Endothelium- and nitric oxide-dependent vasorelaxing activities of gamma-butyrobetaine esters: possible link to the antiischemic activities of mildronate.
Mildronate [3-(2,2,2-trimethylhydrazine) propionate (THP)] is an antiischemic drug acting mainly via inhibition of fatty acid beta-oxidation. Some effects of the drug cannot be explained by the latter mechanism. We tested the eventual nitric oxide (NO) dependence of the mildronate action. Mildronate, gamma-butyrobetaine (GBB) and GBB methyl ester induced transient increases in nitric oxide (NO) concentrations in rat blood and myocardium. In vitro, these compounds neither modified the activities of purified neuronal and endothelial recombinant nitric oxide synthases (NOSs) nor were able to interact with their active site. GBB induced vasodilatation at high concentrations only (EC50 = 5 x 10(-5) M) while mildronate alone displayed no vasodilating effect although it enhanced the GBB vasodilating activity. GBB methyl and ethyl esters were found more potent vasodilators (EC50 = 2.5 x 10(-6) M). Pretreatment of aortic rings with NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) abolished vasodilating effects of the compounds. A hypothesis explaining NO and endothelium-dependent effects of mildronate and its analogues is proposed.
Sjakste
Nikolajs
N
Faculty of Medicine, University of Latvia, Riga. Nikolajs.Sjakste@lu.lv
Kleschyov
Andrei L
AL
Boucher
Jean-Luc
JL
Baumane
Larisa
L
Dzintare
Maija
M
Meirena
Dainuvite
D
Sjakste
Jelizaveta
J
Sydow
Karsten
K
Münzel
Thomas
T
Kalvinsh
Ivars
I
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001622:Betaine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000145:classification / Q000494:pharmacology*; D002331:Carnitine / Q000037:antagonists & inhibitors / Q000145:classification / Q000494:pharmacology*; D004050:Ditiocarb / Q000494:pharmacology; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D004727:Endothelium / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008763:Methylhydrazines / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000517:prevention & control; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D004338:Drug Combinations; D008763:Methylhydrazines; D009569:Nitric Oxide; D001622:Betaine; C002889:gamma-butyrobetaine; C050147:3-(2,2,2-trimethylhydrazine)propionate; D004050:Ditiocarb; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D002331:Carnitine; D019331:NG-Nitroarginine Methyl Ester