Abstract
BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) are a major cause of upper gastro-intestinal (GI) ulceration and bleeding as well as cardiovascular (CV) diseases (e.g., myocardial infarction and stroke). A feature common to both these adverse events is a variety of vascular reactions. One approach to overcome these side effects has been the development of nitric-oxide (NO)-donating NSAIDs. The NO is considered to overcome some of these vascular reactions caused by NSAIDs. Unfortunately, the NO-NSAIDs developed so far have not had the expected benefits compared with NSAIDs alone.ObjectivesUsing in vitro preparations it is hoped to gain insight into the vascular and smooth muscle reactions induced by NO-NSAIDs compared with NSAIDs as a basis for improving the protective responses attributed to the NO-donating properties of these drugs.MethodsA range of NO-NSAIDs was synthesized based on the esterification of NSAIDs with the nitro-butoxylate as a prototype of an NO-donor. These compounds, as well as NO-donor agents and NSAIDS, were examined for their possible effects on isolated segments of digital arteries of fallow deer, which provide a robust model for determining the effects of vasodilator and vasoconstrictor activities, in comparison with those of standard pharmacological agents.ResultsThe NO-NSAIDs were found to antagonise the smooth muscle contractions produced by 5-hydroxytryptamine (serotonin, 5-HT). However, while almost all their parent NSAIDs had little or no effect, with the exception of the R-(−)-isomers of both ibuprofen and flurbiprofen, which caused vasodilatation, all the NO-NSAIDs tested antagonised the increase in tension produced by 5-HT.ConclusionsR-(−)-ibuprofen and R-(−)-flurbiprofen, along with the nitro-butoxyl esters of the NSAIDs examined, produce relaxation of segments of deer digital artery smooth muscle in vitro. The evidence presented suggests that their mechanism involves the release of NO or its products.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) are amongst the most widely used drugs for prescription and non-prescription (‘over-the-counter’ or OTC) medications for the treatment of musculo-skeletal and various acute and chronic painful and inflammatory conditions (Rainsford 2007)
NSAIDs, together with the intermediates used in the synthesis of the nitrobutoxy compounds described below, were obtained from Sigma-Aldrich (Poole, Dorset, UK). 5-Hydroxytryptamine, phenylephrine (PHE), the soluble guanylate cyclase inhibitor 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and other laboratory reagents were obtained from Sigma-Aldrich (Poole, Dorset, UK)
Removal of the vascular endothelium reduced (p < 0.001) but did not eliminate the vasodilator actions of R-(−)- ibuprofen (Fig. 10.), suggesting a role for NO in the relaxation produced. These relaxant effects were reduced to near control values by the soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (Feelisch et al 1999; ODQ: 1 × 10–5 M) (Fig. 11). These results demonstrate that the NO-donating analogues of aspirin, indomethacin, etc., significantly reduced the contractile responses of vascular smooth muscle to electrical stimulation and to applied 5-HT and PHE, while, with the exception of ibuprofen and flurbiprofen, the parent NSAIDs were without effect
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) are amongst the most widely used drugs for prescription and non-prescription (‘over-the-counter’ or OTC) medications for the treatment of musculo-skeletal and various acute and chronic painful and inflammatory conditions (Rainsford 2007). The initiation of vascular constriction by NSAIDs is considered to be related to excess production of vasoconstrictor peptido-leukotrienes which occurs from the diversion of arachidonic acid through the 5-lipoxygenase pathway as a result of NSAIDs inhibiting the cyclo-oxygenases (Rainsford 1986, 1993a, b, 1999; Rainsford et al 1995; Gyömber et al 1996a, b) This is accompanied by accumulation, endothelial interactions and activation of polymorphonuclear (neutrophil) and other leucocytes that contribute to mucosal damage (Rainsford et al 1995; 2012; McCafferty et al 1995; Appleyard et al 1996; Wallace and Cirino 1994; Wallace 1997; Wallace et al 1999; Muscará, et al 2000). The evidence presented suggests that their mechanism involves the release of NO or its products
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