摘要:

Angiotensin II (Ang II) has been implicated in the regulation of smooth muscle cell proliferation after vascular injury, but the molecular mechanisms of this effect remain obscure. The aims of the present study were 1) to determine if Ang II was mitogenic (in a defined serum-free medium) for aortic smooth muscle cells derived from spontaneously hypertensive rats, either alone or in combination with epidermal growth factor, basic fibroblast growth factor, or platelet-derived growth factor-BB; and 2) to determine if the Ang II effects were mediated by autocrine production of transforming growth factor-β (TGF-β). Results demonstrated that Ang II increased the proliferative response of smooth muscle cells to epidermal growth factor or platelet-derived growth factor-BB. Ang II alone and in combination with basic fibroblast growth factor induced a small delayed increase (48–72 hours after treatment) in DNA synthesis and [3H] thy mi-dine labeling indexes without an increase in cell number. Ang II effects were at least partially mediated by autocrine production of active TGF-β in that 1) treatment with Ang II increased TGF-β activity in conditioned media and 2) TGF-β neutralizing antibody inhibited Ang II-induced increases in DNA synthesis. However, treatment with exogenous TGF-β at concentrations induced by Ang II failed to elicit a mitogenic response, thus implicating other autocrine factors in mediation of Ang II effects. Results suggest a potential mechanism whereby Ang II might regulate smooth muscle cell mitogenesis after vascular injury.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

To evaluate the effect of thrombin on the dynamics of thrombolysis, we infused rabbits with heparin or hirudin alone or in conjunction with tissue-type plasminogen activator (t-PA) and monitored the kinetics of fibrinolysis and changes in ex vivo platelet aggregation responses over time. Both heparin and hirudin enhanced total fibrinolysis in an ex vivo arteriovenous shunt preparation: 82±2% and 79±2%, respectively, compared with 51±8% for t-PA alone (p<0.05) and 50±4% for t-PA plus aspirin (p<0.05). Heparin coadministered with t-PA significantly reduced the half-time for clot lysis compared with t-PA alone (p<0.05), whereas hirudin coadministered with t-PA significantly reduced the half-time for clot lysis compared with that for t-PA alone, t-PA plus aspirin, and t-PA plus heparin (5.5±0.6 versus 12.1±2.0 versus 12.6±2.2 versus 10.0±0.8 minutes, respectively; p<0.05). Both heparin and hirudin prevented the increase in ADP-induced platelet aggregation normally seen with t-PA alone (p<0.01 byttest; p<0.05 by two-way analysis of variance). These data demonstrate that selective, antithrombin III-independent thrombin inhibitors can enhance the efficacy of thrombolysis by modulating the dynamics of the process and preventing platelet activation associated with plasminogen activator therapy.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Smooth muscle cell (SMC) proliferation is a poorly understood process that plays a critical role in several pathological states, including atherosclerosis and hypertension. Recent work suggests that the oncogene c-myb and myosin, a ubiquitous cytoskeletal protein, may be directly involved in this process. We have used antisense nonmuscle myosin heavy chain (NMMHC) or c-myb phosphorothiolate oligonucleotides to inhibit proliferation of SMCs in vitro. The suppression of growth is accompanied by reductions in the concentrations of NMMHC and c-myb mRNAs as well as decreases in the levels of the corresponding proteins. The specificity of the antiproliferative effect is underscored by the absence of any detectable growth inhibition with sense NMMHC or c-myb phosphorothiolate oligonucleotides, an antisense c-myb mismatch phosphorothiolate oligonucleotide, or an antisense thrombomodulin phosphorothiolate oligonucleotide. Furthermore, the treatment of SMCs with antisense phosphorothiolate oligonucleotides for as little as 2 hours causes maximal inhibition of cell growth over the next 72 hours. Under these conditions, SMCs attain normal rates of growth over the following 48 hours, which shows that proliferation is suppressed in a reversible fashion by antisense phosphorothiolate oligonucleotides. These experiments indicate that both c-myb and nonmuscle myosin play critical roles in SMC proliferation and that reductions of either mRNA by antisense phosphorothiolate oligonucleotides arrest the process.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Reports have suggested that the fast inward sodium current (INa) in cardiac tissues may be modulated by β-adrenergic stimulation and that such modulation may affect conduction in the setting of myocardial ischemia and infarction. However, many of these studies have used dissociated myocytes or broken cell preparations, whose responses need not necessarily reflect those of syncytial preparations. To investigate further the possibility that β-adrenergic stimulation of INamay differ in various preparations, we compared the effects of the β-agonist isoproterenol (ISO) on syncytial canine Purkinje fibers and ventricular muscle preparations, as well as isolated ventricular myocytes. Alterations of the maximum rate of rise of the action potential upstroke (Vmax) were used as an index of changes of INa. ISO (1 μM) had no effect on Vmaxof upstrokes of normally polarized (fast responses) or partially depolarized (elevated [K+]0, depressed fast responses) syncytial ventricular muscle preparations or Purkinje fibers. In contrast, lower concentrations of ISO (0.5–1.0 μM) modulated Vmaxof isolated ventricular myocytes, depending on the technique used to monitor transmembrane potential. When 2.7 M KCI-filled microelectrodes were used, ISO reduced Vmaxof partially depolarized myocytes without affecting Vmaxof normally polarized myocytes. However, when myocytes were dialyzed using patch pipettes, ISO reduced Vmaxof partially depolarized myocytes and increased Vmaxof normally polarized myocytes, effecting a hyperpolarized shift of the normalized inactivation curve relating Vmaxto resting membrane potential. The different β-adrenergic responses of syncytial preparations and nondialyzed and dialyzed myocytes suggest that differences in the ionic or metabolic condition of the preparations likely alter cAMP-dependent responses and channel phosphorylation. These results suggest that β-adrenergic modulation of INacan occur under some experimental conditions but that extrapolation of data obtained using isolated myocytes to syncytial preparations in vitro or in vivo requires further evaluation.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Single atrial cells from guinea pig heart were voltage-clamped using the whole-cell configuration of the patch-clamp technique under conditions in which most of the ionic and exchange currents known in cardiac cells were minimized. Extracellular 5 or 50 μM ATP activated a CI−current, in addition to a rapidly desensitizing cation-selective current. A nonhydrolyzable ATP analogue, adenosine-5'-O-(3-thiotriphosphate) (50 μM), also evoked these two currents, indicating involvement of purinoceptors rather than ecto-ATPase on the membrane. ADP, AMP, and adenosine were also effective in inducing the CI−current, showing no clear order of potency for the purinoceptor subtypes involved. The purinoceptor-activated CI−current, like the β-catecholamine-cAMP-dependent cardiac CI−current, showed outward rectification and time independence.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Tumor necrosis factor (TNF) and interferon gamma (IFN-γ) are pleuripotent cytokines and have multiple functions during the inflammatory response. Using a murine model of autoimmune myocarditis, we studied the role of TNF and IFN-γ in myocardial inflammation. Neutralizing monoclonal antibodies against TNF-α/β and IFN-γ were administered to myosin-immunized A/J mice to assess the effect on the severity of myocardial inflammation. Anti-TNF treatment significantly reduced the severity of myocarditis compared with rat immunoglobulin G or saline controls (p < 0.0007) when given before myosin immunization. Myosin-specific lymph node T-cell proliferation studies showed no difference in the proliferative response between the anti-TNF-treated mice and controls. Administration of anti-TNF to mice after myosin immunization had no effect on the severity of inflammation. This suggests that TNF is an important mediator early in the pathogenesis of myocardial inflammation in this model of myocarditis. Neutralization of IFN-γ significantly increased the severity of myocarditis compared with rat immunoglobulin G and saline controls (p < 0.0065), suggesting that IFN-γ may function as an important regulatory cytokine early in the pathogenesis of myocardial inflammation. Understanding the functions of cytokines during the inflammatory response to myocardial injury may provide important information on possible methods to limit myocardial damage.

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID