Effect of some phosphodiesterase inhibitors on adenylate cyclase from the liver fluke, Fasciola hepatica.

The present investigation was prompted by our previous finding that in the liver fluke, Fasciola hepatica, some phosphodiesterase inhibitors, instead of potentiating the rise in endogenous cAMP caused by 5-hydroxytryptamine (5-HT), antagonized it. Papaverine, 1-ethyl-4-(isopropylidenehydrazino)-1H-pyrazolo-(3,4-b)-pyridine-5-carboxylic acid, ethyl ester, HCl (SQ 20009), 6,7-dimethyl-4 ethyl-quinazoline (Quazodine) and caffeine inhibited 5-HT-activated adenylate cyclase from particulate fractions of the liver fluke. This may explain their in vivo antagonism to the 5-HT-mediated rise in endogenous cAMP levels. Isobutylmethylxanthine (IBMX), which did not antagonize the 5-HT effect in vivo, did not inhibit 5-HT-activated adenylate cyclase in fluke particles. None of the above compounds inhibited the NaF-activated adenylate cyclase. Kinetic studies showed that inhibition of 5-HT-activated adenylate cyclase by papaverine or SQ 20009 was not competitive with the substrate, ATP, or with GTP. While high levels of 5-HT decreased the degree of inhibition by papaverin and SQ 20009. the kinetics of inhibition does not appear to be strictly competitive.