Alex Bobik

Determination of norepinephrine apparent release rate and clearance in humans.

A method for estimating the rate of entry of norepinephrine into plasma (norepinephrine apparent release rate) and clearance of norepinephrine from plasma in humans is presented. The procedure involves the intravenous infusion of tritiated l-norepinephrine, of sufficiently high specific activity to avoid elevating blood pressure, until plateau concentration is reached in plasma, and measurement of norepinephrine specific activity under steady state conditions. In ten normal subjects at rest, the apparent release rate of norepinephrine was 0.54 ± 0.20 μg/m2/min. (mean ± standard deviation). It was significantly lower in four patients with idiopathic peripheral autonomic insufficiency, 0.19 ± 0.12 μg/m2/min., but in the latter, despite reduced norepinephrine release, plasma norepinephrine concentration was near normal because of slowed clearance of norepinephrine from the circulation, 1.69 ± 0.44 l/min. compared with 2.80 ± 0.73 l/min. in normal subjects (p<0.05). In four normal subjects given the norepinephrine uptake inhibitor, desipramine, to slow removal of norepinephrine from the circulation, again the plasma concentration of neurotransmitter was higher than would be expected from the existing apparent release rate of norepinephrine. The findings suggest that methods which measure the dynamic processes of norepinephrine release and removal quantify sympathetic nervous activity better than steady state plasma norepinephrine measurements alone.

Increased Expression of the DNA-Binding Cytokine HMGB1 in Human Atherosclerotic Lesions: Role of Activated Macrophages and Cytokines

Objective—Atherosclerosis is a chronic inflammatory response of the arterial wall to injury. High-mobility group box 1 (HMGB1) is a DNA-binding protein, which on release from cells exhibits potent inflammatory actions. We examined its expression in atherosclerotic lesions and regulation by cytokines. Methods and Results—In atherosclerotic lesions, HMGB1 protein is expressed by endothelial cells, some intimal smooth muscle cells, and macrophages. As atherosclerosis develops and progresses from fatty streaks to fibrofatty lesion, the number of HMGB1-producing macrophages increases markedly. Studies using the THP-1 cell line indicated that HMGB1 mRNA expression could be markedly upregulated by inflammatory cytokines, interferon (IFN)-&ggr;, tumor necrosis factor (TNF)-α and also transforming growth factor (TGF)-β. IFN-&ggr;, TNF-α, TWEAK, and TGF-β induced an intracellular redistribution of HMGB1 and stimulated secretion by THP-1 cells and human blood monocytes. Inhibitors of MEK1/MEK2, protein kinase C, and PI-3/Akt, which inhibit lysosomal degranulation and mRNA translation, attenuated cytokine-induced HMGB1 secretion. Conclusions—Macrophage is the major cell type responsible for HMGB1 production in human atherosclerotic lesions. Inflammatory cytokines and TGF-β increase HMGB1 expression and secretion by monocyte/macrophages. HMGB1 appears to be a common mediator of inflammation induced by inflammatory cytokines and is likely to contribute to lesion progression and chronic inflammation.

Norepinephrine kinetics in essential hypertension. Defective neuronal uptake of norepinephrine in some patients.

SUMMARY To assess sympathetic nervous system function in essential hypertension, we measured tbe rates of release to and removal from plasma of the sympathetic neurorransmltter, norepinephrine. In normal subjects, disappearance of tritiated /-norepinephrlne from plasma, after infusion to steady state, was biexponential, with

Sympathoadrenal system is critical for structural changes in genetic hypertension.

= 2.0 ± 0.4 minutes (mean ± standard deviation) and

Angiotensin II and noradrenaline increase PDGF-BB receptors and potentiate PDGF-BB stimulated DNA synthesis in vascular smooth muscle

= 33 ± 15 minutes. Tbe rapid component of removal seemed to represent neuronal uptake of norepinephrine: the

Reduction of first‐pass hepatic clearance of propranolol by food

was lengthened by the selective inhibitor of neuronal norepinephrine uptake, desipramine; it was not changed by the extraneuronal uptake blocker, cortlsol; and it was prolonged in patients with peripheral sympathetic nerve dysfunction (idiopathic autonoroic insufficiency). In eight of 37 hypertensive patients, tbe