N-substituted analogues of S-nitroso-N-acetyl-D,L-penicillamine: chemical stability and prolonged nitric oxide mediated vasodilatation in isolated rat femoral arteries

1 Previous studies show that linking acetylated glucosamine to S-nitroso-N- acetyl-D,L-penicillamine (SNAP) stabilizes the molecule and causes it to el icit unusually prolonged vasodilator effects in endothelium-denuded, isolat ed rat femoral arteries. Here we studied the propanoyl (SNPP; 3 carbon side -chain), valeryl (SNVP; 5C) and heptanoyl (SNHP; 7C) N-substituted analogue s of SNAP (2C) to further investigate other molecular characteristics that might influence chemical stability and duration of vascular action of S-nit rosothiols. 2 Spectrophotometric analysis revealed that SNVP was the most stable analog ue in solution. Decomposition of all four compounds was accelerated by Cu(I I) and cysteine, and neocuproine, a specific Cu(I) chelator, slowed decompo sition of SNHP. Generation of NO from the compounds was confirmed by electr ochemical detection at 37 degrees C. 3 Bolus injections of SNAP (10 mu l; 10(-8)-10(-3) M) into the perfusate of precontracted, isolated rat femoral arteries taken from adult male Wistar rats (400-500 g), caused concentration-dependent, transient vasodilatations irrespective of endothelial integrity. Equivalent vasodilatations induced by SNVP and SNHP were transient in endothelium-intact vessels but failed to recover to pre-injection pressures at moderate and high concentrations (10 (-6)-10(-3) M) in those denuded of endothelium. This sustained effect(>1 h) was most prevalent with SNHP and was largely reversed by the NO scavenger, haemoglobin. 4 We suggest that increased lipophilicity of SNAP analogues with longer sid echains facilitates their retention by endothelium-denuded vessels; subsequ ent slow decomposition within the tissue generates sufficient NO to cause p rolonged vasodilatation. This is a potentially useful characteristic for ta rgeting NO delivery to areas of endothelial damage.