Effect on coronary artery flow reserve and resistance in the remote area after acute coronary artery occlusion in the pig model.

BACKGROUND: It has been reported that vasodilator function in remote myocardial regions supplied by "angiographically normal" coronary arteries is impaired in patients after acute myocardial infarction (MI). The aim of this study was to determine whether coronary artery flow reserve and coronary artery resistance in remote, nonischemic areas are also altered in experimental MI. METHODS: Experiments were performed in anesthetized pigs. In group 1 infarction was induced by ligation of the left-anterior descending artery (LAD); group 2 consisted of sham-operated animals. Hemodynamic parameters, coronary artery resistance, and myocardial blood flow (MBF) were measured before and 4 hours after MI under rest and during infusion of adenosine. RESULTS: Coronary artery dilation by adenosine caused a similar increase in MBF before and 4 hours after coronary artery occlusion. Resting MBF after acute MI was not altered, although a significant reduction (15%; P < .04) in mean aortic pressure was observed compared with baseline. Coronary artery resistance was significantly reduced by adenosine (P < .04) before MI, as well as at 4 hours after MI (P < .03). Coronary artery flow reserve was not adversely affected. The sham-operated animals showed similar results without any significant differences between the two study groups. CONCLUSION: This study indicates that an acute MI in pigs did not increase coronary artery resistance in the remote area after MI and therefore did not adversely affect coronary artery flow reserve in the nonischemic vascular bed. Further studies are necessary to fully understand the exact mechanism of the alterations in remote flow reserve of patients after MI.

Role of oxidants in influenza virus-induced gene expression.

Influenza virus-induced epithelial damage may be mediated, in part, by reactive oxygen intermediates (ROIs). In this study, we investigated the role of ROIs in the influenza virus-induced gene expression of antioxidant enzymes and in the activation of nuclear factor-kappa B (NF-kappa B), an oxidant-sensitive transcriptional factor. Influenza virus infection increased production of intracellular ROIs in A549 pulmonary epithelial cells. Induction of manganese superoxide dismutase (MnSOD) mRNA correlated with increased MnSOD protein and enzyme activity. Influenza virus infection also activated NF-kappa B binding as determined by an electrophoretic mobility shift assay. Pretreatment of A549 cells with N-acetyl-L-cysteine attenuated virus-induced NF-kappa B activation and interleukin (IL)-8 mRNA induction but did not block induction of MnSOD mRNA. In contrast, pyrrolidine dithiocarbamate blocked activation of NF-kappa B and induction of MnSOD and IL-8 mRNAs. Treatment with pyrrolidine dithiocarbamate also markedly decreased virus-induced cell death. Thus oxidants are involved in influenza virus-induced activation of NF-kappa B, in the expression of IL-8 and MnSOD, and in virus-induced cell death.

Quantitative evaluation of manganese-52m as a myocardial perfusion tracer in pigs using positron emission tomography.

There is a need for a quantitative myocardial perfusion agent that does not require an on-site cyclotron. Early studies with manganese demonstrated that this trace metal is of potential use for myocardial imaging. 52mMn can be produced in a 52Fe-52mMn generator and is suitable for positron emission tomographic (PET) imaging. The purpose of this study was to evaluate 52mMn with regard to its potential to quantitatively assess myocardial perfusion. Dynamic PET imaging was performed in six pigs with various doses of dipyridamole to increase blood flow. Retention (R) and model-based K1 values were correlated with microsphere blood flow. The models consisted of one (K1, k2) and two (K1, k2, k3) tissue compartments. Anterior, lateral and septal regions showed a good myocardium-to-background ratio; the evaluation of the inferior wall was impaired by high liver uptake. Linear regression yielded the following equations: K1=1.152 flow+0.059 (r=0.92), R=0.069 flow+0.034 (r=0.84). Based on these regressions, K1 increased 2.7-fold and R 2.6-fold in the examined flow range of 0.5-2 ml/min/g (fourfold increase), demonstrating an underestimation of higher flow rates by both measures. It is concluded that 52mMn allows the qualitative assessment of myocardial perfusion but does not meet the requirements of a quantitative myocardial perfusion agent.

Calcium mediates expression of stress-response genes in prostaglandin A2-induced growth arrest.

We have explored the mechanisms involved in the induction of five stress-response genes (heme oxygenase [HO], c-fos, Egr-1, gadd153, and HSP70) in human diploid fibroblasts growth-arrested by treatment with the antiproliferative prostaglandin A2 (PGA2). The kinetics of c-fos and Egr-1 induction were found to be rapid with maximum expression occurring within 60 min of treatment, whereas maximum expression of HO, gadd153, and HSP70 occurred between 4 and 8 h of treatment. Nuclear run-on assays and measurements of mRNA clearance in the presence of actinomycin D demonstrated that increases in both the rates of gene transcription and/or mRNA stability contribute to the genetic response to PGA2. Although the mechanisms responsible for increasing the mRNA levels differ for the individual genes, additional experiments provided evidence that alterations in intracellular calcium ([Ca2+]i) levels were important in initiating the genetic response to PGA2. PGA2 treatment resulted in a rapid increase in [Ca2+]i with the dose-response relationship for Ca2+ mobilization consistent with that seen for the induction of all five genes. [Ca2+]i chelators that attenuate Ca2+ mobilization by PGA2 also blocked the mRNA induction by PGA2 treatment. Density-inhibited confluent cells were less responsive than proliferating subconfluent cells with respect to Ca2+ mobilization after PGA2 treatment. This was correlated with a lower level of gene induction. These studies support the hypothesis that increased Ca2+ mobilization is an early and central event in the signal transduction pathway (or pathways) mediating the activation of genes in response to PGA2 treatment.

[Therapy proposals for the quarantine of African green monkeys (Cercopithecus aethiops)]. / Therapievorschläge für die Quarantänehaltung von afrikanischen grünen Meerkatzen (Cercopithecus aethiops).

Attenuated live virus vaccines are usually tested in vivo for neurovirulent properties by using African green monkeys. This report describes the health condition of animals that have been imported from Ethiopia. The monkeys were strongly malnourished when they arrived at the institute. One animal died during the shipment. In spite of many diagnostic and therapeutic efforts only 14 of 29 monkeys survived the 120-day-quarantine. Most animals died of infections of the respiratory and gastrointestinal tracts within 4 weeks after arrival.

Suppression of B cell function by methotrexate and trimetrexate. Evidence for inhibition of purine biosynthesis as a major mechanism of action.

Methotrexate (MTX) is a widely used drug in the treatment of a variety of human neoplasms. Trimetrexate (TMQ) is a lipid-soluble quinazoline derivate of MTX that, unlike MTX, is not dependent upon membrane folate transport for cellular entry. A number of studies have demonstrated that MTX and, more recently, TMQ possess potent immunosuppressive properties. To examine the cellular events associated with the immunomodulatory effects of anti-folates on humoral immunity, a murine B cell maturation model was used. In vitro, MTX and TMQ reduced the number of antibody-forming cells to SRBC, as well as IgM production. B cells stimulated with anti-Ig demonstrated a dose-related suppression in [3H]UdR incorporation after addition of either drug, suggestive of a decrease in de novo DNA synthesis. B cell activation events preceding S phase were also suppressed by both anti-folates, as evidenced by inhibition of RNA synthesis. However, neither drug affected surface expression of Ia Ag nor inositol phosphate accumulation. Addition of TdR caused a slight non-significant increase in the antibody-forming cell response in the presence of 10(-7) M MTX. However, addition of hypoxanthine or adenine, but not guanine, resulted in complete restoration. Timed addition revealed that the ability of MTX to suppress antibody responses was diminished if added after 48 h of culture, similar to the reversal of this suppression mediated by hypoxanthine. Cell cycle analysis of LPS-stimulated B lymphocytes demonstrated that both drugs modulated events preceding, as well as during, the S phase. The present studies suggest that although drug-induced impairments in dTMP biosynthesis may be responsible for deficient lymphoid proliferation, anti-folate-induced impairment in purine biosynthesis is a major mechanism in anti-folate-induced suppression of humoral immunity.