated Cardiomyopathy (Circulation Research1992;71:18–26) |
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Circulation Research,
Volume 71,
Issue 6,
1992,
Page 1538-1538
Anne-Marie Brillantes,
Paul Allen,
Toshiyuki Takahashi,
Seigo Izumo,
Andrew Marks,
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ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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