Nitroxyl: a vasodilator of human vessels that is not susceptible to tolerance.
Pre-clinical studies have identified nitroxyl (HNO), the reduced congener of nitric oxide (NO•), as a potent vasodilator which is resistant to tolerance development. The present 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) with similar potency. In human radial arteries, GTN-induced relaxation was reduced by the NO• scavenger hydroxocobalamin (HXC; P<0.05) but was unaffected by the HNO scavenger L-cysteine. Alternately, AS was unaffected by HXC but was reduced by L-cysteine (5-fold shift, P<0.05). The sGC (soluble guanylate cyclase) inhibitor ODQ abolished responses to both AS and GTN in arteries and veins (P<0.05). Inhibition of voltage-dependent potassium channels (Kv 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-dependent. Critically, a concentration-dependent development of tolerance to GTN (1 and 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-dependent pathway. Unlike GTN, however, it does not develop tolerance in human blood vessels.
*Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
Karen L
KL
Andrews
*Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
Natalie G
NG
Lumsden
*Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
Julie
J
Farry
*Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
Ann-Maree
AM
Jefferis
†Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
Barbara K
BK
Kemp-Harper
*Vascular Pharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
Jaye P F
JP
Chin-Dusting
D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009573:Nitrites / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000378:metabolism; D017534:Radial Artery / Q000187:drug effects* / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D012501:Saphenous Vein / Q000187:drug effects* / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009573:Nitrites; D009589:Nitrogen Oxides; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; C021229:oxyhyponitrite; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D005996:Nitroglycerin; C039900:nitroxyl; D006152:Cyclic GMP