1 The effect of L-NG-nitro arginine (L-NOARG) was compared with that of L-NG-monomethyl arginine (L-NMMA) on vasodilatation of the isolated aorta of the rabbit and perfused mesentery of the rat in response to acetylcholine (ACh) and sodium nitroprusside (NP). 2 L-NOARG (1.5-100Mm) and L-NMMA (3-100Mm) produced concentration-related contraction of the rabbit aorta precontracted with phenylephrine (700-900nM). Similarly, L-NOARG (10-2001pM) and L-NMMA (30-100 gM) elevated perfusion pressure of the noradrenaline (NA, 0.6-2.5mM)-preconstricted rat mesentery preparation. 6 These results identify L-NOARG as a potent, L-arginine reversible inhibitor of endothelium-dependent vasodilatation. The available data suggests that L-NOARG, like L-NMMA, inhibits endothelial nitric oxide (NO) biosynthesis.
1 Nitroaspirin (2.5 ± 50 mg kg 71 , i.p. or 2.5 ± 100 mg kg 71 , p.o.) and aspirin (2.5 ± 100 mg kg 71 , i.p. or p.o.) exhibit anti-in¯ammatory activity in the carrageenan-induced hindpaw oedema model in the rat. When administered i.p., nitroaspirin was a more eective anti-oedema agent than aspirin particularly in the`early' phase (i.e. up to 60 min) of the response.
Nitroparacetamol (NCX-701) is a newly synthesized nitric oxide-releasing derivative of paracetamol. Following i.p. administration, nitroparacetamol inhibits carrageenan-induced hindpaw oedema formation (ED 50 , 169.4 mmol kg 71 ) and mechanical hyperalgesia (ED 50 , 156 mmol kg 71 ) in the rat. In contrast, the parent compound, paracetamol, exhibits no signi®cant anti-oedema activity in this model (ED 50 41986 mmol kg 71 , i.p.) and is markedly less potent than nitroparacetamol as an inhibitor of carrageenan-mediated hyperalgesia (ED 50 , 411.6 mmol kg 71 , i.p.). In a second model of nociception (inhibition of acetic acid induced abdominal constrictions in the mouse), nitroparacetamol administered orally (ED 50 , 24.8 mmol kg 71 ), was again considerably more potent than paracetamol (ED 50 , 506 mmol kg 71 , p.o.). Thus, compared with paracetamol, nitroparacetamol not only exhibits augmented antinociceptive activity in both rat and mouse but, intriguingly, is also antiin¯ammatory over a similar dose range.
Kingdom of Saudia ArabiaParacetamol (5 mmol kg 71 , i.p.) caused liver damage in rats as indicated by increased plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and glutamate dehydrogenase (GDH) activities. No change in plasma bilirubin or creatinine was noted. An equimolar dose of nitroparacetamol (a nitric oxide (NO)-releasing derivative of paracetamol) did not alter plasma levels of any of the markers of liver/kidney damage. No di erence in plasma or liver paracetamol was apparent in animals injected with paracetamol or nitroparacetamol. These results indicate that NO released from nitroparacetamol exhibits hepatoprotective activity in these animals and suggest that nitroparacetamol may therefore be considered as a safer alternative to paracetamol in the clinic.
1 The eect of several nitric oxide releasing-non-steroidal anti-in¯ammatory drugs (NO-NSAID) and nitroprednisolone on blood vessel relaxation in vitro and in vivo was studied. Nitro¯urbiprofen (NOF; EC 50 , 688.8+93.8 mM), nitroaspirin (NOA; EC 50 , 57.9+6.5 mM), nitroparacetamol (NOPARA; EC 50 , 71.5+14.6 mM) and nitroprednisolone (EC 50 , 15.1+1.4 mM) caused concentration-related relaxation of noradrenaline (NA)-contracted rat aortic rings. All NO releasing compounds tested were approximately three orders of magnitude less potent than sodium nitroprusside (SNP, EC 50 , 35.7+3.5 nM). 2 The vasorelaxant eect of NOF and NOPARA in the rat aorta was potentiated by zaprinast (5 mM) and reduced by ODQ (5 mM). Flurbiprofen and paracetamol (100 mM) caused minimal (510%) relaxation of the rat aorta and did not aect the response to SNP. The eect of NOF was unchanged in the presence of L-NAME (100 mM; EC 30 , 181.8+35.1 mM cf. EC 30 , 125.1+17.0 mM, P40.05) but increased by removal of the endothelium (EC 30 , 164.3+26.3 mM cf. EC 50 , 688.8+93.8 mM, P50.05). 3 NOF (0.1 ± 50 mM) produced a small but not concentration-related vasodilation of the NApreconstricted (i.e.`high tone') perfused rat mesentery preparation (cf. SNP, EC 30 , 4.4+0.7 mM). In contrast, NOF (1 ± 100 mM) produced concentration-related vasodilation of the`high tone' perfused rat kidney with an EC 50 of 33.1+4.4 mM. , i.p.) aected mean arterial blood pressure (MAP) or heart rate (HR) of pentobarbitone-anaesthetized rats over a 1 h period. 5 NO-NSAID relax blood vessels in vitro by an NO-dependent mechanism. The absolute vasorelaxant eect of NO releasing drug varies greatly with the choice of compound and between blood vessel preparations.
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