Effects of Ibuprofen, and Some Analogues, on the Muscle Tone of Isolated Segments of the Common Digital Artery of the Fallow Deer (Dama dama)

摘要

Nitric oxide (NO) has a variety of actions in inflammation, haemostasis and thrombosis, including the potential to reduce the local toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) in the gastrointestinal tract. NO-donating non-steroidal anti-inflammatory drugs (NO-NSAIDs) have been developed as one of several attempts to reduce the toxicity of their parent compounds. Such compounds should also dilate blood vessels and possibly increase local blood flow to aid absorption of ingested drug. A simple, reliable and economical method of study that did not use experimental animals was required. To this end, changes in isometric tension of isolated rings of the common digital artery of the fallow deer, killed for the venison market, in response to selected NO-NSAIDs and their parent NSAIDs (notably aspirin, ibuprofen, diclofenac and flurbiprofen) were measured. The nitrobutoxyl ester of aspirin (NO-aspirin) but not its butyl ester reduced contractions induced by 5-hydroxytryptamine (serotonin, 5HT) and phenylephrine (PHE). These effects of NO-aspirin were reduced by addition of methylene blue to sequester the released NO. Nitrobutoxyl esters of diclofenac, flurbiprofen, ibuprofen, and naproxen also caused relaxation of agonist-stimulated or electrically stimulated contractions. Relaxation was also caused by ibuprofen, flurbiprofen and diclofenac of agonist-stimulated or electrically stimulated arterial rings, with the R(-)-enantiomers of ibuprofen and flurbiprofen being more potent than their S(+)-enantiomers. The soluble guanylate cyclase (sGC) inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced the effect, suggesting that these NSAIDs largely act through changes in sGC. These results show that NSAIDs and their NO derivatives may differ in their relaxant effects according to the type of NSAID.The observation that R(-)-ibuprofen is the more potent enantiomer in relaxing the vessel rings suggests that this component of racemic ibuprofen could be useful in enhancing the rate of absorption through the gut wall, with a consequent reduction in local toxicity.