Endothelium- and nitric oxide-dependent vasorelaxing activities of gamma-butyrobetaine esters: possible link to the antiischemic activities of mildronate.

6533b7cefe1ef96bd1257b6e

RESEARCH PRODUCT

Endothelium- and nitric oxide-dependent vasorelaxing activities of gamma-butyrobetaine esters: possible link to the antiischemic activities of mildronate.

Jelizaveta Sjakste Karsten Sydow Thomas Münzel Maija Dzintare Jean-luc Boucher Ivars Kalvinsh Andrei L. Kleschyov Nikolajs Sjakste Dainuvite Meirena Larisa Baumane

subject

Male Endothelium Nitric Oxide Synthase Type III Stereochemistry Drug Evaluation Preclinical Myocardial Ischemia Vasodilation Aorta Thoracic Nitric Oxide Muscle Smooth Vascular Nitric oxide chemistry.chemical_compound Carnitine medicine Animals Endothelium Rats Wistar Pharmacology chemistry.chemical_classification biology Electron Spin Resonance Spectroscopy Active site Fatty acid Drug Synergism Rats Nitric oxide synthase Betaine Vasodilation Drug Combinations medicine.anatomical_structure Enzyme NG-Nitroarginine Methyl Ester chemistry biology.protein Propionate Nitric Oxide Synthase Ditiocarb Methylhydrazines

description

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.

year	journal	country	edition	language
2004-01-05	European journal of pharmacology

10.1016/j.ejphar.2004.05.006 https://pubmed.ncbi.nlm.nih.gov/15219822