THE INVOLVEMENT OF THE RELEASE OF NITRIC-OXIDE IN THE PHARMACOLOGICALACTIVITY OF THE NEW FUROXAN DERIVATIVE CHF-2363

1 The mechanism of action and the pharmacological effects of the new f uroxan derivative, CHF 2363 (4ethoxy-3-phenylsulphonylfuroxan), were i nvestigated. 2 Pre-incubation of CHF 2363 with human platelet-rich pla sma produced a concentration-dependent inhibition of the platelet aggr egation induced by collagen, adenosine diphosphate (ADP) and platelet activating factor (PAF). The test compound was about 5 times more pote nt than sodium nitroprusside. 3-Isobutyl-1-methyl-xanthine (IBMX) pote ntiated the antiaggregating effect of CHF 2363. 3 CHF 2363 was a poten t inhibitor of rubbed endothelium rabbit aortic ring contraction induc ed by noradrenaline. Comparison of IC50 values showed that CHF 2363 wa s as potent as glyceryl trinitrate (GTN). 4 Increasing concentrations of CHF 2363 elevated platelet guanosine 3':5'-cyclic monophosphate (cy clic GMP) levels. Adenosine 3':5'-cyclic monophosphate (cyclic AMP) le vels were unaffected. 5 Oxyhaemoglobin reduced all the pharmacological actions of the test compound. Moreover, CHF 2363 concentration-depend ently released nitric oxide (NO) in platelet-rich plasma. The NO relea se was correlated to its ability to increase platelet cyclic GMP level s. 6 After exposure of rat aortic strips to supramaximal concentration s of GTN (550 mu M), the vasorelaxant activity of CHF 2363 did not cha nge, although that of GTN decreased about 55 fold. 7 It has been concl uded that the new furoxan derivative CHF 2363 exerts a potent antiaggr egating and vasorelaxant activity via NO release and increase of cycli c GMP levels. No in vitro cross tolerance between GTN and CHF 2363 was observed.