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), [CuACHTUNGTRENUNG(PipNONO)Cl] and [NiACHTUNGTRENUNG(PipNONO)Cl],
and the NiII complex derived from the Schiff base between HPip-
NONO and salicylaldehyde, [Ni(SalPipNONO)], are described.
Compounds [CuACHTUNGTRENUNG(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 [CuACHTUNGTRENUNG(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