Modulation of alpha 1-adrenoceptors in rat left ventricle by ischaemia and acyl carnitines: protection by ranolazine.
Myocardial alpha 1-adrenoceptor number has been reported to increase during ischaemia in myocytes consequent to an increase in acyl carnitine levels. We investigated whether this phenomenon occurs in vivo and whether the novel antiischaemic agent ranolazine will protect against it. Thirty-minute occlusion of the left anterior descending coronary artery (LAD) in anaesthetised rats produced an approximate doubling of the left ventricular (LV) alpha 1-adrenoceptor population. The carnitine palmitoyl transferase 1 (CPT1) inhibitor sodium 2-[5-(4-chlorophenyl)-pentylene]oxiran-2-carboxylate (POCA 100 micrograms/kg) reduced this ischaemia-induced increase when administered intraperitoneally (i.p.) 15 min before ischaemia and abolished the increase when administered intravenously (i.v.). The CPT1 inhibitor sodium 2-tetradecyl oxirane carboxylate dihydrate (TGDA) (500 micrograms/kg) inhibited the upregulation when administered i.p. and significantly decreased alpha 1-adrenoceptor density when administered i.v.; however, this agent, unlike POCA, reduced [3H]-prazosin binding directly. The alpha 1-adrenoceptor antagonist prazosin (100 micrograms/kg i.v.) did not prevent the increase. Direct addition of palmitoyl carnitine (10 microM) to membranes from nonischaemic myocardium caused a doubling in alpha 1-adrenoceptor number, and this effect was selective for heart membranes as compared with cerebral cortex; beta-adrenoceptor number was not modified. Ranolazine (500 micrograms/kg) inhibited upregulation when administered 15 min i.v. before ischaemia or after 3-day twice-daily (b.i.d.) i.p. pretreatment. This drug did not inhibit CPT1 directly.(ABSTRACT TRUNCATED AT 250 WORDS)
Allely
M C
MC
Syntex Research Centre, Riccarton, Edinburgh, Scotland.
Brown
C M
CM
Kenny
B A
BA
Kilpatrick
A T
AT
Martin
A
A
Spedding
M
M
D000083:Acetanilides; D000818:Animals; D002331:Carnitine / Q000502:physiology*; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004082:Dihydroalprenolol / Q000378:metabolism; D004095:Dihydropyridines / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology*; D010172:Palmitoylcarnitine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*
D000083:Acetanilides; D004095:Dihydropyridines; D010879:Piperazines; D011942:Receptors, Adrenergic, alpha; D010172:Palmitoylcarnitine; D004082:Dihydroalprenolol; D000069458:Ranolazine; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine