Calcium-and G-protein-related spasmolytic effects of nonsteroidal anti-inflammatory drugs on rat uterus contractions in vitro.

The effects of the nonsteroidal anti-inflammatory drugs (NSAIDs) acetylsalicylic acid, metamizole, phenylbutazone, indometacin, piroxicam, naproxen, tolmetin, diclofenac, and mefenamic acid on methacholine (10 mumol/l), prostaglandin F2 alpha (1 mumol/l), and KCl (60 mmol/l) induced contractions of isolated rat uterus were assayed. All of these cause a concentration-dependent inhibition of methacholine and prostaglandin F2 alpha-induced contractions with the exception of acetylsalicylic acid, metamizole, and naproxen. All except acetylsalicylic acid and metamizole relaxed in a concentration-dependent manner the tonic contractions induced by KCl. CaCl2 (0.1-10 mmol/l) totally counteracted the relaxant effects of naproxen and tolmetin, but not those of the other NSAIDs. Bay K8644 did not revert the effect of the NSAIDs. Pertussis toxin (50 micrograms/l) did not modify the effect of indometacin, mefenamic acid, and tolmetin, but partially antagonized the effects of diclofenac and naproxen and increased the effect of phenylbutazone and piroxicam. These results suggest that some of the NSAIDs assayed induce smooth muscle relaxation by mechanisms independent of prostaglandin synthesis inhibition, but related to the inhibition of extracellular calcium influx through mechanisms related or unrelated to pertussis toxin sensible G proteins.