Analysis of vasodilator responses to novel nitric oxide donors in the hindquarters vascular bed of the cat

Controlled release of nitric oxide (NO.) may be useful in the treatment of a variety of vascular disorders. NO. donors of the diazeniumdiolate family with different rates of spontaneous NO. release have been synthesized. In t he current study responses to seven diazeniurndiolate NO. donors (DEA/NO., DETA/NO., OXI/NO., PIPERAZI/NO., PROLT/NO., SPER/NO., and SULFI/NO.) were i nvestigated in the hindquarters vascular bed of the cat. Intravenous inject ions of all NO. donors caused dose-dependent decreases in systemic arterial pressure and the rank order of potency was SNP > DEA/NO. > PIPERAZI/NO. > SPER/NO. > PROLI/NO. > OXI/NO., Injections of all NO. donors into the hindl imb perfusion circuit caused dose-related decreases in hindquarters perfusi on pressure that were similar to the order of potency in decreasing systemi c arterial pressure. The rank order of the time required for the response t o return to 50% of the maximal decrease in pressure (T-1/2) and total durat ion of action of the NO. donors was SPER/NO. > PIPERAZI/NO. > DEA/NO. > OXV NO. > DETA/NO. > PROLI/NO. > SULFI/NO.. After treatment with the NO. syntha se inhibitor, N-omega-nitro-L-arginine methyl ester (100 mg/kg, i.v.), hind limb vasodilator responses to the NO. donors were not significantly differe nt, but vasodilator responses to acetylcholine were significantly reduced. After treatment with zaprinast (2 mg/kg, i.v.), a type V cyclic 3 ', 5 ' -g uanosine monophosphate-specific phosphodiesterase inhibitor, the duration o f vasodilator responses to the NO. donors, as measured by T-1/2, was increa sed significantly, whereas the duration of the response to the beta (2)-adr energic receptor agonist albuterol was unchanged. These data suggest that d iazeniumdiolate NO. donors are endothelium-independent, directly stimulate soluble guanylate cyclase, and decrease vascular resistance by increasing c yclic 3 ', 5 ' -guanosine monophosphate levels in the hindquarters vascular bed of the cat.