The novel guanidine ME10092 protects the heart during ischemia-reperfusion.
The novel guanidine N-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine [ME10092; a metabolite to the strongly cardioprotective hydroxyguanidine N-(3,4-dimethoxy-2-chlorobenzylideneamino)-N'-hydroxyguanidine (PR5)] was administered intravenously to rats subjected to left coronary artery clamping followed by reperfusion. Administration of 1-10 mg/kg of ME10092 1 or 5 min before 10 min of coronary artery occlusion followed by 20 min reperfusion significantly and dose-dependently inhibited the reperfusion-induced burst of arrhythmia, and markedly improved the survival of the animals. This dose schedule also dose-dependently and significantly inhibited the ST-segment elevation seen on the ECG during the artery occlusion, and attenuated the secondary rise in ST-segment during the reperfusion. Even when ME10092 was administered 5 min after the start of the reperfusion, the ST-segment elevation became significantly attenuated. Administration of ME10092 (3 plus 1.5 mg/kg) to animals subjected to 1 h left coronary occlusion followed by 2 h reperfusion reduced the heart infarction size by about 40%. ME10092 also dose-dependently reduced the heart rate, both during normal conditions and during ischemia and reperfusion. Moreover, the highest dose of ME10092 used (10 mg/kg) strongly attenuated the reduction in blood pressure seen during 10 min left coronary occlusion, as well as it attenuated the rebound rise in blood pressure seen during the 20 min reperfusion phase; that is, resulting in a normalisation of the blood pressure disturbances caused by the ischemia-reperfusion. We also showed that after its p.o. administration, the PR5 hydroxyguanidine became completely metabolised to its guanidine ME10092, with no detectable traces of PR5 being present 30 and 60 min after the administration. Moreover, after the p.o. administration of ME10092, no signs of the formation of PR5 were seen on analysis of the rats' plasma. In view of the practically indistinguishable pharmacological effects of ME10092 and PR5, we suggest the strong cardioprotective effects of these compounds to be mediated by a direct effect by ME10092 per se.
Dambrova
Maija
M
Department of Pharmaceutical Biosciences, Division of Pharmacology, Uppsala University, Box 591, BMC, SE751 24, Uppsala, Sweden.
Veveris
Maris
M
Cirule
Helena
H
Pugovichs
Osvalds
O
Post
Claes
C
Lundstedt
Torbjörn
T
Kalvinsh
Ivars
I
Skottner
Anna
A
Wikberg
Jarl E S
JE
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D019791:Guanidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology
C408692:1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine; D006146:Guanidines; D019791:Guanidine