Prostaglandin deficiency promotes sensitization of adenylyl cyclase

Inhibition of prostaglandin synthesis by the drug indomethacin suppresses t he synthesis of the cyclic AMP antagonist, prostaglandylinositol cyclic pho sphate (cyclic PIP), and leads to a metabolic state comparable to type II d iabetes. It was of interest whether prostaglandin-deficiency likewise cause s sensitization of adenylyl cyclase, as this has been reported for the diab etic state. In liver plasma membranes of indomethacin-treated male rats, ba sal and forskolin-stimulated cyclic AMP synthesis remained unchanged when c ompared to untreated control rats. In control rats, stimulation of cyclic A MP synthesis by fluoride (2.2-fold) or glucagon (3.5-fold) was much lower t han stimulation by forskolin (6.6-fold). In contrast, in indomethacin-treat ed rats, stimulation of cAMP synthesis by fluoride (4.6-fold) or glucagon ( 5.2-fold) nearly matched the stimulation by forskolin (6.4-fold). The level of alpha(1)-adrenergic receptors was slightly reduced, from 450 to 320 fmo l/mg protein, by the indomethacin treatment. Independent of the treatment b y indomethacin, stimulation of cyclic AMP synthesis by adrenaline failed, i n agreement with the low density of adrenergic beta-receptors. In conclusio n, PGE deficiency sensitizes adenylyl cyclase in rat liver for G protein-co upled receptors (glucagon) and also for fluoride.