Pharmacology of Leukotriene C4 in Guinea-Pig

Abstract

A central role of polyunsaturated fatty acids as precursors of various substances which can act as mediators or modulators of different cellular functions is widely recognized. The recent discovery that some arachidonic acid metabolites, derived from 5-1ipoxigenase pathway, can display potent biological actions which are similar to that of slow reacting substance of anaphylaxis (SRS-A), stimulated a fresh interest in the field of asthma and other allergic diseases (1) (2). These compounds, first discovered in polymorphonuclear leukocites obtained from peritoneal cavity of rabbits, possess a conjugated triene in their molecular structure and have been therefore named leukotrienes (LTs) (3). Among them, the dihydroxy acid leukotriene B4 (LTB4) causes chemotaxis and chemochinesis (4), responses which are involved in inflammation, whereas the peptidolipids leukotriene C4 (LTC4), D4 (LTD4) and E4 (LTE4) induce alterations occurring in immediate type hypersensitivity reactions (5). Several investigators have demonstrated that LTC4, LTD and LTE4 bring about a severe cons-triction in guinea-pig and LTE4 peripheral airways with a poten- cy greater than histamine (6) (7). Studies performed in conscious guinea-pigs pointed out that the modifications in dynamic compliance (CD vn) and lung resistance (RL) due to cysteine-containing LTs are associated with a fall in mean systemic arterial pressure: these effects, both on airway and cardiovascular systems were interpreted as direct in nature (7). Beside causing constriction of gastrointestinal and respiratory smooth muscle, LTs have been reported to cause a marked vasoconstriction in the microvasculature of guinea-pig skin and in the coronary circulation. SRS-A and LTC4 are also able to increase formation and release of thromboxane A2 (TXA2) in guinea-pig perfused lungs, an effect which is prevented by cyclo-oxygenase inhibitors and by FPL-55712, a SRS-A receptor antagonist (8). These observations and the early evidence of Berry and Collier (9), emphasizing the ability of aspirin to antagonize SRS-A induced bronchoconstriction in guinea-pig, prompted us to examine whether the biological activity of LTC4 is actually direct or merely mediated by other arachidonic acid metabolites. Bronchodilators currently employed in the treatment of asthma have been also considered in view of their ability to protect guinea-pig from pulmonary and cardiovascular actions of LTC4.