ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—IKs, an important repolarizing current in heart, is an antiarrhythmic drug target and is markedly increased by activation of protein kinase A (PKA; eg, by &bgr;-adrenergic stimulation). Because &bgr;-adrenergic stimulation is a frequent trigger of arrhythmias, we hypothesized that PKA stimulation inhibits drug block.Methods and Results—CHO cells were transfected with KCNQ1 cDNA (encoding the pore-forming subunit) with or without the ancillary subunit KCNE1. IC50for quinidine block of basalIKswas 5.8±1.2 &mgr;mol/L, versus 19.9±3.2 &mgr;mol/L (P<0.01) for PKA-stimulated current. A similar >3-fold shift was apparent in the absence of KCNE1 and with theIKs-specific blocker chromanol 293B. The first current recorded after channels were held at rest and exposed to the drug was reduced ≈40%, and further depolarizations increased the block with a time constant (&tgr;) of 181±27 seconds. By contrast, PKA-stimulated channels displayed a <5% first-pulse block and much slower block development (&tgr;=405±85 seconds). Alanine substitution at 3 potential PKA target sites (S27, S468, and T470) generated anIKsthat did not increase with PKA stimulation; this mutant retained wild-type drug sensitivity that was unaffected by PKA.Conclusions—Activation of this key intracellular signaling pathway blunts drug block. The onset of block and the data with the PKA-resistant mutant support the concept that phosphorylation of the KCNQ1 subunit directly modulates drug access to a binding site on the channel. These data identify a novel mechanism for modulation of drug-channel interactions that may be especially important during &bgr;-adrenergic stimulation.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—The combination of a single-bolus fibrinolytic and a low-molecular-weight heparin may facilitate prehospital reperfusion and further improve clinical outcome in patients with ST-elevation myocardial infarction.Methods and Results—In the prehospital setting, 1639 patients with ST-elevation myocardial infarction were randomly assigned to treatment with tenecteplase and either (1) intravenous bolus of 30 mg enoxaparin (ENOX) followed by 1 mg/kg subcutaneously BID for a maximum of 7 days or (2) weight-adjusted unfractionated heparin (UFH) for 48 hours. The median treatment delay was 115 minutes after symptom onset (53% within 2 hours). ENOX tended to reduce the composite of 30-day mortality or in-hospital reinfarction, or in-hospital refractory ischemia to 14.2% versus 17.4% for UFH (P=0.080), although there was no difference for this composite end point plus in-hospital intracranial hemorrhage or major bleeding (18.3% versus 20.3%,P=0.30). Correspondingly, there were reductions in in-hospital reinfarction (3.5% versus 5.8%,P=0.028) and refractory ischemia (4.4% versus 6.5%,P=0.067) but increases in total stroke (2.9% versus 1.3%,P=0.026) and intracranial hemorrhage (2.20% versus 0.97%,P=0.047). The increase in intracranial hemorrhage was seen in patients >75 years of age.Conclusions—Prehospital fibrinolysis allows 53% of patients to receive reperfusion treatment within 2 hours after symptom onset. The combination of tenecteplase with ENOX reduces early ischemic events, but lower doses of ENOX need to be tested in elderly patients. At present, therefore, tenecteplase and UFH are recommended as the routine pharmacological reperfusion treatment in the prehospital setting.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background—Recent studies in animals suggest that circulating recipient endothelial precursors may participate in the biology of transplant vasculopathy. It is currently unknown whether a similar interaction between recipient endothelial cells and the vessel wall occurs in human subjects undergoing allogeneic cardiac transplantation.Methods and Results—Circulating endothelial cells and endothelial progenitor cells (EPCs) were quantified in 15 cardiac transplantation subjects with and without angiographic evidence of vasculopathy. In a separate series of experiments, the origin (donor or recipient) of transplant plaque endothelial cells was assessed in subjects who had undergone a gender-mismatched cardiac transplantation and had histological evidence of severe vasculopathy at the time of heart explantation. Circulating EPC outgrowth colonies in peripheral blood were significantly reduced in subjects with transplant vasculopathy compared with those without angiographic evidence of disease (EPC colony-forming units [CFUEPC]: 4.5±1.9 versus 15.1±3.7,P<0.05). There was no significant difference in circulating endothelial cell numbers as defined by day 4 culture acetylated LDL/lectin assay in either of these patient groups. In a separate group of 5 subjects who underwent gender-mismatched cardiac transplantation, there was a significant seeding of recipient endothelial cells (range: 1% to 24% of all luminal endothelial cells) in large-vessel lumen and adventitial microvessel lumen of arteriopathic vessels. No opposite-sex chimeric cells were observed in control gender-matched transplantation scenarios.Conclusions—These data suggest that the human cardiac transplant arteriopathy is associated with reduction in circulating endothelial precursors and with seeding of recipient-derived endothelial cells at the site of plaque development.

ISSN:0009-7322    

出版商:OVID    

年代:2003

数据来源: OVID