Vasorelaxant effect of nitric oxide releasing steroidal and nonsteroidal anti-inflammatory drugs

1 The effect of several nitric oxide releasing-non-steroidal anti-inflammatory drugs (NO-NSAID) and nitroprednisolone on blood vessel relaxation in vitro and in vivo was studied. Nitroflurbiprofen (NOF; EC50, 688.8 +/- 93.8 mum), nitroaspirin (NOA; EC50, 57.9 +/-6.5 mum), nitroparacetamol (NOPARA; EC50, 71.5 +/- 14.6 mum) and nitroprednisolone (EC50, 15.1 +/-1.4 mum) 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, EC50, 35.7 +/-3.5 nM). 2 The vasorelaxant effect of NOF and NOPARA in the rat aorta was potentiated by zaprinast (5 mum) and reduced by ODQ (5 mum). Flurbiprofen and paracetamol (100 mum) caused minimal (< 10%) relaxation of the rat aorta and did not affect the response to SNP. The effect of NOF was unchanged in the presence of L-NAME (100 mum; EC30, 181.8 +/- 35.1 mum cf. EC30, 125.1 +/- 17.0 mum, P >0.05) but increased by removal of the endothelium (EC30, 164.3 +/- 26.3 mum cf. EC50, 688.8 +/- 93.8 mum, P <0.05). 3 NOF (0.1-50 mum) produced a small but not concentration-related vasodilation of the NA-preconstricted (i.e. 'high tone') perfused rat mesentery preparation (cf. SNP, EC30, 4.4 +/-0.7 mum). In contrast, NOF (1-100 muM) produced concentration-related vasodilation of the 'high tone' perfused rat kidney with an EC50 of 33.1 +/-4.4 mum. 4 Neither NOF (74 mg kg(-1), i.p.) nor NOA (91.9 mg kg(-1), i.p.) nor equimolar doses of flurbiprofen (50 mg kg(-1), i.p.) or aspirin (50 mg kg(-1), i.p.) affected 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 effect of NO releasing drug varies greatly with the choice of compound and between blood vessel preparations.