Inhibition of long-chain fatty acid metabolism does not affect platelet aggregation responses.
A number of anti-anginal agents (perhexiline, amiodarone, trimetazidine) have been shown to inhibit myocardial carnitine palmitoyltransferase-1, which controls access of long-chain fatty acids to mitochondrial sites of beta-oxidation. In view of clinical data suggesting that perhexiline improves symptomatic status in unstable angina pectoris, and the known role of mitochondrial beta-oxidation in platelet metabolism, we compared the platelet carnitine palmitoyltransferase-1 inhibitory and putative anti-aggregatory effects of perhexiline, amiodarone and trimetazidine with those of specific carnitine palmitoyltransferase-1 inhibitors: etomoxir and hydroxyphenylglyoxylate in both normal subjects and patients with stable angina. All of the compounds examined inhibited platelet carnitine palmitoyltransferase-1 activity; rank order of potency etomoxir > malonyl-CoA > hydroxyphenylglyoxylate > amiodarone > or = perhexiline > trimetazidine. However, only perhexiline, amiodarone and trimetazidine inhibited platelet aggregation. We conclude that (a) the carnitine palmitoyltransferase-1 inhibitors perhexiline, amiodarone and trimetazidine exert significant anti-aggregatory effects which may be therapeutically relevant and, (b) these effects are independent of carnitine palmitoyltransferase-1 inhibition.
Department of Physiology, The University of Adelaide, SA, Australia.
S R
SR
Willoughby
Y Y
YY
Chirkov
J A
JA
Kennedy
G A
GA
Murphy
L P
LP
Chirkova
J D
JD
Horowitz
D000328:Adult; D000368:Aged; D000638:Amiodarone / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016022:Case-Control Studies; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010480:Perhexiline / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D014292:Trimetazidine / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; D014665:Vasodilator Agents; D002334:Carnitine O-Palmitoyltransferase; D010480:Perhexiline; C054207:etomoxir; D000638:Amiodarone; D014292:Trimetazidine