Spasmolytic and calmodulin inhibitory effect of non-steroidal anti-inflammatory drugs in vitro.
The effect of several anti-inflammatory drugs (NSAIDs), the calmodulin inhibitor W-7 and cortisol on vanadate-induced tonic contraction and on calmodulin dependent cAMP-phosphodiesterase activity have been assayed. Indomethacin, diclofenac, phenylbutazone, mefenamic acid, naproxen, tolmetin, piroxicam, aspirin and W-7, but not metimazol, produce dose-dependent relaxation of vanadate-induced tonic contraction on isolated rat uterus. Cortisol relaxes the vanadate contraction up to 45%. None of the drugs assayed inhibit the basal activity of phosphodiesterase with concentrations lower than 1 mM. However, indomethacin, diclofenac, phenylbutazone, mefenamic acid, naproxen, piroxicam, aspirin and W-7 inhibit, in a concentration-dependent way, the calmodulin-stimulated activity of phosphodiesterase. The maximum inhibition achieved with tolmetin (1 mM) and cortisol (1 mM) was 38% and 24%, respectively. Metamizol has no effect on basal or/and stimulated phosphodiesterase. This, as far as we know, is the first description of relationship between NSAIDs and calmodulin-dependent processes and our results suggest that the inhibition of calmodulin with NSAIDs may be directly related to their pKa and liposolubility.
Cantabrana
B
B
Laboratorio de Farmacología, Dpto. Medicina, Facultad de Medicina, Oviedo, Spain.
Perez Vallina
J R
JR
Menéndez
L
L
Hidalgo
A
A
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D005260:Female; D006854:Hydrocortisone / Q000494:pharmacology; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D014638:Vanadates / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002147:Calmodulin; D010276:Parasympatholytics; D013449:Sulfonamides; D014638:Vanadates; C017967:W 7; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D006854:Hydrocortisone