Histamine isolation

The histamine content of isolated HHMC (=3 pg/cell) was comparable to lung parenchymal and skin mast cells. The mean tryptase content of HHMC (=24 pg/10 cells)... 

FIGURE 1.6 Interaction between the full agonist histamine and the H2-receptor partial agonist impromidine on isolated ventricular strips from human myocardium. The concentration-response curve on the left is for histamine alone, and those on the right show the response to impromidine acting either on its own (open squares) or in the presence of a constant concentration (100 pM) of histamine (open diamonds). (From English, T. A. H. et al Br. J. Pharmacol., 89, 335-340, 1986.)... 

Black, J. W., Leff, R, and Shankley, N. R, Further analysis of anomalous pXj values for histamine H2-receptor antagonists on the mouse isolated stomach assay, Br. J. Pharmacol., 86, 581-587, 1985. 

Nakamura, H., Sano, H., Yamazaki, M., Sugiyama Y., Carrier-mediated active transport of histamine H2 receptor antagonists, cimetidine and nizatidine, into isolated rat hepato-cytes contribution of type I system,... 

Inhibition by H3 receptor may not be direct. Release measured by in vivo techniques. Release from isolated perfused heart. 5Sorne effects of histamine on dopaminergic parameters found to depend on noradrenergic activity. 

FIGURE 14-3 Synthesis and metabolism of histamine. Solid lines indicate the pathways for histamine formation and catabolism in brain. Dashed lines show additional pathways that can occur outside the nervous system. HDC, histidine decarboxylase HMT, histamine methyltransferase DAO, diamine oxidase MAO, monoamine oxidase. Aldehyde intermediates, shown in brackets, have been hypothesized but not isolated. 

Histamine synthesis in the brain is controlled by the availability of L-histidine and the activity of histidine decarboxylase. Although histamine is present in plasma, it does not penetrate the blood-brain barrier, such that histamine concentrations in the brain must be maintained by synthesis. With a value of 0.1 mmol/1 for L-histidine under physiological conditions, HDC is not saturated by histidine concentrations in the brain, an observation that explains the effectiveness of large systemic doses of this amino acid in raising the concentrations of histamine in the brain. The essential amino acid L-histidine is transported into the brain by a saturable, energy-dependent mechanism [5]. Subcellular fractionation studies show HDC to be localized in cytoplasmic fractions of isolated nerve terminals, i.e. synaptosomes. 

Neurotensin (NT) is a tridecapeptide (Table 4.2) first isolated from brain and gut by Carraway and Leeman [75] and reported by them to induce a rapid and transient hypotension, a cutaneous vasodilatation, and a cyanosis of the extremities in the anaesthetized rat. This report, along with others [76-78] indicating that the NT-induced hypotension and increased vascular permeability could be blocked by histamine receptor antagonists such as mepy-ramine [77] or by pretreatment with compound 48/80 [76], suggested that endogenous histamine (perhaps released from tissue mast cells) was involved in producing some of the biological effects of NT [78]. 

NT was initially reported to stimulate the non-cytotoxic release of histamine from isolated rat peritoneal mast cells by workers in our laboratory [40, 79]. This observation has now been confirmed and extended by several other workers [80-85]. When added to isolated rat serosal mast cells, NT initiates the secretion of histamine which is dependent upon calcium and energy [79]. Secretion begins at about 10 nanomolar NT and reaches an initial plateau of some 20% histamine release at 10 piM NT [79] (Figure 4.2) while higher levels... 

Some workers have reported a failure of NT to elicit significant histamine release (< 5% at 10 /xM NT) from isolated peritoneal mast cells obtained from Wistar strain rats [82]. In these studies, when NT was added to mast cells from the pleural cavity [82] or when the C-terminal octapeptide (NT6 13) or the C-terminal hexapeptide (NT8 13) was added to peritoneal mast cells, a significant (>20% histamine release) secretory response occurred [82]. In our laboratory a significant difference in the responsiveness to NT of peritoneal and pleural mast cells from Sprague-Dawley rats has also been found, pleural cells eliciting a higher percentage of histamine release than peritoneal cells for an equimolar concentration of NT (19.2 2% release for peritoneal mast cells versus 45 + 6% release for pleural mast cells at 10 /xM NT). Moreover, we have also observed anecdotally differences between various populations of mast cells and between various populations of rats in terms of their responsiveness to the same batch of NT. 

The ability of SP to stimulate histamine release from isolated rat peritoneal mast cells is now well demonstrated [31, 97-101], The release is rapid (< 1 min), non-cytotoxic, dependent on a supply of Ca and metabolic energy, and independent of cell-bound IgE [99]. Moreover, as with other peptides, its secretory effect on the mast cell is affected by moderate levels of extracellular cations. For example, the addition of Ca to the bathing medium after the addition of SP increased the secretory response of the cells, while adding calcium (0.1-1 mM), magnesium (1-10 mM) or cobalt (0.01-1 mM) to the cell suspension before SP inhibited histamine release, suggesting the possibility of cation competition for SP binding [99]. 

In humans, the intradermal injection of SP (10 7-10 5 M) produces a flare, wheal and itching, and these effects are prevented by pretreatment with chlorcyclizine (an antihistamine) or by local pretreatment with compound 48/80 [ 103, 104]. It causes histamine release from sections of human foreskin [105]. These authors suggested that SP is significantly less active on isolated rat peritoneal mast cells than in human skin. 

Dynorphin, a-neoendorphin and /1-endorphin each produced a dose-dependent (10 6 M to 10 4 M) release of histamine from rat peritoneal mast cells but not from rat mucosal mast cells which were isolated following collagenase digestion [128]. When administered intradermally to the forearms of human volunteers, dynorphin, /f-endorphin, Leu-enkephalin and morphiceptin each produced a wheal and flare reaction at nM concentrations. Mast cell degranulation was confirmed by electron microscopy of biopsy samples and by its inhibition by hyroxyzine pretreatment [129]. 

Several other cell types have also been shown to secrete histamine-releasing activity, some of which may be peptide in nature (although more work is necessary for a definitive characterization). For example, human lung macrophages cultured for 24 h have been shown to release a soluble factor (12 and 30 kDa) that stimulates isolated human lung mast cells and human basophils to release histamine [ 145]. The generation and release of this factor developed over time (> 1 h) and was blocked by cycloheximide, indicating that protein... 

Bk has been shown to stimulate histamine release from isolated peritoneal rat mast cells [30, 87] and this secretory response, like that elicited by other peptides, requires a source of metabolic energy and is prevented by depletion of cellular Ca [30, 87]. The subsequent treatment of such cellular Ca-depleted mast cells with Bk produces an inactivation or desensitization phenomenon to the subsequent addition of extracellular Ca (secretion declines as the time... 

Figure 4.6. Log dose-response relationships for the effects of synthetic neurotensin, synthetic brady-kinin, and various preparations of NRP on the release of histamine from isolated rat mast cells [73], Each point is the mean obtained for two separate incubations.

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