Differential inhibitory potencies of non-steroidal antiinflammatory drugs on smooth muscle prostanoid synthesis

In isolated rat aorta and urinary bladder, indomethacin inhibited the synthesis of the prostaglandins (PG) PGI₂, PGE₂, PGF_2α and TXA₂ equipotently when PG synthesis was stimulated with excitatory receptor agonists (noradrenaline and carbochol), fluoride (a G protein activator), phorbol ester (a protein kinase C (PKC) activator) and calcium ionophore A23187 (a creator of artificial calcium channels). However, there was a marked right shift (30 fold) in the indomethacin concentration-inhibition curves when PG synthesis was stimulated by arachidonate (PG substrate) and trauma (freeze fracturing and sonication). Although less potent than indomethacin, the NSAIDs tiaprofenic acid and ibuprofen showed a similar disparity between the IC₅₀s with the same PG stimulators. Since PG synthesis stimulated by receptor agonists, fluoride, phorbol ester and A23187 is dependent on calcium channel activation whereas trauma and arachidonate-stimulated PG synthesis bypass calcium channel activation, these data indicate that NSAIDs inhibit not only cyclooxygenase but also (and more potently) the mobilisation of Ca²⁺ linked to PG synthesis in these tissues.