thioperamide and Anaphylaxis

In anaphylactic shock (AS), the relative effects of the autacoids including histamine, prostaglandins, and leukotrienes on causing cardiovascular collapse and the extent to which receptor blocking agents and pathway inhibitors may prevent this collapse are not clear. In a ragweed model of anaphylaxis, we examined whether pretreatment with H1, H2, H3 receptor blockers, and cyclooxygenase and leukotriene pathway inhibitors was useful in preventing the depression in left ventricular (LV) contractility known to occur in this model. The dose of allergen was varied to produce similar degrees of shock between treatments. The animals were studied under pentobarbital anesthesia in which the treatment studies were approximately 3 wk apart. LV volumes were measured by sonomicrometric techniques. During challenge, mean arterial blood pressure (Pa), cardiac output (Q), and LV end-diastolic pressure (LVEDP) decreased approximately 50% compared with preshock values in all treatments. Histamine H3 receptor blockade was associated with higher heart rates (HR) and higher stroke work (SW) (p < 0.05) as compared with the other treatment studies. We conclude that histamine H3 activation by inhibiting adrenergic neural norepinephrine release contributes to cardiovascular collapse in AS.

Topics: Anaphylaxis; Animals; Chlorpheniramine; Cyclooxygenase Inhibitors; Dogs; Hemodynamics; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Indoles; Indomethacin; Leukotrienes; Lipoxygenase Inhibitors; Myocardial Contraction; Piperidines; Prostaglandins; Quinolines; Ranitidine; Receptors, Histamine H3; Stroke Volume; Ventricular Function, Left

In anaphylactic shock (AS), the relative effects of the autacoids including histamine, prostaglandins (prost), and leukotrienes (leuk) on causing cardiovascular collapse and the extent to which receptor blocking agents and pathway inhibitors may prevent this collapse are not clear.. In randomized design, we investigated whether blockade of histamine H1, H2, and H3 receptors or inhibition of the cyclooxygenase (cyclo) and lipoxygenase pathways (lipox) prevented AS in ragweed sensitized dogs. Seven dogs were studied under pentobarbital anesthesia in which the treatment studies were approximately 2 weeks apart.. During H1 receptor blockade, the decreases in blood pressure and cardiac output otherwise observed in AS were attenuated (P < 0.05) and the release of prost, thromboxanes, and leuk were reduced as compared with nontreatment studies. Cyclo inhibition also attenuated cardiovascular collapse and mediator release in AS, but the other treatments showed no effects.. H1 receptor blockade and cyclo may attenuate cardiovascular shock in AS. These agents inhibit autacoid release from mast cells in addition to any specific receptor blocking and pathway inhibition effects.

Topics: Analysis of Variance; Anaphylaxis; Animals; Cardiovascular System; Cyclooxygenase Inhibitors; Dogs; Hemodynamics; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Indoles; Indomethacin; Inflammation Mediators; Lipoxygenase Inhibitors; Piperidines; Quinolines; Random Allocation; Ranitidine; Receptors, Histamine H3

Anaphylactic histamine release from isolated rat peritoneal mast cells was concentration-dependently blocked by a 5-min treatment with exogenous histamine at 0.9 and 9 microM and enhanced by a 20- to 30-min treatment with thioperamide (H3-antagonist) at 3 microM with significance, but little affected by mepyramine (H1-antagonist) and cimetidine (H2-antagonist) at the cell concentration of 10(6) mast cells/ml. At a low concentration of mast cells (10(4) mast cells/ml), (R)-alpha-methylhistamine (alpha-MH), an H3-agonist, at 0.9-90 microM also inhibited the release in a concentration-dependent fashion. Thioperamide, but neither mepyramine nor cimetidine, significantly restored the decreased release by alpha-MH. However, the complete restoration by thioperamide could not be achieved because the drug itself slightly but concentration-dependently inhibited anaphylactic histamine release. On the other hand, not only betahistine and dimaprit but also alpha-MH did not suppress histamine release from the mast cells induced by compound 48/80. In rat plasma, considerable levels of histamine were detected. From these results, it is strongly suggested that histamine H3-like receptors are largely responsible for the negative feedback regulation of the anaphylactic histamine release from rat peritoneal mast cells.

Topics: Anaphylaxis; Animals; Anticonvulsants; Chromatography, High Pressure Liquid; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Histamine; Histamine Agonists; Histamine Antagonists; Histamine Release; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Mast Cells; Methylhistamines; p-Methoxy-N-methylphenethylamine; Peritoneal Cavity; Peritoneum; Piperidines; Pyrilamine; Rats; Rats, Wistar; Receptors, Histamine H3

Whether anaphylactic histamine release from rat peritoneal mast cells is influenced by betahistine, a histamine H1-receptor agonist/H3-antagonist, and dimaprit, an H2-agonist, was examined. Treatment with dimaprit at 6 and 60 microM for 20 min significantly inhibited the anaphylactic histamine release, whereas betahistine at up to 80 microM under the same conditions did not affect it. Treatment with dimaprit at 6 and 60 microM for 1 to 20 min and for 5 to 20 min, respectively, caused a time-dependent inhibition of the release, but up to 30 min treatment with 8 and 80 microM betahistine had no effect. The decreased histamine release induced by dimaprit was recovered by neither mepyramine nor cimetidine. However, thioperamide, an H3-selective antagonist, dose-dependently restored the diminished release. From these results, the inhibition of anaphylactic histamine release by dimaprit is not produced by the stimulation of H2-receptors, but involves the stimulation of H3-like receptors or H3-subtype receptors, which are distinct from the H3-receptors located in brain, and suggests that the receptor plays an important role in the negative feedback regulation of histamine release.

Topics: Anaphylaxis; Animals; Anticonvulsants; Betahistine; Cimetidine; Dimaprit; Histamine H2 Antagonists; Histamine Release; In Vitro Techniques; Indicators and Reagents; Male; Mast Cells; Piperidines; Pyrilamine; Rats; Rats, Wistar