Differential effects of anticholinergic drugs on platelet aggregation induced by platelet-activating factor and other agents

Abstract

formation of various lipoxygenase products. A typical radiochromatographic scan obtained after t.1.c. of the products of incubation is shown in Fig. 1 . The lipoxygenase products were identified by co-migration with authentic hydroxy acid standards. A characteristic pattern of one major ( K , 0.6) and one minor ( K , 0.15) peak can be seen (Fig. 1). The major compound co-migrated with 1 2-hydroxyeicosatetraenoic acid. When 5-hydroxytryptamine (1-100 p ~ ) was added to the incubation mixture, mean 12-hydroxyeicosatetraenoic acid production exceeded the control value by 1.15-fold to 4.1-fold in a concentration-related manner ( I ’ < 0.001. t i = 7). Addition of nordihydroguaiaretic acid, an inhibitor of lipoxygenase activity, and ketotifen to the incubation mixture caused a concentration-dependent inhibition of the conversion of arachidonic acid to lipoxygenase products by human platelets. The mean values ( ~ s . E . M . ) for inhibiting the production of 12-hydroxyeicosatetraenoic acid by SOo% ( lC5,,) for ketotifen and nordihydroguaiaretic acid were 79 k 9 and 35 k 4 p ~ , respectively. lndomethacin (up t o 2 0 0 PM), an inhibitor of fatty acid cyclo-oxygenase activity, had no inhibitory effect on 5-hydroxytryptamine-induced stimulation o f 12-hydroxyeicosatetraenoic acid production, whereas it stimulated the production o f trihydroxyeicosatrienoic acid ( K , 0. 15) 3-fold. In separate experiments we have found that ketotifen also inhibits rat lung arachidonate lipoxygenase and soybean lipoxygenase activities. These experiments demonstrate that ketotifen inhibits arachidonate lipoxygenase activity in platelets. Since 12hydroxyeicosatetraenoic acid and its labile precursor 12hydroperoxyeicosatetraenoic acid are potent chemotactic and vasoactive agents (Goetzl & Sun, 1Y79), we suggest that ketotifen may directly influence S-hydroxytryptamineinduced stirnulation of platelet arachidonate lipoxygenase activity.