A. Sydbom

Histamine release from isolated rat mast cells by neurotensin and other peptides

The histamine-releasing activity of some basic peptides was tested on mast cells from Sprague-Dawley or Brown Norway rats. Somatostatin, bombesin, vasoactive intestinal peptide (VIP) or substance P did not give any histamine release in concentrations up to 10−6M. Somatostatin in 10−5M concentration released 25% of total histamine. However, neurotensin induced a significant histamine release from Brown Norway mast cells at 10−8M. The neurotensin-induced histamine release was found to be selective and in some aspects similar to that induced by compound 48/80.

The histamine-releasing effect of dynorphin and other peptides possessing Arg-Pro sequences

The basic opioid peptide dynorphin was tested for histamine-releasing activity on peritoneal rat mast cells. Dynorphin was found to induce a dose-dependent histamine release from the mast cells. The threshold concentration was 2×10−7M and release was maximal (40% of total) at 2×10−6M of the peptide. The dynorphin-induced histamine release was a very rapid process completed within 10 seconds at 37°C. The release was independent of extracellular calcium. Experiments with naloxone and a specific kappa-agonist (U-50,488H) gave results indicating that the dynorphin induced histamine release was probably not mediated through opioidk-receptors.A couple of other Arg-Pro containing peptides of different origin were also screened for histamine-releasing activity. Most of these peptides elicited a more or less pronounced histamine release, provided the peptide contained more than 5 amino acids, suggesting that the Arg-Pro sequence is of importance for the histamine-releasing effect of peptides such as dynorphin.

Are the anti-allergic actions of theophylline due to antagonism at the adenosine receptor

Adenosine potentiated anaphylactic histamine release from isolated rat mast cells in a dose-dependent manner between 10−8 and 10−5M. Adenosine was found to be present during a normal incubation of mast cells, but the concentration was low (2×10−8M). In rat plasma the concentration was 1.5×10−7M. The effect of 10−5M adenosine was dose-dependently inhibited by theophylline. 50% inhibition was found at 3×10−5M theophylline. Cyclic nucleotide phosphodiesterase inhibition required much higher concentrations (IC50∼10−3M). It is suggested that some of the anti-allergic actions of theophylline (clinical concentration range: 10−5–10−4M) does not involve cyclic nucleotides but may be due to inhibition of the effects of endogenous adenosine.

Prostaglandin modulation of mast cell-dependent inflammation.

ConclusionsProstaglandin E2 may have a dual action during acute inflammation: 1. Inhibition of inflammatory mediator release, and 2. Enhancement of mediator target action, presumably by increasing local blood flow/pressure.The PGE2-sensitive enhancement of the antigen response by indomethacin suggests that endogenous vasodilating prostaglandins (possibly PGE2) predominantly were antiinflammatory.The antiallergic action of PGE2 was most likely secondary to inhibited release of inflammatory mediators from mast cells. One of these mediators was identified as histamine.

Prostaglandin E2 prevents diclofenac-induced enhancement of histamine release and inflammation evoked byin vivo challenge with compound 48/80 in the hamster cheek pouch

Based on observations obtained by the use of intravital microscopy, we report that prostaglandins, (PGs) can exert inhibitory effects on mast cell-dependent inflammation. Thus, the PG-synthesis inhibitors diclofenac and indomethacin potentiated extravasation of plasma evoked by challenge with the mast cell secretagogue compound 48/80. Although the plasma leakage induced by compound 48/80 was in large mediated by histamine, neither diclofenac nor indomethacin potentiated the plasma leakage caused by exogenous histamine. These findings indicated that endogenous PGs inhibited the mast cell-dependent reaction at the level of mediator release. This mode of action was confirmed, as diclofenac was found to enhance thein vivo release of histamine that ensued challenge with compound 48/80. Moreover, the enhancement of the response to compound 48/80 observed after diclofenac treatment was prevented by local administration of PGE2 (30 nM). This inhibition included both the histamine release and the plasma leakage. In addition, diclofenac enhanced the leukocyte emigration after compound 48/80 challenge, and PGE2 reversed also this effect, suggesting that endogenous PGs (e.g. PGE2) also inhibited the release of chemotactic, mediators.

Stimulus-dependence and time-course of histamine and leukotriene release from chopped and dispersed human lung tissue

The calcium ionophore A23187 and anti-human IgE provoked a dose-dependent release of histamine and cysteinyl-leukotrienes (LTC4, LTD4 and LTE4) from dispersed human lung cells. Optimal release of histamine peaked at 3 min after challenge whereas the release of cysteinyl-leukotrienes peaked at 30 min. The molar ratio between released histamine and cysteinyl-leukotrienes was approximately 100∶1. The ionophore, but not anti-IgE caused additional formation of LTB4 in the dispersed cells or the chopped lung, indicating that this chemoattractant is formed from cells not primarily activated by IgE-dependent mechanisms. Indomethacin failed to alter release of histamine or leukotrienes from dispersed cells, whereas further inhibition of lipoxygenases by NDGA abolished leukotriene formation and reduced the release of histamine.

Stimulation of histamine release by the peptide kinetensin

The peptide kinetensin isolated from pepsin-treated human plasma induced a dose-dependent release of histamine when exposed to rat peritoneal mast cells. The threshold concentration was around 10−6M, the ED50 was 10−5M, and the optimal concentration of between 10−4 to 10−3M released 80% of the total histamine. Kinetensin was 10 to 100 times less potent than neurotensin and equipotent with the opioid peptide dynorphin. The histamine release was clearly temperature-dependent, with no release occurring at 0° or 45°C and with an optimum around 37°C. The histamine release was significantly reduced in the absence of extracellular calcium. Kinetensin also induced a dose-dependent increase in vascular permeability when injected intradermally into rats. The findings indicate that kinetensin is a potent histamine releaser in the rat and may serve as an inflammatory mediator.

Effects of β-endorphin on rat mast cells

The endogenous opioid peptide β-endorphin induced a dose-dependent release of histamine from rat peritoneal mast cells. The threshold concentration was around 10−6M and the optimal concentration of 2×10−5M released 35% of the total histamine. The release of histamine was very rapid, complete within 10 s, and very similar to that induced by neurotensin or compound 40/80. The histamine release was temperature dependent and inhibited at increased extracellular calcium concentrations. Taken together, the findings indicate that the release of histamine induced by β-endorphin is a specific, energydependent process. The pattern of release has much in common with that induced by other basic peptides, such as neurotensin, dynorphin and substance P.

Histamine secretion induced by neuromedin-N

Neuromedin-N dose-dependently stimulated the release of histamine from rat serosal mast cells and was 10 to 100 times less potent than neurotensin. The threshold concentration was 10−6M, and 10−3M neuromedin-N released 31% of the total cell histamine content. The histamine release induced by neuromedin-N was temperture-dependent with an optimum around 30–37°C. Skin vascular permeability increased dose-dependently in response to intradermal injections of neuromedin-N and this peptide was 10 to 100 time less potent than neurotensin. Mepyramine inhibited the effect on vascular permeability suggesting that the effect of neuromedin-N was mediated via the release of histamine.

Sir James Black and the European Histamine Research Society

I first met Sir James Black at the International Pharmacology Meeting in Helsinki in 1975. I was a young PhD student in my very first years and had the honour to be seated next to him at a dinner banquet. He was very kind and amusing and gave me lots of friendly advice for my work and experiments. Later I was also given some samples of the H2 blockers, burimamide and metiamide, to test in my system with rat isolated mast cells.