Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction.
The inhibition of gamma-butyrobetaine (GBB) hydroxylase, a key enzyme in the biosynthesis of carnitine, contributes to lay ground for the cardioprotective mechanism of action of mildronate. By inhibiting the biosynthesis of carnitine, mildronate is supposed to induce the accumulation of GBB, a substrate of GBB hydroxylase. This study describes the changes in content of carnitine and GBB in rat plasma and heart tissues during long-term (28 days) treatment of mildronate [i.p. (intraperitoneal) 100 mg/kg/daily]. Obtained data show that in concert with a decrease in carnitine concentration, the administration of mildronate caused a significant increase in GBB concentration. We detected about a 5-fold increase in GBB contents in the plasma and brain and a 7-fold increase in the heart. In addition, we tested the cardioprotective effect of mildronate in isolated rat heart infarction model after 3, 7, and 14 days of administration. We found a statistically significant decrease in necrotic area of infarcted rat hearts after 14 days of treatment with mildronate. The cardioprotective effect of mildronate correlated with an increase in GBB contents. In conclusion, our study, for the first time, provides experimental evidence that the long-term administration of mildronate not only decreases free carnitine concentration, but also causes a significant increase in GBB concentration, which correlates with the cardioprotection of mildronate.
Liepinsh
Edgars
E
Latvian Institute of Organic Synthesis, Riga, Latvia.
Vilskersts
Reinis
R
Loca
Dagnija
D
Kirjanova
Olga
O
Pugovichs
Osvalds
O
Kalvinsh
Ivars
I
Dambrova
Maija
M
D000818:Animals; D001622:Betaine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology; D002331:Carnitine / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003326:Coronary Circulation / Q000187:drug effects; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D008297:Male; D008763:Methylhydrazines / Q000008:administration & dosage / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D050563:gamma-Butyrobetaine Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism
D002317:Cardiovascular Agents; D008763:Methylhydrazines; D001622:Betaine; C002889:gamma-butyrobetaine; C050147:3-(2,2,2-trimethylhydrazine)propionate; D050563:gamma-Butyrobetaine Dioxygenase; D002331:Carnitine