5-hydroxy-6-8-11-14-eicosatetraenoic-acid and Bronchial-Spasm

The likelihood that the leukotriene products derived from the 5-lipoxygenase pathway mediate aspects of obstructive airways diseases is strongly suggested by their documented capacities to effect airway spasmogenicity, airway hyperreactivity, tissue edema formation, mucus secretion, and tissue infiltration by leukocytes. That the various leukotriene components of SRS-A have unique receptors on responding tissues and are recoverable from airway surfaces in several inflammatory lung diseases and that several resident and infiltrating cell types have significant potential for leukotriene biosynthesis lend further support to their postulated pathobiologic roles. To fulfill Koch's postulates for proof of leukotrienes' etiologic role, it remains to be shown that inhibition of their biosynthesis or specific antagonism at their end-organ receptors can greatly ameliorate these disease states.

Topics: Animals; Arachidonate Lipoxygenases; Bronchial Spasm; Dose-Response Relationship, Drug; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Leukotriene B4; Lipoxygenase; Lung; Lung Diseases, Obstructive; Macrophages; Mast Cells; Monocytes; Pulmonary Alveoli; Pulmonary Ventilation; Receptors, Leukotriene; Receptors, Prostaglandin; SRS-A; Vital Capacity

Several calcium-entry blockers, i.e., verapamil, nifedipine, flunarizine and diltiazem, were evaluated for their effects in models of immediate hypersensitivity disease. Verapamil, flunarizine and diltiazem were all effective in inhibiting antigen-induced bronchospasm in the guinea pig; however, the effects seen were at relatively high doses compared to the doses known to cause cardiovascular effects. Nifedipine caused no significant inhibition of resistance or compliance changes induced by antigen. Flunarizine, verapamil and diltiazem were ineffective in inhibiting antigen-induced histamine release from rat peritoneal mast cells in vitro. Although these compounds were active inhibitors of 5-D-[5,6,8,9,H,12,14,15-3H(N)]-hydroxy-6,8,11,14-eicosatetraenoic acid production in rat basophilic leukemia-1 cells, only flunarizine and verapamil showed effects on the 5-lipoxygenase enzyme when assayed directly. Also, these compounds were ineffective on SRS-A mediated bronchospasm in vivo. These data suggest that the currently available calcium entry blockers have little potential use in immediate hypersensitivity reactions.

Topics: Animals; Arachidonate Lipoxygenases; Arachidonic Acids; Bronchial Spasm; Calcium Channel Blockers; Cinnarizine; Diltiazem; Flunarizine; Guinea Pigs; Histamine Release; Hydroxyeicosatetraenoic Acids; Hypersensitivity, Immediate; Lipoxygenase; Male; Mast Cells; Nifedipine; Rats; Verapamil