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Effect of aspirin nitroxybutyl ester on rings of digital artery of the fallow deer
Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is frequently accompanied by unwanted actions, such as gastric irritation and erosion associated with reduced secretion of protective prostaglandins and decreased mucosal blood flow (see Whittle, 2003). Various strategies have been tried to reduce their onset and severity. One is the coupling of a nitric oxide (NO) containing moiety to an NSAID (NO-NSAID), such as nitroxybutyl aspirin (NCX-4016) which leads to a reduction in gastric irritancy (Tashima et al., 2000). To study further the possibility that part of the beneficial effect of NO-NSAIDs could be the result of increased blood flow removing the drug from the gastric mucosa more effectively, it was decided to examine the actions of aspirin and its butyl and nitroxybutyl esters (synthesised at Sheffield Hallam University) on the tension developed by rings of the common digital artery of the fallow deer. Arteries were obtained from the forefeet of fallow deer (Dama dama ) of either sex (38-48 kg body weight) killed under E.U. red meat regulations. Rings (2-3 mm) were mounted in 10 ml organ baths in Krebs-Henseleit physiological solution aerated with 95% O2 and 5% CO2 and subjected to a tension of 3.0 g. Control experiments where the responses of the rings were compared with those of the whole perfused forelimb confirmed that these rings from a conductance artery were a reliable model of the responses of the whole vascular bed. Concentration-response curves were generated from the changes in isometric tension caused by the cumulative addition of 5-hydroxytryptamine (5-HT) in the presence and absence of aspirin and its analogues. Neither the presence of aspirin or of aspirin butyl ester at concentrations up to 10-4 M, had any significant effect on the responses of the rings to 5-HT (EC50 of 5-HT, control: 1.40 ± 0.07 x 10-6 M, aspirin [10-4 M]: 1.33 ± 0.15 x 10-6 M and aspirin butyl ester [10-4 M]: 1.31 ± 0.11 x 10-6 M; n = 4 animals). However when the experiment was repeated in the presence of 10-4 M aspirin nitroxybutyl ester, the concentration-response curve to 5-HT was significantly shifted to the right (EC50 of 5-HT, control: 9.01 ± 0.72 x 10-7 M, aspirin nitroxybutyl ester [10-4 M]: 5.20 ± 0.49 x 10-6 M, P < 0.001 [Student’s unpaired t-test], n = 3 animals). While the addition of 2 ml of guinea pig blood to the bathing fluid had little effect on the action of 5-HT, it greatly reduced the effectiveness of aspirin nitroxybutyl ester (EC50 of 5-HT with ester [10-4] alone: 4.57 ± 0.13 x 10-6 M, with ester plus blood: 1.97 ± 0.17 x 10-6 M; the control value was 6.58 ± 0.47 x 10-7 M). In a further series of experiments, arterial rings were contracted with 5-HT (10-5 M) to produce a contraction that was maintained for an hour or more. Addition of aspirin had no significant effect, while aspirin butyl ester caused a transient relaxation. Aspirin nitroxybutyl ester not only caused complete reversal of the 5-HT-induced contraction but relaxed the rings to zero tension, where it remained for at least 60 min. In conclusion, these experiments indicate aspirin nitroxybutyl ester is able to oppose the vasoconstrictor action of 5-HT in isolated rings of deer common digital artery; an effect that can last for at least an hour. Such a time scale of action could well be sufficient to promote increased blood flow in the stomach and enhanced absorption of the anti-inflammatory agent. The fact that its action is impaired by the presence of guinea pig blood would, however, suggest that, in vivo, it would not be as effective but is consistent with these actions being due to NO released from the compound.
Tashima, K. et al., (2000) Life Sciences, 67, 1639-1652. |