Nitric oxide releasing metal-diazeniumdiolate complexes strongly induce vasorelaxation and endothelial cell proliferation.
The preparation, characterization, and NO-releasing properties of metal complexes derived from N-aminoethylpiperazine-N-diazeniumdiolate (HPipNONO), [Cu(PipNONO)Cl] and [Ni(PipNONO)Cl], and the Ni(II) complex derived from the Schiff base between HPipNONO and salicylaldehyde, [Ni(SalPipNONO)], are described. Compounds [Cu(PipNONO)Cl] and [Ni(SalPipNONO)] release NO at a much slower rate than HPipNONO in aqueous buffer in the pH range between 6.8 and 8.0. The kinetics of NO release by [Ni(SalPipNONO)] is complex, with an apparent stepwise release of NO molecules. Both [Cu(PipNONO)Cl] and [Ni(SalPipNONO)] are effective vasorelaxant agents of precontracted rabbit aorta rings, and are active in the nM concentration range. In addition, these complexes promote the proliferation of endothelial cells. Both vascular activities were inhibited by a specific inhibitor of guanylate cyclase, suggesting the involvement of the cGMP pathway. In all biological assays, the reference agent sodium nitroprusside was shown to be 10-1000-fold less potent than the two metal-NONOates.
Ziche
Marina
M
Sezione di Farmacologia, Dipartimento di Biologia Molecolare, Università di Siena, Via Aldo Moro 2, 53100 Siena, Italy.
Donnini
Sandra
S
Morbidelli
Lucia
L
Monzani
Enrico
E
Roncone
Raffaella
R
Gabbini
Roberta
R
Casella
Luigi
L
D000818:Animals; D001391:Azo Compounds / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D003300:Copper / Q000737:chemistry / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D009532:Nickel / Q000737:chemistry / Q000494:pharmacology; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D011817:Rabbits; D012545:Schiff Bases / Q000737:chemistry; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology*
D001391:Azo Compounds; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D012545:Schiff Bases; D014665:Vasodilator Agents; C452539:diazeniumdiolate; D009569:Nitric Oxide; D003300:Copper; D009532:Nickel; D006162:Guanylate Cyclase; D006152:Cyclic GMP