Activation of thrombin receptor increases intracellular Na+ during myocardial ischemia.
Recent evidence indicates that factors involved in the activation of the coagulation system eliciting an intracoronary thrombus may contribute importantly to arrhythmogenesis during acute myocardial ischemia. In the present study, the influence of the thrombin receptor activating peptide, SFLLRNPNDKYEPF (SFLL), on intracellular Na+ ([Na+]i) and tissue lysophosphatidylcholine (LPC) content during ischemia was investigated in an isolated, blood-perfused rabbit papillary muscle preparation. During normoxic perfusion, [Na+]i, determined by an intracellular Na(+)-selective electrode, was 11.6 +/- 0.2 mM (n = 14) in the presence of a physiological concentration of LPC (125 microM) bound to albumin (control group). The addition of SFLL (100 microM, n = 12) to the LPC-containing perfusate had no significant additional effects on [Na+]i, twitch tension, action potential duration, or tissue LPC content. During zero flow ischemia, [Na+]i in the control group rose to 15.5 +/- 1.4 mM (P < 0.05) at 6 min, whereas [Na+]i in the group treated with SFLL increased rapidly from the preischemic value of 11.7 +/- 0.3 to 23.5 +/- 1.9 mM (P < 0.01 compared with that in the control group) over the same time period. This rapid rise in [Na+]i was associated with a greater accumulation of tissue LPC, an arrhythmogenic lipid metabolite, and the development of early ventricular arrhythmias. These results indicate that an increase in [Na+]i induced by activation of the thrombin receptor, likely mediated through its effect on the accumulation of LPC within ischemic myocardium, may be responsible for arrhythmogenesis during myocardial ischemia secondary to activation of the coagulation system.
Yan
G X
GX
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Park
T H
TH
Corr
P B
PB
D000818:Animals; D004594:Electrophysiology; D007425:Intracellular Membranes / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism*; D010210:Papillary Muscles / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010477:Perfusion; D011188:Potassium / Q000378:metabolism; D011817:Rabbits; D018179:Receptors, Thrombin / Q000502:physiology*; D012016:Reference Values; D012964:Sodium / Q000378:metabolism*
D008244:Lysophosphatidylcholines; D010446:Peptide Fragments; D018179:Receptors, Thrombin; C072032:thrombin receptor peptide (42-55); D012964:Sodium; D011188:Potassium