ANALYSIS OF THE RELATIONSHIP BETWEEN PHARMACOLOGICAL INHIBITION OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE AND RELAXATION OF CANINE TRACHEAL SMOOTH-MUSCLE

Dose-response curves for muscular relaxation produced by five phosphodiesterase inhibitors were compared to curves for inhibition of phosphodiesterase-catalyzed breakdown of cyclic AMP or cyclic GMP. The rank-order of potency of the agents as muscular relaxants was similar to their order of potency as phosphodiesterase inhibitors. When enzyme activity was measured with 1.5. 38 or 400 μM cyclic AMP or 1.5 μM cyclic GMP as substrate, it was found that two agents, caffeine and SQ 20,009 [1-ethyl-4-(isopropylidenehydrazino)-1H-pyrazolo-(3,4-b) -pyridine-5-carboxylic acid, ethyl ester, HCl], inhibited activity in concentrations equal to or slightly less than were required for muscular relaxation. The remaining three agents, theophylline, MIX (1-methyl-3-isobutylxanthine), and ICI 58,301 (3-acetamido-6-methyl-8-n-propyl-s-triazolo [4,3-a]pyrazine), were required in 2.4 to 10.3-fold higher concentrations for enzyme inhibition than for muscular relaxation. It was concluded that, although these findings are generally consistent with the hypothesis that phosphodiesterase inhibition is important in the mechanism of action of the drugs tested, it may be necessary to take into account additional, presently unknown factors to explain fully the relaxant effects of these drugs on respiratory smooth muscle. © 1979.