A comparison of the inhibition of phosphodiesterase activity and allergic histamine release by disodium cromoglycate and compound I.C.I. 74917.

Compounds that increase cellular cyclic AMP concentrations, such as isoprenaline, adrenaline and prostaglandin El, inhibit the release of histamine from sensitive tissues after antigen challenge (Assem & Schild, 1969; Lichtenstein & Margolis, 1968). The present paper describes experiments that show that I.C.I. compound 74917, Bufrolin (6-n-butyl-2,8-dicarboxy-4,10-dioxo-1,4,7,1O-tetrahydro-l,7-phenanthroline), an antiallergic compound approximately 100 times as potent as disodium cromoglycate (Evans & Thompson, 1975), is a phosphodiesterase inhibitor four to five times as potent as disodium cromoglycate. Comparison of the K, values for these and other compounds on mast-cell-enzyme preparations suggest that the anti-allergic activities of disodium cromoglycate and I.C.I. 74917 do not involve the inhibition of phosphodiesterase. Disodium cromoglycate has been shown to be an inhibitor of cyclic AMP phosphodiesterase from several tissues, and in most cases was more potent than theophylline, the standard inhibitor (Ray & Warren, 1974). Taylor et al., (1974) have studied the inhibition of histamine release from rat peritoneal mast cells by combinations of disodium cromoglycate, theophylline and isoprenaline. By using the proportion of cells degranulated as a measure of histamine release, they have shown synergism between cromoglycate and isoprenaline, but not between cromoglycate and theophylline, in contradiction to other published work (Koopman et al., 1970). They concluded that disodiumcromoglycateexerts its anti-allergicactivity by inhibiting cyclic AMP phosphodiesterase. The lack ofeffect of disodiumcromoglycate on smooth muscle was interpreted to mean that at least two phosphodiesterase isoenzymes exist. These were an isoenzyme predominating in smooth muscle which was sensitive to theophylline and not disodium cromoglycate, and an isoenzyme present in mast cells, which was more sensitive to disodium cromoglycate than theophylline. The development of tolerance to disodium cromoglycate was similarly explained in these terms, by suggesting that inhibition of the disodium cromoglycate-sensitive phosphodiesterase would result in a compensatory activation of non-sensitive phosphodiesterase. The work described below was designed to determine whether the inhibition of phosphodiesterase by compound I.C.I. 7491 7 and disodium cromoglycate correlates with their potencies as anti-allergic compounds.