Nitroxyl: a vasodilator of human vessels that is not susceptible to tolerance

This study explores the efficacy of HNO in human blood vessels and describes, for the first time, a vasodilator for humans that is not susceptible to tolerance. Human radial arteries and saphenous veins were obtained from patients undergoing coronary artery graft surgery and mounted in organ baths. Repeated vasodilator responses to the HNO donor, Angeli’s salt (AS), and NO• donor, glyceryl trinitrate (GTN) were determined. AS and GTN induced concentration-dependent vasorelaxation of both human radial arteries (AS pEC50: 6.5±0.2 –log M) and saphenous veins (pEC50: 6.7±0.1 –log M) with similar potency. In human radial arteries, GTN-induced relaxation was reduced by the NO• scavenger, hydroxocobalamin (P<0.05) but unaffected by the HNO scavenger L-cysteine. Alternately, AS was unaffected by HXC but reduced by L-cysteine (5-fold shift, P<0.05). The sGC inhibitor, ODQ abolished responses to both AS and GTN in arteries and veins (P<0.05). Inhibition of voltage-dependent K+ channels with 4-AP also significantly reduced responses to AS (pEC50: 5.5) and GTN, suggesting that the relaxation to both redox congeners is cGMP- and Kv channel-dependant. Critically, a concentration-dependent development of tolerance to GTN (1 & 10 µM; P<0.05), but not to AS, was observed in both saphenous veins and radial arteries. Like GTN, the HNO donor, AS, causes vasorelaxation of human blood vessels via activation of a cGMP-depend...
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research