610 Medizin und Gesundheit
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To study the activation of HIV by human spumaretrovirus (HSRV) the long terminal repeats (LTRs) of HSRV, HIVl and HIV2 were examined with respect to their ability to function as transcriptional promoters in virus infected and uninfected cells. Transient transfections using plasmids in which the L TRs of the three viruses were coupled to the bacterial chloramphenicol acetyltransferase (CA T) gene revealed (i) the level of cat gene expression directed by the HSRV LTR was markedly increased in HSRV infected cells compared to uninfected cells, (ii) cat gene expression driven by the HIV1 LTR, but not by the HIV2 LTR could be enhanced upon HSRV infection, whereas (iii) neither in HIV1 nor in HIV2 infected cells an effect on HSRV LTR driven cat geneexpression was detected.
Ich habe versucht darzulegen, daß mechanistische Überlegungen zur Extrapolation der Dosis-WirkungsBeziehung herangezogen werden können. Ein nichtlinearer Verlauf ist nicht nur bei den epigenetischen Kanzerogenen wahrscheinlich, sondern auch bei den DNA-bindenden. Echte Schwellen sind aber nur in solchen Fällen zu erwarten, wo kein endogenes Korrelat besteht. Immerhin können auch steile Nichtlinearitäten zu einer drastischen Risikoreduktion führen, so daß die Anstrengungen dahin gehen sollten, die Steigung und den Bereich des überproportionalen Abfalls experimentell zu zeigen. In einer heterogenen Population kann die 0 0- sis-Wirkungs-Kurve zusätzliche "Wellen" bekommen und wird dadurch grundsätzlich flacher. Im Extremfall ergibt sich eine lineare Dosis-Wirkungs-Beziehung unabhängig vom Wirkmechanismus des Kanzerogens. Diese Proportionalität zwischen tiefster Dosis und Effekt wird bei genotoxischen Kanzerogenen aus mechanistischen Gründen schon für eine homogene Population postuliert, doch kann dies in einer heterogenen Population auch bei epigenetischen Kanzerogenen in Frage kommen.
The selective opioid mu receptor agonist dermorphin increased the locomotor activity of rats dose dependently at 1 0 to 1 00 pmol/kg i.c.v. Respiratory rate, relative tidal volume and respiratory minute volume also increased unrelated to changes in locomotor activity. Higher doses, on the other hand, produced catalepsy and respiratory depression. Pretreatment of the rats with the mu,-selective antagonist naloxonazine (10 mg/kg i.v.) blocked the stimulant locomotor and respiratory effects of low doses of dermorphin (1 0--1 00 pmol/kg), but potentiated the respiratory depressant effect of a high dose (1 0 nmol/kg) of dermorphin. The selective benzodiazepine antagonist flumazenil (5 mg/kg), which has been shown previously to antagonize catalepsy and respiratory depression produced by relatively high doses of dermorphin, did not antagonize the respiratory or locomotor stimulant effect of dermorphin. The data suggest that mu\(_1\)-opioid receptors are responsible for the low dose stimulant effects of dermorphin on locomotor activity and respiration whereas mu\(_2\) receptors mediate the respiratory depressant effect of dermorphin.
Cardiovascular Effects of Anatoxin-A in the Conscious Rat. SJREN, A.-L., AND FEUERSTEIN, G. (1990). Toxicol. Appl. Pharmacol. 102,91-100. The effects ofanatoxin-A on mean arterial pressure (MAP), heart rate, cardiac index (CI), and blood flow (BF) in hindquarter (HQ), renal (R). and mesenteric (M) vascular beds were studied after intravenous (iv) and intracerebroventricular (icv) administration in the conscious rat. The pharmacological profile of anatoxin-A was further compared to nicotine administered iv and icv. MAP and heart rate were measured from femoral artery, CI by thermodilution method, and blood flow by Doppler velocimetry. Anatoxin-A and nicotine (30, 100 and 300 1-!g/kg iv) produced an increase in MAP with concomitant bradycardia. The highest doses increased Cl. MBF and RBF decreased due to a vasoconstriction in M and R vasculature. These effects were attenuated by the ganglion blocker chlorisondamine (5 mg/kg, iv). Anatoxin-A ( 100 1-!g/k~ iv) increased plasma epinephrine Ievels by 2- fold with virtually no effect on norepinephrine whereas nicotine ( 100 ~oLg/kg, iv) increased plasma epinephrine and norepinephrine by 20- to 30-fold. Central administration of anatoxin-A and nicotine (30-100 ,ug/kg icv) increased MAP with no effect on heart rate and produced M and R vasoconstriction. In summary, the present study demonstrates that anatoxin-A acts as a nicotinic cholinergic agonist in the c.onscious rat after both systemic and centrat administration. Anatoxin-A and nicotine produced pressor and reno-splanchnic vasoconstrictor responses and at high doses increased cardiac output. These effects were mediated by activation ofthe nicotinic receptors in the adrenal medulla and sympathetic ganglia. However, marked differences were found in the potency ofanatoxin-A versus nicotine to stimulate the sympathoadrenomedullary axis.
Neoplastic cell transfonnation induced by estrogens and some other carcinogen& such as benzene appears to involve the induction of mitotic aneuploidy rather than DNA damage and point mutations. As metabolic activation may also play an important roJe in the mechanism of carcinogenesis of these nongenotoxic compounds, we have studied the Interaction of reactive quinone metabolites of various estrogens and of benzene with the major microtubular protein, tubulin, in a cell-free system. Covalent binding of the radioactively labeled metabolites to the a- and 13-subunit of tubulin was found to depend on the structure of the metabolite. When the adducted tubulins were tested in vitro for their ability to polymerize to microtubules, Inhibition of microtubule assembly was obsened in every case, although to varying extents. It is proposed that the fonnation of covalent tubulin adducts may impair the formation of mitotic spindies and thus contribute to chromosomal nondisjunction and aneuploidy induction.