Heme oxygenase (Ho) has been shown to Provide cytoprotection to the vascular system in diabetes. Isolated femoral arteries from diabetic rats treated with cobalt protoporphyrin (CoPP) exhibited increased relaxation to acetylcholine (ACh), which was markedly decreased in control diabetic rats. In control rats treated with either CoPP or with CO releasing molecules-3(CORM-3), but not in rats treated with biliverdin, we observed an increased dilatory response to ACh. The inhibition of guanylyl-cyclase (GC) with 1H[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) caused a contractile response to ACh in control rats and in biliverdin-treated rats, while in rats treated with CoPP and CORM-3, the ACh dilatory effect wits only decreased. Moreover, the inhibition of HO with chromium mesoporphyrin did not change the response to ACh in rats treated with CoPP, Suggesting that the improving effect of overproduction of CO on vascular reactivity is due to it decrease in iNOS and the beneficial effect on vascular function. (c) 2005 Elsevier Inc. All rights reserved.