| Nitric oxide (NO) donors are often times used interchangeably and indiscriminately as prodrugs of NO. However, two major NO donors, nitroglycerin (NTG) and S-nitroso-N-acetylpenicillamine (SNAP) were shown to exert different tolerance properties on left ventricular hemodynamics. It is not known whether other critical pharmacological differences may exist between these two NO donors. Thus, this thesis work aimed to compare and contrast the scopes covering, and the mechanism underlying, the diverse actions of NO donors in a variety of animal preparations. At the organ level, NTG and SNAP were demonstrated to exert dissimilar effects on renal hemodynamics in normal conscious rats: NTG increased while SNAP decreased renal blood flow. In receptor regulation, NTG was shown to reduce the sensitivity of baroreceptor reflex, while SNAP did not exert this effect. In action on the central nervous system (CNS), NTG significantly increased c-fos gene activation, an index for increased neuronal activity, in the nucleus of solitary tract, while SNAP did not exert comparable CNS effects. Since renal hemodynamics are regulated in part by baroreceptor reflex and the CNS, the dissimilar effects of NTG and SNAP on these two systems suggested possible mechanistic linkages between these phenomena. The basic cellular mechanisms exerted by NO donors were also examined. Our data showed that NO donors exhibited different resistance toward the inhibition of the heme-site of soluble guanylate cyclase (sGC) mediated through 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). The order of resistance was determined to be SNAP, S-nitrosoglutathione > diethylenetriamine-NO (DETA-NO) > sodium nitroprusside (SNP), N-hydroxybenzenesulfonamide (Piloty's acid), 3-morpholinosydnonimine (SIN-1) > tetranitromethane, NTG. Zaprinast, a predominant inhibitor of cGMP-dependent phosphodiesterase, and a sulfhydryl donor, N-acetylpenicillamine (NAP), were demonstrated to reverse ODQ inhibition of SNAP- and SNP-mediated aortic vasorelaxation, but not for that NTG. These results are consistent with the interpretation that NTG-induced aortic relaxation is exclusively mediated by activation of the heme-site of sGC, while SNAP and SNP can activate an additional biochemical signaling pathway, possibly through the sulfhydryl site of sGC. The diverse scopes of NO donor action demonstrated in this thesis research reveal the complexity of their pharmacology and underscore the view that NO donors can not be considered as a homogenous group of pharmacological agents. |
