A new class of nitroderivatives of non-steroidal anti-inflammatory drugs has recently been synthesized (Nicox Ltd., London, UK). In order to improve gastric tolerance of the parent compound, a side-chain, able to release nitric oxide, has been added to the core structure of the molecule. We studied in vitro the effects of nitrofenac and two NO-aspirins (NCX 4215 and NCX 4016) on platelets and isolated arteries to identify any possible effect due to the release of nitric oxide or to the inhibition of cyclo-oxygenase activity. Nitrofenac induced a dose-dependent relaxation both with intact (46% with 1 times 10-3 mol/L) and endothelium-denuded (75% with 1 times 10-3 mol/L) rings of rat aorta precontracted with epinephrine, while diclofenac did not affect this contraction (0% relaxation in intact and 22% in rubbed arteries). Pretreatment with diclofenac 1 times 10-3 mol/L significantly increased the vasorelaxant effects of nitrofenac at each drug concentration, both in intact (86% with 1 times 10-3 mol/L) and rubbed preparations (89%). NO-aspirins, unlike acetylsalicylic acid, were able to relax both intact and endothelium-denuded rings of rat aorta (100% relaxation). Methylene blue and oxyhaemoglobin completely reversed the relaxation induced by nitrofenac and NO-aspirins, both in rubbed and intact aortic rings. Both NO-aspirins exhibited antiaggregating properties in arachididonic acid-stimulated human platelets, measured using a turbidimetric method (NCX 4215, 1 times 10-3 mol/L: 70% inhibition; NCX 4016, 1 times 10-4 mol/L: 100%), NCX 4016 proving as effective as acetylsalicylic acid 1 times 1 mol/L. Thrombin-induced platelet aggregation was inhibited in acetylsalicylic acid-treated platelets (NCX 4215, 1 times 10-3 mol/L: 50%, NCX 4016, 1 times 10-4 mol/L: 92%). NCX 4016 was also able to prevent thrombin-induced intracellular free calcium increase, effect not observed with acetylsalicylic acid. In vitro thromboxane A-2 production in human platelets, assayed by RIA as thromboxane B-2 serum concentration, was reduced by NCX 4215, 1 times 10-3 mol/L (76%) and virtually abolished by NCX 4016 5 times 10-5 mol/L (95% inhibition). These results demonstrate in vitro the antiaggregating activity of NO-aspirins, NCX 4016 being more active than NCX 4215, and the vasorelaxant effects of all the tested molecules. The mechanism involved is two-fold: release of nitric oxide and inhibition of cyclo-oxygenase.
Effects of a new class of NO-releasing NSAIDs on platelets and isolated arteries
MINUZ, Pietro;
1996-01-01
Abstract
A new class of nitroderivatives of non-steroidal anti-inflammatory drugs has recently been synthesized (Nicox Ltd., London, UK). In order to improve gastric tolerance of the parent compound, a side-chain, able to release nitric oxide, has been added to the core structure of the molecule. We studied in vitro the effects of nitrofenac and two NO-aspirins (NCX 4215 and NCX 4016) on platelets and isolated arteries to identify any possible effect due to the release of nitric oxide or to the inhibition of cyclo-oxygenase activity. Nitrofenac induced a dose-dependent relaxation both with intact (46% with 1 times 10-3 mol/L) and endothelium-denuded (75% with 1 times 10-3 mol/L) rings of rat aorta precontracted with epinephrine, while diclofenac did not affect this contraction (0% relaxation in intact and 22% in rubbed arteries). Pretreatment with diclofenac 1 times 10-3 mol/L significantly increased the vasorelaxant effects of nitrofenac at each drug concentration, both in intact (86% with 1 times 10-3 mol/L) and rubbed preparations (89%). NO-aspirins, unlike acetylsalicylic acid, were able to relax both intact and endothelium-denuded rings of rat aorta (100% relaxation). Methylene blue and oxyhaemoglobin completely reversed the relaxation induced by nitrofenac and NO-aspirins, both in rubbed and intact aortic rings. Both NO-aspirins exhibited antiaggregating properties in arachididonic acid-stimulated human platelets, measured using a turbidimetric method (NCX 4215, 1 times 10-3 mol/L: 70% inhibition; NCX 4016, 1 times 10-4 mol/L: 100%), NCX 4016 proving as effective as acetylsalicylic acid 1 times 1 mol/L. Thrombin-induced platelet aggregation was inhibited in acetylsalicylic acid-treated platelets (NCX 4215, 1 times 10-3 mol/L: 50%, NCX 4016, 1 times 10-4 mol/L: 92%). NCX 4016 was also able to prevent thrombin-induced intracellular free calcium increase, effect not observed with acetylsalicylic acid. In vitro thromboxane A-2 production in human platelets, assayed by RIA as thromboxane B-2 serum concentration, was reduced by NCX 4215, 1 times 10-3 mol/L (76%) and virtually abolished by NCX 4016 5 times 10-5 mol/L (95% inhibition). These results demonstrate in vitro the antiaggregating activity of NO-aspirins, NCX 4016 being more active than NCX 4215, and the vasorelaxant effects of all the tested molecules. The mechanism involved is two-fold: release of nitric oxide and inhibition of cyclo-oxygenase.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
