EFFECTS OF SCA40 ON HUMAN ISOLATED BRONCHUS AND HUMAN POLYMORPHONUCLEAR LEUKOCYTES - COMPARISON WITH ROLIPRAM, SKF94120 AND LEVCROMAKALIM

1 SCA40 (0.1 nM-0.1 mM) produced concentration-dependent suppression o f the spontaneous tone of human isolated bronchus (-log EC(50)=6.85+/- 0.09; n=10) and reached a maximal relaxation similar to that of theoph ylline (3 mM). The potency (-log EC(50) values) of SCA40 compared to o ther relaxants was rolipram (7.44+/-0.12; n=9)>SCA40 greater than or e qual to levcromakalim (6.49+/-0.04; n=6)>SKF94120 (5.87+/-0.10; n=9). 2 When tested against the activity of the isoenzymes of cyclic nucleot ide phosphodiesterase (PDE) isolated from human bronchus, SCA40 proved highly potent against PDE III (-log IC50=6.47+/-0.16; n=4). It was ma rkedly less potent against PDE IV (4.82+/-0.18; n=4) and PDE V (4.32+/ -0.11; n=4). 3 Human polymorphonuclear leukocytes (PMNs) stimulated wi th N-formylmethionyl-leucyl-phenylalanine (FMLP) produced a concentrat ion-dependent superoxide anion generation and elastase release. SCA40 (1 nM-10 mu M) produced a concentration-related inhibition of FMLP (30 nM similar to EC(50))-induced superoxide production (-log IC50=5.48+/ -0.10; n=6) and elastase release (-log IC50=5.50+/-0.26; n=6). Rolipra m was an effective inhibitor of superoxide generation and elastase rel ease (-log IC50 values similar to 8) while SKF94120 and levcromakalim were scarcely effective. 4 FMLP (30 nM) and thimerosal (20 mu M) induc ed leukotriene B-4 production and elevation of intracellular calcium c oncentration in human PMNs. The production of leukotriene B-4 was inhi bited by SCA40 in a concentration-related manner (-log IC50=5.94+/-0.2 2; n=6) but SCA40 was less effective against the elevation of intracel lular calcium. Rolipram was an effective inhibitor of leukotriene B-4 synthesis (-log IC50 similar to 7) and intracellular calcium elevation (-log IC50 similar to 6) while SKF94120 and levcromakalim were scarce ly effective. 5 It is concluded that SCA40 is an effective inhibitor o f the inherent tone of human isolated bronchus. The bronchodilatation produced by SCA40 appears mainly related to PDE inhibition since the p otency of SCA40 as a relaxant of human isolated bronchus was found to be close to its potency as inhibitor of PDE III activity isolated from human bronchus. In addition, SCA40 exhibited inhibitory effects on hu man PMN function stimulated by FMLP. These effects may be related to t he ability of SCA40 to inhibit PDE IV from human PMNs while the contri bution of PDE V inhibition is uncertain. We found no evidence of a rol e for levcromakalim-sensitive plasmalemmal K+-channels in human PMNs.