Effect of a prostaglandin antagonist, N-0164, on cAMP generation and hydrolysis in the rat uterus

N-0164 (sodium-p-benzyl-4-[1-oxo-2-(4-chlorobenzyl)-3-phenyl propyl] phenylphosphonate) (20–100 μM), an antagonist of the contractile effect of prostaglandins, reversed the prostaglandin E₂ (PGE₂) inhibition of isoproterenol-induced cAMP accumulation in rat uterus. N-0164, at the same concentrations, was a potent cAMP-phosphodiesterase inhibitor in broken cell preparations and potentiated the cAMP response to isoproterenol in intact tissue. The potency of N-0164 to inhibit cAMP-phosphodiesterase and to reverse the effect of PGE₂ on the cAMP response to isoproterenol were comparable (ec₅₀:50 and 60 μM respectively). In the presence of 10 mM theophylline, N-0164 did not affect the inhibitory effect of PGE₂. Furthermore, N-0164 produced similar proportional increases in the cAMP response to isoproterenol in the presence and absence of PGE₂. These results suggest that the apparent reversal by N-0164 of the PGE₂ effect on the cAMP response to isoproterenol is not due to its prostaglandin antagonistic action but to inhibition of cAMP-phosphodiesterase. N-0164, at concentrations lower than those inhibiting cAMP-phosphodiesterase, selectively inhibited the PGE₂-induced contractions of the rat uterus (ec₅₀, 4 μM), while at higher concentrations it also diminished carbachol-induced contractions. These results indicate that in the rat uterus N-0164 has at least two effects, prostaglandin antagonism and cAMP-phosphodiesterase inhibition, and suggest that the contractile effect of PGE₂ is independent of the effect of PGE₂ on the isoproterenol-induced rise in cAMP.