1 Interleukin-13 (IL-113) is a potent stimulant of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production in vascular smooth muscle (VSM) cells in culture. These studies investigate the role of adenosine 3':5'-cyclic monophosphate (cyclic AMP) in this process. 2 Dibutyryl cyclic AMP (db cyclic AMP, 0.1-1 mM), forskolin (1-1OI1M) and the phosphodiesterase inhibitor, Ro 20-1724 (1-10jM), all of which increase intracellular cyclic AMP, had no effect on NO production when added alone but markedly enhanced NO production by IL-lP-stimulated VSM cells in a dose-dependent manner. Consistent with a cyclic AMP-mediated action, isoprenaline (1-10 1iM) increased NO production from IL-lp-stimulated cells. Dibutyryl cyclic GMP (db cyclic GMP) had no effect at concentrations up to 1 mM. 3 Pursuing these observations, iNOS protein levels were examined by Western blot analysis and iNOS mRNA levels were measured by reverse transcription and amplification of the resultant cDNA using the polymerase chain reaction. In addition to enhancing NO production, db cyclic AMP increased iNOS protein and mRNA above that produced by IL-1P alone.4 These data demonstrate a major effect of cyclic AMP on cytokine-induced NOS activity in VSM cells, mediated at least in part by regulating synthesis of iNOS, and has implications for the pathogenesis and management of septic shock.
1 These studies examine the effect of retinoids on interleukin 1P (IL-1p)-induced nitric oxide synthase (NOS) activity in cultured rat aortic vascular smooth muscle (VSM) cells and isolated rat aortic rings. 2 All-trans-retinoic acid (all-trans-RA, 0.1-101M) and its active analogues produced concentrationdependent inhibition of IL-1IP (0.1-10 ng ml1')-induced nitrite production in cultured VSM cells. In contrast, the inactive retinoid, Ro 14-6113 (0.1-101iM), had no effect on IL-lp-induced nitrite production.3 Since some of the actions of retinoids are mediated by induction of transforming growth factor beta (TGF-P), its effect on inducible NOS activity in VSM cells was examined. TGF-P produced concentrationdependent (0.1-10 ng ml-') inhibition of IL-1P-induced nitrite production and the maximum effect (approximately 90% inhibition) was significantly greater than that seen with all-trans-RA (approximately 70% with 10 gM). However, an anti-TGF-P antibody (50 jig ml 1) which blocked the effect of exogenous TGF-P (5 ng ml-') did not significantly reverse the inhibitory action of all-trans-RA (10 LM).4 In addition to inhibiting IL-lp-induced nitrite production, all-trans-RA (10 tM) reduced substantially inducible NOS mRNA and protein levels in IL-lB-induced VSM cells (P<0.01). 5Incubation of isolated rat aortic rings with IL-l ,B (10 ng ml-') caused a progressive resistance of the rings to the vasoconstrictor action of phenylephrine (10 nM to 10 gLM). This effect was abolished by the addition of the nitric oxide synthase inhibitor L-NG-monomethyl-L-arginine (L-NMMA, 1 mM). Alltrans-RA (10IM) also markedly and significantly reversed this IL-1p-induced vascular hyporeactivity (P<0.01). 6 These data show that all-trans-RA and other active retinoids are able to block cytokine-stimulated expression of inducible NOS in cultured VSM cells and isolated aortic rings.
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A 56-year-old man with a previous deep venous thrombus presented with dyspnoea after a leg massage. A transthoracic echocardiogram demonstrated a "worm-shaped" right atrial embolus, most probably a femoral cast. A pulmonary artery angiogram confirmed a large wedge-shaped perfusion defect caused by a pulmonary embolus. There are previous case reports about leg massage causing pulmonary emboli but this is the first reported event where the thrombus has been visualised directly. Also, it demonstrates the important role that echocardiography plays in pulmonary embolus.
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