The aim of this study was to investigate in human skin in vivo the role of nitric oxide in maintaining resting vascular tone, in the vasodilatation caused by local warming and by ultraviolet B light exposure, and in the response to exogenous calcitonin gene-related peptide (CGRP). Cutaneous blood flow was assessed by planimetry of the visible erythema or pallor and by laser Doppler flowmetry. Intradermal injection of the inhibitor of nitric oxide synthase, NG-nitro-L-arginine methyl ester (L-NAME; 25 nmol), into forearm skin produced a visible pallor and a reduction of blood flow at a controlled ambient temperature of 21 degrees C. The control, NG-nitro-D-arginine methyl ester (D-NAME; 25 nmol) or NG-monomethyl-L-arginine (L-NMMA; 25 nmol) did not cause pallor or reduce blood flow. L-NAME and L-NMMA caused dose- and time-dependent increases in pallor, and reductions in cutaneous blood flow in skin that had been locally warmed by immersion in water at 45 degrees C and in skin that had been exposed to ultraviolet B light. D-NAME and D-NMMA at comparable concentrations did not have the effects on skin blood flow observed with the L forms. L-NAME and L-NMMA both inhibited the increased blood flow in human skin caused by the intradermal injection of CGRP (12.5 or 25 pmol). The reduction of CGRP-induced increase of blood flow by L-NAME was reversed by L-arginine. Neither D-NAME nor D-NMMA inhibited the increase in blood flow caused by CGRP. Neither L-NAME nor L-NMMA inhibited the increase in blood flow in human skin caused by the intradermal injection of prostaglandin E2 (63 pmol). The data show that nitric oxide is involved in the maintenance of resting blood flow in human skin and also in the cutaneous vasodilator responses to local warming, ultraviolet B irradiation, or injection of CGRP.
We have attempted to reproduce the findings of Benveniste and co-workers, who reported in 1988 that degranulation of human basophil leukocytes is triggered by very dilute (10(2)-10(120)) antiserum against IgE. The results were contrary to conventional scientific theory and were not satisfactorily explained. Following as closely as possible the methods of the original study, we can find no evidence for any periodic or polynomial change of degranulation as a function of anti-IgE dilution. Our results contain a source of variation for which we cannot account, but no aspect of the data is consistent with the previously published claims.
1 Antigen-stimulated histamine secretion from rat peritoneal mast cells was inhibited when extracellular chloride was replaced by either isethionate or gluconate anions, but the histamine release still remained quite substantial. 2 Rat peritoneal mast cells take up 36C1 and the uptake reaches a steady state after 60 min incubation with the isotope. At steady state, the intracellular chloride level in the cells was calculated to be 29± 11.5mM. 3 The chloride uptake in mast cells was exponential with a rate constant of 0.036 min-' in resting cells. When the cells were stimulated with antigen, and rate constant for chloride uptake increased to 0.90 min-': an increase of 25 fold. Under identical experimental conditions histamine release increased 3 fold. 4 The rate of chloride uptake in either resting cells or in antigen-stimulated cells was not changed when the extracellular medium was nominally calcium-free but histamine release was almost completely inhibited in the absence of extracellular calcium. 5 The putative chloride channel blocker DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid) 0.3 to 30 MM, produced a concentration-related inhibition of antigen-stimulated histamine secretion but DIDS (30 MM) did not inhibit the antigen-stimulated increase of chloride uptake. 6 The cyclic AMP analogue, dibutyryl cyclic AMP (1 mM) produced a delayed increase in chloride uptake in resting mast cells but neither dibutyryl cyclic AMP nor 8-bromo cyclic AMP per se induced any histamine secretion. 7 Ouabain (1 mM) which inhibits the Na+/K+ ATPase in rat peritoneal mast cells, failed to affect the uptake of chloride in resting mast cells. 8 The Na/K/2C1-cotransport inhibitor, furosemide (0.7 mM), slowed the unstimulated chloride uptake in resting mast cells and abolished the increased antigen-induced chloride uptake when added together with antigen. In contrast, spontaneous and antigen-induced histamine release were unaffected by the presence of furosemide. However, when furosemide was added to the cell suspension 5 min before stimulation, furosemide was without effect on the antigen-induced chloride uptake. 9 In addition to the chloride uptake mediated by chloride channels which may be related to the mechanism of histamine secretion, crosslinking of the high affinity membrane receptors for IgE is followed by a fast chloride uptake that is likely to occur through a furosemide-sensitive Na/K/2C1-cotransporter.
The action of the neuropeptide substance P as a histamine-releasing agent has been compared in histamine-containing cells from a variety of different tissues and species. Peritoneal mast cells from rat, mouse and hamster but not human cells gave a concentration-dependent release of histamine in response to substance P. Release was greater in the absence than in the presence of calcium in the extracellular medium. Mast cells from rat mesentery, lung and heart released histamine in response to substance P, but heart mast cells responded only weakly. All guinea-pig mast cells and histamine-containing cells from human tissues did not give any substantial substance-P-induced release of histamine. The data provides further evidence for the functional heterogeneity of histamine-containing cells.
It has been argued that the digital cutaneous microvasculature is the site of the anomaly which causes Raynaud's phenomenon (RP). Both endothelin-1 (ET-1), a potent vasoconstrictor peptide present in the digital cutaneous microvasculature, and calcitonin gene-related peptide (CGRP), a powerful vasodilator present in digital cutaneous perivascular nerves, have been implicated in the pathogenesis of RP. Circulating ET-1 levels are raised, and there is a diminution of CGRP-containing perivascular nerves in finger skin in RP. We undertook a pharmacological study to investigate the sensitivity of the digital cutaneous microvasculature to intradermal ET-1 and CGRP. Differences were found in RP compared with normal digital skin, supporting the idea that the digital cutaneous microvasculature is actively involved in the pathogenesis of RP. In RP, the erythematous response to ET-1 was diminished at both 20 and 5 degrees C (a low temperature at which RP classically occurs) providing pharmacological support for the morphological evidence that in RP there is a deficiency of CGRP-containing nerves in the distal digital skin.
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