Organophosphate-induced histamine release from mast cells.

To examine the hypothesis that soman intoxication leads to degranulation of mast cells with the release of histamine, we studied the effects of soman on rat peritoneal mast cells (RPMC) in vitro and in vivo. In vitro studies were performed with RPMC harvested from Edgewood rats, and challenged with soman (10(-8)-3 X 10(-3) M) in Tyrode's buffer. The RPMC exhibited a dose-dependent release of histamine, with maximal release of 50% at 3 to 6 X 10(-4) M. The release process is an active, secretory, noncytotoxic event, which is calcium and temperature dependent, requires metabolic energy and is influenced by intracellular levels of cyclic AMP. We next studied the in vivo effects of disodium cromoglycate (DSCG, 10(-4) M) on soman and Compound 48/80-induced histamine release. In vivo studies were performed by the i.p. injection of 5 ml of Tyrode's buffer containing soman (O-1 LD50), or Compound 48/80 as a positive control, with or without DSCG. The fluid recovered after approximately 10 min in the peritoneal cavity was examined for percentage of histamine release. In vivo, Compound 48/80 induced 49 +/- 1% histamine release, with no inhibition by DSCG (Compound 48/80 plus DSCG induced 49 +/- 0.4% histamine release). On the other hand, soman (1 LD50) induced 17 +/- 5% extracellular histamine release, with complete inhibition by DSCG (soman plus DSCG induced 3 +/- 1% histamine release). The data indicate that soman induced a dose-dependent release of histamine from RPMC, and provide evidence that histamine is a potentially important mediator of the pathophysiological response to organophosphate intoxication.(ABSTRACT TRUNCATED AT 250 WORDS)

WR-2721 inhibition of radiation-induced prostaglandin excretion in rats.

Pre-irradiation administration of the radioprotectant drug WR-2721 to rats resulted in a significant reduction in radiation-induced increases in excretion rates of prostaglandins (PGE and PGF2 alpha) and thromboxane (TxB2). In animals not irradiated. WR-2721 did not significantly alter these excretion rates. Dramatic reductions in the levels of urinary PGE and TxB2 were observed following exposure to 9.0 Gy of whole-body, unilateral gamma-radiation in WR-2721-treated animals, whereas changes in PGF2 alpha levels were less pronounced. Radiation-induced diuresis was also significantly depressed in animals given WR-2721 before irradiation. Reduced prostaglandin excretion rates may reflect the general radioprotective capacity of the chemoprotector WR-2721 on the release of prostaglandins from radiation-damaged tissue. The decrease in diuresis may be related to the observed prostaglandin decreases.

Effect of proteases on the beta-thromboglobulin radioimmunoassay.

Rat peritoneal mast cells and mast cell granules were evaluated by radioimmunoassay for the presence of beta-thromboglobulin and platelet factor 4. The initial assays indicated that a beta-thromboglobulin cross reacting material was released from mast cells by compound 48/80 in a similar dose-dependent manner as histamine release. The material was also found to be associated with purified granules. However, the use of protease inhibitors in the buffers completely abolished the positive assays. Further evaluation of the effects of various proteases on the beta-thromboglobulin assay indicated that elastase would also generate a false positive assay which could then be neutralized by the use of alpha 1-antitrypsin as a protease inhibitor. There was no protease effect on the platelet factor 4 radioimmunoassay which always showed no detectable amounts with mast cells, granules or proteases. These results clearly indicate the artifactual positive assays which can arise when using certain radioimmunoassay tests in the presence of cell proteases. The use of protease inhibitors is a necessary control when applying a radioimmunoassay to a system with potentially active proteases.

Canine postradiation histamine levels and subsequent response to Compound 48/80.

Radiation-induced hypotension in the beagle is accompanied by increased intestinal blood flow (IBF) and hematocrit (HCT). This study was performed to correlate these radiation-induced changes with plasma histamine (PH) levels following radiation. The histamine (H) levels were monitored in the systemic arterial circulation (SA) and the hepatic portal vein (HPV) before and after radiation. To examine the effect of radiation on the mobilization of total body H stores, Compound 48/80 was given I.V., and H responses were monitored in both control and radiated animals. Data obtained indicated that 100 Gy, whole-body, gamma-radiation produced a decrease in systemic mean blood pressure (BP), an increase in IBF and an increase in HCT. Concurrently, the mean PH/SA values increased and the PH/HPV levels decreased. Compound 48/80 produced a marked increase in PH levels in both control and radiated animals; however, the levels found in the radiated animals were consistently lower than those in the controls, although not statistically different. This implies that H may mediate these observed intestinal responses and that the mobility of histamine is decreased in radiated animals.

Plasma histamine and hemodynamic responses following administration of nalbuphine and morphine.

A comparative study of plasma histamine levels following administration or morphine and nalbuphine in pentobarbital anesthetized dogs was performed. Two concentrations, 3 mg/kg and 0.3 mg/kg of these drugs were investigated. High dose morphine caused an immediate marked increase in plasma histamine from 5.0 +/- 0.4 to 340 +/- 72 ng/ml. Simultaneous with this increase in plasma histamine was a marked decrease in mean arterial blood pressure within the first minute. In contrast significant alterations in plasma histamine levels were not observed with high or low doses of nalbuphine. A low dose of morphine (0.3 mg/kg) did not increase plasma histamine levels. Heart rate was not changed by any drug treatment. The use of compound 48/80 a specific mast cell degranulating agent allowed for the identification of a specific pool of mast cells capable of responding to morphine. In vitro exposure of purified dog leukocytes to high doses of morphine did not result in histamine release. These results indicate that nalbuphine does not increase plasma histamine, while morphine does, and that the source of the increase in plasma histamine is from tissue mast cells.

Radiation-induced alterations in prostaglandin excretion in the rat.

Dose-related alterations in the levels of prostaglandins (PGF2 alpha and PGE) and thromboxane B2 (TxB2) were observed in the urine of unanesthetized rats following whole-body gamma radiation. Exposure doses of 100 and 900 rads resulted in significant changes in urinary levels of these cyclooxygenase products. These findings suggest the potential use of radioimmunoassay measurement of urinary prostaglandins and thromboxane as a noninvasive indicator of radiation exposure.