Weakly activated signaling cascades can be modeled as linear systems. The input-tooutput transfer function and the internal gain of a linear system, provide natural measures for the propagation of the input signal down the cascade and for the characterization of the final outcome. The most efficient design of a cascade for generating sharp signals, is obtained by choosing all the off rates equal, and a "universal" finite optimal length.

Changes induced by hydrochloric acid in the excitation spectrum of catecholamine fluorophores associated with the innervation of the canine renal vasculature show that there are neuronal elements at the glomerular vascular poles containing predominantly dopamine. In contrast, the catecholamine fluorescence in the periadventitial layer of the arcuate arteries is derived from norepinephrine. The dopamine-containing structures may represent the prejunctional counterpart to the pharmacologically identified dopamine receptors in the renal vasculature. As such, this system may be involved in the normal regulation of renal blood flow and renin release.

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Immunochemical and immunocytochemical techniques have been used to identify and characterize glucagon-related peptides of the rat central nervous system. These peptides show immunoreactivity with antiglucagon sera directed towards the central portion of the hormone, but not with antisera specific for the free COOH terminus of glucagon. Highest concentrations were found in hypothalamus (6.1 i 1.6 ng/g wet weight) although lower amounts (approximately 2 ng/g) were found in cortex, thalamus, cerebellum, and brain stem. During recent years, a number of intestinal peptides, including substance P (1, 2), vasoactive intestinal peptide (3, 4), and cholecystokinin (5-7), have been identified within the mammnalian brain. Immunoreactive and biologically active pancreatic insulin has also been identified in central nervous tissue of the rat and has been localized, in part, to cells in the olfactory lobe and hypothalamus (8). Conversely, somatostatin (9) and thyrotropin-releasing hormone (10), peptides originally identified in the hypothalamus, have now been found in pancreatic islets. Although in many cases the anatomical diversity of these peptides has yet to be explained functionally, these findings emphasize a close relationship among peptides of the nervous system and those of the pancreas and gastrointestinal tract. Peptides related to pancreatic glucagon occur in several tissues of the body and represent an unusual group of proteolytically modified forms: although gastric glucagon appears to be identical to the 29-residue hormone isolated from pancreas (11), intestinal glucagon-like peptides have higher molecular weights and contain the structure of the hormone extended from its NH2 and COOH termini (12-16). By structural (14, 15), immunocytochemical (16), and biosynthetic (17, 18) criteria, it appears that these larger peptides represent incompletely processed forms of proglucagon. The mapping of biological tissues for these glucagon-containing peptides thus permits an assessment of selective posttranslational modificationThe publication costs of this article were defyayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 6229as well as an examination of specific gene expression or cellular uptake. This report describes the identification and localization of higher molecular weight forms of glucagon within the brain of the rat. These peptides, like their intestinal counterparts, appear to have both NH2-terminal and COOH-terminal extensions on the glucagon sequence and probably result from a limited posttranslational modification of the glucagon ptcursor. While this work was in progress, two short reports on the subject appeared (19,20). MATERIALS AND METHODSAntisera and Radioimmunoassays. Three antisera directed against pancreatic glucagon were used in the studies reported here. Antiserum NS (15, 21) is a low-titer serum prepared in a chicken by using a glucagon-albumin conjugate. It reacts well with ...

Serum-deprived human fibroblasts (HSWP cells) were loaded with either the fluorescent pH indicator 6-carboxy-4',5'-dimethylfluorescein or the calcium indicator quin 2, and the fluorescence of the intracellular probes was continuously monitored with a microspectrofluorometer. Addition of a cocktail of peptide growth factors causes intracellular alkalinization, which is blocked by amiloride or by replacement of extracellular Na+ with choline, confirming that mitogenic stimulation activates a Na+-H+ exchanger in HSWP cells. The exchanger is also activated by A23187, acid loading the cells, and stimulation of phospholipase activity with melittin. Growth factors and melittin activation of the exchanger have been demonstrated to be dependent on the mobilization of Ca2+ from intracellular stores. The intracellular alkalization and increase in Ca2+ activity due to both melittin and growth factors is inhibited by phospholipase inhibitors, indicating that phospholipase activity is necessary for the activation of the Na+-H+ exchanger and the mobilization of intracellular Ca2+.

Probucol, 4,4'‐(isopropylidenedithio)bis(2,6‐di‐tert‐butylphenol), has been shown to inhibit atherogenesis in genetically hypercholesterolemic (Watanabe) rabbits. Since atherosclerotic lesions contain macrophages capable of screting interleukin 1 (IL 1) and other cytokines that could contribute to the pathogenesis of the disease, we have investigated whether probucol affects IL 1 secretion. Resident peritoneal macrophages from mice dosed with probucol secreted 40‐80% less IL 1 than macrophages from control animals when stimulated in vitro with lipopolysaccharide (LPS). The inhibitory effect of probucol was observed when IL 1 was assayed by the standard bioassay, the thymocyte proliferation assay, or a competitive IL 1 receptor binding assay. Probucol treatment had no effect on LPS‐induced membrane IL 1 expression; secretion of tumor necrosis factor (TNF); Con A‐induced splenic interleukin 2 (IL 2) and interleukin 3 (IL 3) release; and prostaglandin‐ or zymosan‐induced secretion of prostacyclin, leukotriene C4, acid phosphatase, or superoxide anion. In contrast to the effect of oral administration, direct addition of probucol to macrophage cultures did not inhibit IL 1 release. Probucol administration did, however, inhibit the fall in serum zinc level induced by intravenous injection of LPS in zymosan‐primed mice but had no effect on the LPS‐induced increase in serum triglyceride levels, which indirectly confirms that probucol administration inhibits IL 1 but not TNF secretion. Paw granuloma induced in mice by heat‐killed mycobacteria was inhibited by oral administration of probucol, an effect that may be attributable to inhibition of IL 1 secretion. Probucol neither reduced zymosan‐induced liver granulomata in mice nor inhibited adjuvant‐induced arthritis in rats. We suggest that inhibition of IL 1 secretion from macrophages by probucol contributes to its therapeutic effects in atherosclerosis and may also result in beneficial activity in some chronic inflammatory diseases.— Ku, G.; Doherty, N. S.; Schmidt, L. F.; Jackson, R. L.; Dinerstein, R. J. Ex vivo lipopolysaccharide‐induced interleukin 1 secretion from murine peritoneal macrophages inhibited by probucol, a hypocholesterolemic agent with antioxidant properties. FASEB J. 4: 1645‐1653; 1990.

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