NO-donors, part 9 [1]: Diazeniumdiolates inhibit human platelet aggregation and induce a transient vasodilatation of porcine pulmonary arteries in accordance with the NO-releasing rates

Abstract

Diazeniumdiolates (NONOates), among them a ciprofloxacin-diazeniumdiolate hybrid compound, were synthesized and the pH-, temperature- and structure-dependent liberation of nitric oxide (NO) was monitored by laser magnetic resonance spectroscopy (LMRS). The compounds induced a transient and reversible relaxation (EC50 8.3-150:nM) of pulmonary arteries independently from intact endothelium by stimulation of guanylyl cyclase (sGC). Increase in vascular cGMP was observed and blocking sGC with ODQ, an inhibitor of the NO-sensitive guanylyl cyclase, induced a rightward shift of the concentration-response curves. Repeated exposure did not show homologous desensitization. ADP-induced platelet aggregation (IC50 = 0.15-3 μM, IC50 for SNP: 2 μM) and collagen-induced aggregation were potently inhibited. Preincubation with ODQ also diminished these inhibitory effects. © 2005 Elsevier SAS. All rights reserved.