Kinetics of nitric oxide liberation by 3,4-dihydro-1,2-diazete 1,2-dioxides and their vasodilatory properties in vitro and in vivo.
Derivatives of 3,4-dihydro-1,2-diazete 1,2-dioxides (DD) have been investigated as NO donors in vitro and in vivo. Using nitronylnitroxides as spin traps for NO, these compounds were shown to decompose in water solutions at physiological pH and temperature, producing two molecules of NO per one DD molecule. Rate constants of DD decomposition were found to be in the range from 10(-8) to 6.5 x 10(-7) c-1 in water and between 3 x 10(-7) and 1.6 x 10(-5) c-1 in dimethylsulfoxide. In vitro experiments performed with perfused rat tail artery showed that some of DD derivatives are highly effective vasodilators in concentrations from 5 to 80 microM while standard NO donor 3-(4-morpholino)-sydnonimine, SIN-1, does not lead to arterial vasodilation in these concentrations. Significant (up to 30%) decrease of systolic arterial blood pressure was observed in hereditary hypertensive rats (ISIAH-strain) when some of DD were injected intraperitoneally in doses 40-200 micrograms/kg b.w., while the same effect of trinitroglycerin, TNG, was found at much higher dose equal to 900 micrograms/kg b.w.
Utepbergenov
D I
DI
Institute of Chemical Kinetics & Combustion, Novosibirsk, Russia.
Khramtsov
V V
VV
Vlassenko
L P
LP
Markel
A L
AL
Mazhukin
D G
DG
Tikhonov AYa
Volodarsky
L B
LB
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology*; D003497:Cyclic N-Oxides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide; D005996:Nitroglycerin / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D013599:Systole / Q000187:drug effects; D013623:Tail / Q000098:blood supply; D014665:Vasodilator Agents / Q000737:chemistry* / Q000494:pharmacology
D003497:Cyclic N-Oxides; D007202:Indicators and Reagents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D005996:Nitroglycerin