Marvin M. Goldenberg

Pharmacological effects of non-steroidal antiinflammatory agents on prostaglandin and leukotriene synthesis in mouse peritoneal macrophages

Resident mouse peritoneal macrophages, exposed to zymosan, synthesized and released products of both the cyclooxygenase and lipoxygenase pathways. The effects of various non-steroidal antiinflammatory agents were evaluated for their abilities to inhibit zymosan-stimulated prostaglandin E2 (PGE2) and leukotriene C4 (LTC4) synthesis. The order of potencies to inhibit PGE2 synthesis and release was: indomethacin greater than or equal to sulindac sulfide greater than ibuprofen greater than or equal to aspirin greater than 3-amino-1-[3-(trifluoromethyl)-phenyl]-2-pyrazoline (BW755C) greater than benoxaprofen greater than or equal to nordihydroguaiaretic acid (NDGA) greater than 5,8,11-eicosatriynoic acid (ETYA). BW755C and ETYA also inhibited zymosan-stimulated LTC4 production. None of the compounds tested showed selective inhibition of lipoxygenase products.

The reactivity of rat isolated gastrointestinal tissues to leukotrienes.

Synthetic leukotriene C4 (LTC4) and leukotriene D4 (LTD4) elicit concentration-dependent contractile responses of the stomach and colon of the rat. These responses were inhibited by FPL 55712, the SRS-A antagonist. The duodenum and ileum of the rat failed to respond to either LTC4 or LTD4. Therefore the stomach and colon of the rat posses leukotriene receptors, while such receptors are absent in the duodenum and ileum of the rat.

Pharmacological evidence for a role of lipoxygenase products in platelet-activating factor (PAF)-induced hyperalgesia

Platelet-activating factor (PAF), a potent inflammatory mediator, decreases the nociceptive threshold in the rat hindpaw. Pain sensitivity, measured by the applied pressure necessary to induce vocalization, was increased maximally at 3 and 4 hr after injection of synthetic PAF. The hyperalgesic response to PAF was specifically inhibited by agents that interfere with the lipoxygenase pathway of arachidonic acid metabolism and was not affected by cyclooxygenase inhibitors. BW-755C (3-30 mg/kg, p.o.) and L-615,919 (0.01-0.3 mg/kg, p.o.) significantly reduced PAF-induced hyperalgesia, whereas indomethacin had no effect. The finding that L-615,919, a specific 5-lipoxygenase inhibitor, was a potent inhibitor of this model of hyperalgesia leads to speculation that leukotrienes are important mediators of inflammatory pain.

A pharmacologic analysis of the action of platelet-activating factor in the induction of hindpaw edema in the rat.

Platelet-activating factor (PAF), a phospholipid product of neutrophils, alveolar macrophages, monocytes, and platelets and an important mediator of inflammatory reactions, was studied for its ability to evoke hindpaw edema in the rat. PAF caused edema, peaking at 1 hr and gradually declining over the next 2 hr. The H1 and H2 antihistamines, mepyramine and cimetidine, the serotonin/histamine antagonist, cyproheptadine, and the serotonin antagonist, methysergide, were ineffective in reducing PAF-induced paw edema. Indomethacin, acetylsalicylic acid, and dexamethasone did not inhibit the peak edematous response but significant reduction was noted with only dexamethasone at 3 hr. Prazosin and propranolol did not prevent PAF-induced edema, whereas, yohimbine, phentolamine, rauwolscine, verapamil and theophylline partially inhibited edema. Clonidine and guanfacine did not induce edema when injected into the rat hindpaw. These results suggest that PAF elicits edema at vascular sites of the rat hindpaw which are partially dependent on extracellular Ca2+ movement, are not due to alpha-1 or alpha-2-adrenoreceptor stimulation, histamine, serotonin, or prostaglandin activity, and demonstrates variable sensitivities to agents blocking Ca2+ entry. Inhibition of specific PAF-sensitive receptors await the discovery of specific PAF antagonists.

The effect of calcium antagonists on contractions of the sensitized and normal guinea pig ileum

The purpose of this study was to learn whether a number of Ca2+ antagonists were effective in reducing contractile responses of the isolated ileum of the sensitized and normal guinea pig. Contractions of the normal ileum in response to LTD4, acetylcholine, histamine, and potassium chloride were obtained before and after verapamil, diltiazem and papaverine. Ovalbumin-induced contractions of the ovalbumin-sensitized ileum were obtained in the presence of the three Ca2+ antagonists. In the normal ileum, all the Ca2+ antagonists were highly effective in diminishing the contractile responses to LTD4, acetylcholine, histamine and potassium chloride. In the sensitized ileum, ovalbumin-evoked contractions, with subsequent release of a potent contractile mediator (presumably SRS-A), were Ca2+-dependent since verapamil, diltiazem and papaverine caused a concentration-related reduction of contractions. Thus, the influx of extracellular Ca2+ plays a key role in the contractile responses of the normal and sensitized guinea pig ileum when stimulated by various potent agonists acting on specific receptors or on the cell membrane.