In vitro comparison of two NONOates (novel nitric oxide donors) on rat pulmonary arteries.
The pulmonary vasorelaxant properties of two NONOates (diazeniumdiolates) were examined because this novel group of nitric oxide (NO) donors may be useful in pulmonary hypertension. MAHMA NONOate ((Z)-1-¿N-Methyl-N-[6-(N-methylammoniohexyl)amino]¿ diazen-1-ium-1,2-diolate) and spermine NONOate ((Z)- 1-¿N-[3-aminopropyl]-N-[4-(3-aminopropylammonio)butyl]-amino¿di azen-1-ium-1,2-diolate) decomposed at different rates (half-lives 1.3 min and 73 min, respectively; 37 degrees C, pH 7.3) but generated the same total amount of NO. They fully relaxed submaximally contracted ring preparations of main and intralobar pulmonary arteries from rats. Responses were inhibited by the guanylate cyclase inhibitor, ODQ (1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one). Potency was not affected by choice of contractile spasmogen (phenylephrine, endothelin-1, thromboxane-mimetic) or endothelium removal, and tolerance did not develop; thus the drugs had properties important for use in pulmonary hypertension. MAHMA NONOate was 10-40-fold more potent than spermine NONOate but responses to spermine NONOate were more sustained (spermine NONOate > 60 min; MAHMA NONOate < 7 min). It is concluded that the differences in potency and time-course reflect the different rates of NO generation by these NONOates.
Homer
K
K
Department of Physiology and Pharmacology, The University of Queensland, Brisbane, Australia.
Wanstall
J
J
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006834:Hydrazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D009589:Nitrogen Oxides; D005996:Nitroglycerin / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013096:Spermine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
C105785:1-hexanamine-6-(2-hydroxy-1-methyl-2-nitrosohydrazine)-N-methyl; C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D006834:Hydrazines; D009153:Mutagens; D009589:Nitrogen Oxides; D010069:Oxadiazoles; D011810:Quinoxalines; D014665:Vasodilator Agents; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D005996:Nitroglycerin