EFFECTS OF SCA40 ON BOVINE TRACHEALIS MUSCLE AND ON CYCLIC-NUCLEOTIDEPHOSPHODIESTERASES

While UK-93,928 ydro-6-oxo-9-propyl-1H-purin-2-yl)-4-ethoxyphenyl] sul fonyl]-4-methylpiperazine; 5 nM-5 mu M) was devoid of relaxant activit y, benzafentrine, isoprenaline, levcromakalim and SCA40 -methylaminoim idazo[1,2-a]pyrazine-2-carbonitrile) each relaxed histamine (460 mu M) -precontracted bovine isolated trachealis. Each of these relaxants was antagonised by a K+-rich (80 mM) medium. Except in the case of levcro makalim, nifedipine (1 mu M) offset this antagonism. Charybdotoxin (10 0 nM) antagonised isoprenaline in a nifedipine-sensitive manner but di d not antagonise SCA40 or benzafentrine. Iberiotoxin (100 nM) did not antagonise SCA40. Acting on tissue precontracted with carbachol, SCA40 potentiated isoprenaline but did not potentiate sodium nitroprusside. While levcromakalim (1 and 10 mu M) induced hyperpolarisation, SCA40 (I and 10 mu M) induced little change in the membrane potential of bov ine trachealis. In trachealis preloaded with Rb-86(+), levcromakalim ( 1 and 10 mu M) promoted efflux of the radiotracer while SCA40 (1 and I O mu M) had no effect. Tested as an inhibitor of isoenzymes of cyclic nucleotide phosphodiesterase, SCA40 was most potent against the type I II, less potent against the type IV and least potent against the type I isoenzyme. It is concluded that neither inhibition of phosphodiester ase type V nor the promotion of BKCa channel opening explains the trac heal smooth muscle relaxant activity of SCA40. This compound relaxes b ovine tracheal smooth muscle mainly by inhibiting phosphodiesterase is oenzyme types LIT and IV. (C) 1997 Elsevier Science B.V.