Investigations on the pharmacology of the cardioprotective guanidine ME10092.
The guanidine compound ME10092 (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine), which possesses a strong cardioprotective effect to ischemia-reperfusion, was assessed for different pharmacological actions that may underlie its cardioprotective effect. In the living rat ME10092 decreased the blood pressure and heart rate in a dose-dependent manner. We found ME10092 to bind to alpha 1- and alpha 2-adrenoreceptors with moderate affinity (Ki values 1-4 microM), and to block adrenaline-elicited contractile responses in isolated guinea pig aortas. Our results indicate that ME10092 possesses a certain anti-oxidant profile. Thus, in a competitive manner and with low affinity it inhibited the bovine milk xanthine oxidase enzyme, as well as NAD(P)H oxidase driven oxyradical formation in membrane fractions isolated from the rat brain. By using electron paramagnetic resonance we here show that, after its systemic administration, ME10092 modulates the nitric oxide (NO) content in several tissues of the rat in a time-dependent manner. However, in vitro ME10092 inhibited the activities of nitric oxide synthases nNOS and eNOS, but not that of iNOS. Our data give evidence that the cardioprotective effect of ME10092 could be mediated through pharmacological mechanisms that include some modulation of NO production, as well as possible inhibition of radical formation during ischemia-reperfusion.
Dambrova
Maija
M
Latvian Institute of Organic Synthesis, Riga, Latvia. md@biomed.lu.lv
Liepinsh
Edgars
E
Kirjanova
Olga
O
Petrovska
Ramona
R
Pugovich
Osvalds
O
Baumane
Larisa
L
Uhlen
Staffan
S
Kalvinsh
Ivars
I
Oliver
Douglas
D
Wikberg
Jarl E S
JE
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019556:COS Cells; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007082:Ileum / Q000166:cytology / Q000187:drug effects; D007275:Injections, Intravenous; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy; D009243:NAD / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000145:classification / Q000187:drug effects; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy; D014969:Xanthine Oxidase / Q000737:chemistry / Q000378:metabolism
C408693:1-(3,4-dimethoxy-2--chlorobenzylideneamino)guanidine; D002316:Cardiotonic Agents; D006146:Guanidines; D009419:Nerve Tissue Proteins; D011942:Receptors, Adrenergic, alpha; D009243:NAD; D009569:Nitric Oxide; C496320:NOS1 protein, human; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D014969:Xanthine Oxidase; D019255:NADPH Oxidases