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21. |
Kinetics of Interaction of the Lidocaine Metabolite Glycylxylidide With the Cardiac Sodium ChannelAdditive Blockade With Lidocaine |
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Circulation Research,
Volume 70,
Issue 6,
1992,
Page 1254-1273
David Wendt,
C. Starmer,
Augustus Grant,
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摘要:
The recovery of the sodium channel from blockade by local anesthetic antiarrhythmic drugs is voltage dependent. Recovery from lidocaine-induced blockade is accelerated by hyperpolarization, whereas that from glycylxylidide (GX) blockade has been reported to be slowed by hyperpolarization. This striking difference occurs despite similarities in chemical structure. The fast recovery from GX block at depolarized potentials may lead to a partial reversal of lidocaine blockade when the two drugs are combined. We have examined the kinetics of interaction of GX with the cardiac sodium channel over a range of membrane potentials by measuring whole-cell currents in isolated rabbit myocytes under voltage clamp at 15°C. In the absence of drug, slow inactivation developed with a time constant of 10.7±5.1 seconds (n=6). During exposure to 74 μmol/1 GX, block developed with a time constant of 7.0±3 seconds (n=6). Because of the similar time course of slow inactivation and block, we used a high concentration of GX to induce a level of block sufficient for analysis. The onset of block was slower than that induced by lidocaine and was unaffected by variation of external sodium from 20 to 75 mmol/1. Use-dependent blockade of sodium channels was greater when pulse trains were applied from a holding potential of −100 than −140 mV. This suggested that recovery from GX block might be slower at −100 than −140 mV. Direct measurements gave time constants of recovery of 10.3±4.2 seconds at −100 mV (n=6) and 4.1±0.4 seconds at −140 mV (n=4). The combination of GX with lidocaine produced only additive blocking effects when pulse trains were applied from both holding potentials. Computer simulations of the requirements for the competitive displacement of a sodium channel blocker with slow kinetics by one with fast kinetics suggest that the recovery time constant of the fast drug must be 10–100-fold smaller than that of the slow drug. Rapid association kinetics effected by a large binding rate constant or a higher concentration of the fast blocking drug is also important. The simulations suggest that, for the interaction of GX and lidocaine, only additive blocking action should be observed over the range of stimulus frequencies used in these experiments.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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22. |
Bovine Angiotensin Converting Enzyme cDNA Cloning and RegulationIncreased Expression During Endothelial Cell Growth Arrest |
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Circulation Research,
Volume 70,
Issue 6,
1992,
Page 1274-1281
Shaw-Yung Shai,
Robert Fishel,
Brian Martin,
Bradford Berk,
Kenneth Bernstein,
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摘要:
Angiotensin converting enzyme (ACE) is a zinc-containing dipeptidase that converts angiotensin I to angiotensin II, a powerful vasoconstrictor and smooth muscle growth factor. ACE activity has been shown to be dynamically regulated by hormones, ACE inhibitors, and endothelial cell growth state. To study how ACE expression is regulated, we isolated and sequenced the bovine ACE gene using both ACE-specific cDNA and genomic clones. Bovine ACE cDNA encodes a single polypeptide of 1,306 residues with a molecular mass of 150 kd. Bovine ACE is approximately 80% homologous to that of other species. It contains two homologous domains of equal size. Alignment of ACE sequences from bovine, human, mouse, and rabbit reveals that during evolution both domains have been highly conserved. We used the bovine ACE cDNA to study regulation of ACE gene expression during density-dependent growth arrest. As endothelial cells became growth-arrested (6 days after confluence), there was a 12-fold increase in ACE activity and a 90% decrease in DNA synthesis. Immunocytochemically detectable ACE markedly increased in growth-arrested cells. The increase in ACE was due to increased ACE gene expression, as assayed by RNase protection, which showed a 20-fold increase in ACE-specific mRNA. The present study shows that bovine ACE is highly regulated by endothelial cell growth state at the level of protein and mRNA expression. Such dynamic regulation may have important consequences for angiotensin II production during endothelial cell proliferation after arterial injury.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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23. |
Recruitment of an Inotropic Reserve in Moderately Ischemic Myocardium at the Expense of Metabolic RecoveryA Model of Short‐term Hibernation |
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Circulation Research,
Volume 70,
Issue 6,
1992,
Page 1282-1295
Rainer Schulz,
Brian Guth,
Karl Pieper,
Claus Martin,
Gerd Heusch,
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摘要:
The regional, functional as well as metabolic consequences of inotropic stimulation on myocardium subjected to prolonged moderate ischemia were investigated. In 35 enflurane-anesthetized swine the left anterior descending coronary artery was cannulated and perfused at constant flow. The vein paralleling the left anterior descending coronary artery was cannulated for measurement of lactate and oxygen content. Transmural biopsies from the anterior myocardium were taken for the measurement of ATP, creatine phosphate, and glycogen. After control measurements, flow was adjusted to reduce regional contractile function (expressed as a work index, determined by sonomicrometry) by approximately 50%o. After either 5, 25, 40, or 85 minutes of moderate ischemia, dobutamine was infused for 5 minutes into the ischemic region. In a separate group of five swine also subjected to 85 minutes of ischemia followed by infusion of dobutamine and 2 hours of reperfusion, triphenyltetrazolium chloride staining and light microscopy were used to identify infarcted tissue. Moderate ischemia (regional myocardial blood flow, 0.21±0.07 ml min−1g−1determined by radiolabeled microspheres) was associated with a reduction of creatine phosphate after 5 minutes (from 9.35±2.54 to 6.43±1.06 μmol/gwet wt,p<0.05) and a further reduction after 25 minutes (3.18±0.69 μmol/g wet wt,p<0.05). Thereafter, creatine phosphate recovered despite continued ischemia (after 40 minutes, 4.95±1.37 μmol/g wet wt; after 85 minutes, 5.78±2.27 μmol/g wet wt). Lactate consumption during control conditions was reversed to production after 5 minutes of ischemia, which moderated during more prolonged ischemia. Without changing regional myocardial blood flow, infusion of dobutamine increased the work index significantly at any time point but also caused worsening of metabolic markers of ischemia. Nevertheless, even after 85 minutes of ischemia followed by the infusion of dobutamine and 2 hours of reperfusion, there was no evidence of necrosis. This experimental model provides a means of characterizing the mechanisms of short-term hibernation.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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24. |
Nitric Oxide Modulates Coronary Autoregulation in the Guinea Pig |
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Circulation Research,
Volume 70,
Issue 6,
1992,
Page 1296-1303
Masayuki Ueeda,
Scott Silvia,
Ray Olsson,
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摘要:
A guinea pig heart Langendorff preparation was used in the present study to test the hypothesis that the coronary endothelium modulates coronary autoregulation through the production of nitric oxide (NO). Pacing at 250 beats per minute and venting the left ventricle to ensure that the hearts did no external work were performed in an attempt to reduce the metabolic stimulus to coronary vasomotion and keep it constant. We measured the responses of coronary flow and oxygen metabolism to stepwise changes of the perfusion pressure over the range between 18 and 85 mm Hg. The hearts exhibited autoregulation between 25 and 55 mm Hg and active vasodilation at perfusion pressures above that range. Perfusion with 100 μMNG-nitro-l-arginine (NNIA), an inhibitor of NO synthase, decreased coronary flow over the entire range of perfusion pressures and abolished active vasodilation over 65 mm Hg, thus widening the autoregulatory range. The administration of 200 μM l-arginine, but not d-arginine, reversed the action of NNLA. Inhibition of the cyclooxygenase pathway by 10 μM indomethacin did not affect autoregulation. Perfusion with 1 nM arginine vasopressin, a direct smooth muscle constrictor, lowered coronary flow rate to the same extent as NNLA at 55 mm Hg but did not prevent the pressure-dependent increase in flow above that pressure. These observations suggest that 1) the coronary endothelium actively modulates coronary autoregulation through the production of NO but not prostanoids, 2) mechanical stress (shear stress and/or stretching secondary to vasodilation) may be the stimulus to NO production, especially above the autoregulatory range, and 3) autoregulatory tone is likely to be myogenic in origin rather than mediated by extrinsic vasoconstrictors.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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25. |
α1‐Receptor‐Independent Activation of Protein Kinase C in Acute Myocardial IschemiaMechanisms for Sensitization of the Adenylyl Cyclase System |
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Circulation Research,
Volume 70,
Issue 6,
1992,
Page 1304-1312
R. Strasser,
R. Braun-Dullaeus,
H. Walendzik,
R. Marquetant,
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摘要:
The activity of the adrenergic system plays an important role in the genesis of malignant arrhythmias and the spreading of the infarcted zone in acute myocardial ischemia. Acute myocardial ischemia induces an increased activity of adenylyl cyclase. This sensitization at the enzyme level as shown in the isolated perfused rat heart occurs rapidly after the onset of ischemia (5–15 minutes) and is rapidly reversible on reperfusion. With prolonged ischemia, it is only transient and is followed by a gradual loss of the adenylyl cyclase activity. The increased activity of adenylyl cyclase is even retained after partial purification, suggesting a covalent modification of the enzyme. Blockade of α1-adrenergic receptors does not prevent this sensitization, demonstrating that it occurs independently of α1-adrenergic receptor activation. Only blockade of protein kinase C by various inhibitors, such as polymyxin B or staurosporine, is able to completely prevent this sensitization process. Moreover, in acute myocardial ischemia an activation of protein kinase C could be identified using its translocation from the cytosol to the particulate fraction as an indicator. Blockade of α1-adrenergic receptors using prazosin fails to prevent the activation of protein kinase C and consequently the sensitization of the adenylyl cyclase system, indicating that the ischemia-induced translocation of protein kinase C occurs independently of α1-adrenergic receptors. These data characterize for the first time an important interaction of two effector enzymes of two distinct signal transduction pathways, i.e., the adenylyl cyclase system and the protein kinase C system in acute myocardial ischemia. Further studies are necessary to identify the mechanisms involved in the activation of protein kinase C in acute ischemia in order to develop therapeutic strategies to prevent such activation of protein kinase C and consequently the sensitization of adenylyl cyclase.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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26. |
Calcitonin Gene‐Related Peptide Mediates Nitroglycerin and Sodium Nitroprusside‐Induced Vasodilation in Feline Cerebral Arterioles |
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Circulation Research,
Volume 70,
Issue 6,
1992,
Page 1313-1319
Enoch Wei,
Michael Moskowitz,
Pia Boccalini,
Hermes Kontos,
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摘要:
The cerebral vasodilator response induced by topical nitroglycerin and nitroprusside was examined in cats equipped with cranial windows for the observation of the cerebral microcirculation. In cats subjected to chronic unilateral trigeminal ganglionectomy, the vasodilator responses to nitroprusside and nitroglycerin were markedly depressed on the denervated side. Application of a selective calcitonin gene-related peptide (CGRP) antagonist [CGRP(8–37)] on the innervated side reduced the response to nitrodilators to the same extent as seen on the denervated side. The vasodilator response to acetylcholine was unaffected by trigeminal ganglionectomy. CGRP(8–37) almost abolished the vasodilator response to nitroglycerin and sodium nitroprusside and to CGRP, but did not affect the response to adenosine or to adenosine diphosphate. Pretreatment with LY83583, a drug that lowers cyclic GMP levels, diminished the vasodilation to CGRP and to nitroprusside but not to adenosine. We conclude that the nitrovasodilators activate sensory fibers to release CGRP, which in turn relaxes cerebral vascular smooth muscle by activating guanylate cyclase. Hence, nitrovasodilators possess a novel mechanism of action within the cephalic circulation which may explain both the occurrence of vasodilation and headache.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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27. |
Subcellular Distribution of β2‐Adrenergic Receptors Delineated With Quantitative Ultrastructural Autoradiography of Radioligand Binding Sites |
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Circulation Research,
Volume 70,
Issue 6,
1992,
Page 1320-1325
Jeffrey Saffitz,
Stephen Liggett,
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摘要:
β-Adrenergic receptors play a critical role in signal transduction in the cardiovascular system. Regulation of β-adrenergic receptor expression depends on multiple factors, including rates of synthesis and degradation of receptor protein and trafficking of receptors between the cell surface and putative intracellular compartments. To characterize the subcellular distribution of β-adrenergic receptors and to delineate the ultrastructure of intracellular compartments in which adrenergic receptors reside in the steady state, we studied Chinese hamster fibroblast cells transfected with the human β2-adrenergic receptor gene. β2-Adrenergic receptors of these cells were covalently labeled with the lipophilic photoactivatable antagonist [125]iodocyanopindolol diazarine, and specific radioligand binding sites were localized at the ultrastructural level of resolution with quantitative electron microscopic autoradiography. The density of β2-adrenergic receptors was −100-fold greater in the plasmalemma than in any other compartment. Approximately 50% of total cellular receptors were identified on the cell surface in an apparently random, nonclustered distribution and without association with clathrin-coated pits or other cell surface structural specializations. The remaining receptors were distributed among intracellular membranous compartments, including smooth vesicles, rough endoplasmic reticulum, and the Golgi apparatus, organelles presumably involved in stages of receptor synthesis, degradation, or trafflicking. In the basal state, there was no association of β2-adrenergic receptors with coated intracellular vesicles typical of the endocytotic pathway of selected cell surface receptors that function to internalize their extracellular ligands. These results are the first to rigorously quantify the subcellular distribution of β-adrenergic receptors and unequivocally establish the presence of a substantial pool of intracellular receptors.
ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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28. |
Acknowledgment to Reviewers |
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Circulation Research,
Volume 70,
Issue 6,
1992,
Page 1326-1329
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ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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29. |
Author Index |
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Circulation Research,
Volume 70,
Issue 6,
1992,
Page 1331-1332
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ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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30. |
Subject Index |
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Circulation Research,
Volume 70,
Issue 6,
1992,
Page 1333-1348
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ISSN:0009-7330
出版商:OVID
年代:1992
数据来源: OVID
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