NO-donors, part 9 : diazeniumdiolates inhibit human platelet aggregation and induce a transient vasodilatation of porcine pulmonary arteries in accordance with the NO-releasing rates.
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 (EC(50) 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 (IC(50) = 0.15-3 microM, IC(50) for SNP: 2 microM) and collagen-induced aggregation were potently inhibited. Preincubation with ODQ also diminished these inhibitory effects.
Abuo-Rahma
Gamal El Din A A
Gel D
Institut für Pharmazie, Friedrich-Schiller-Universität Jena, Philosophenweg 14, D-07743 Jena, Germany.
Horstmann
Axel
A
Radwan
Mohamed F
MF
El-Emam
Ali
A
Glusa
Erika
E
Lehmann
Jochen
J
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001391:Azo Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D003094:Collagen / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D007834:Lasers; D009682:Magnetic Resonance Spectroscopy; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000502:physiology*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
D001391:Azo Compounds; D020030:Nitric Oxide Donors; D010975:Platelet Aggregation Inhibitors; C452539:diazeniumdiolate; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D003094:Collagen; D006162:Guanylate Cyclase; D006152:Cyclic GMP