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, PGF2 alpha and TXA2 equipotently when PG synthesis was stimulated with excitatory receptor agonists (noradrenaline and carbachol), 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.
Department of Chemical Pathology and Human Metabolism, Royal Free Hospital, London, U.K.
J Y
JY
Jeremy
D P
DP
Mikhailidis
P
P
Dandona
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D015237:Dinoprost / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D011863:Radioimmunoassay; D051381:Rats; D013928:Thromboxane A2 / Q000096:biosynthesis; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011453:Prostaglandins; D013928:Thromboxane A2; D015237:Dinoprost; D015232:Dinoprostone