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.