BACKGROUND:L-Arginine reduces platelet aggregation and adhesion in ex vivo studies, but there is no evidence as yet that it has a therapeutic effect on clinical end points. Doppler ultrasound can detect cerebral emboli noninvasively. Such embolic signals are common after carotid endarterectomy, and their frequency predicts risk of stroke recurrence. We used this situation to determine the antiplatelet efficacy of L-arginine and S-nitrosoglutathione (GSNO), a physiological nitric oxide donor with possible platelet specificity. METHODS AND RESULTS:Patients undergoing carotid endarterectomy were randomized in a double-blind manner between L-arginine (n=14), GSNO (n=14), or placebo (n=14) administered intravenously for 90 minutes, starting 30 minutes after skin closure. All patients were pretreated with aspirin and given heparin during surgery. Transcranial Doppler recordings were made from the ipsilateral middle cerebral artery for 4 hours after surgery, beginning 30 minutes after skin closure, and also at 6 and 24 hours. There were highly significant reductions in the number of Doppler embolic signals in the L-arginine and GSNO groups; first 4 hours, median (range) number of embolic signals, placebo 44.7 (6 to 778), L-arginine 9.5 (0 to 225), and GSNO 0.8 (0 to 8), both P<0.001 versus control values. The reduction in the signals persisted at the 24-hour recording. CONCLUSIONS:Intravenous L-arginine and GSNO attenuate Doppler embolic signals in humans. Modulation of the NO system with these agents may have applications in the treatment of thromboembolic disease. This study demonstrates the potential application of ultrasonic embolic signal detection to examine the efficacy of new antiplatelet agents in relatively small numbers of patients.
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BACKGROUND:L-Arginine reduces platelet aggregation and adhesion in ex vivo studies, but there is no evidence as yet that it has a therapeutic effect on clinical end points. Doppler ultrasound can detect cerebral emboli noninvasively. Such embolic signals are common after carotid endarterectomy, and their frequency predicts risk of stroke recurrence. We used this situation to determine the antiplatelet efficacy of L-arginine and S-nitrosoglutathione (GSNO), a physiological nitric oxidedonor with possible platelet specificity. METHODS AND RESULTS:Patients undergoing carotid endarterectomy were randomized in a double-blind manner between L-arginine (n=14), GSNO (n=14), or placebo (n=14) administered intravenously for 90 minutes, starting 30 minutes after skin closure. All patients were pretreated with aspirin and given heparin during surgery. Transcranial Doppler recordings were made from the ipsilateral middle cerebral artery for 4 hours after surgery, beginning 30 minutes after skin closure, and also at 6 and 24 hours. There were highly significant reductions in the number of Doppler embolic signals in the L-arginine and GSNO groups; first 4 hours, median (range) number of embolic signals, placebo 44.7 (6 to 778), L-arginine 9.5 (0 to 225), and GSNO 0.8 (0 to 8), both P<0.001 versus control values. The reduction in the signals persisted at the 24-hour recording. CONCLUSIONS: Intravenous L-arginine and GSNO attenuate Doppler embolic signals in humans. Modulation of the NO system with these agents may have applications in the treatment of thromboembolic disease. This study demonstrates the potential application of ultrasonic embolic signal detection to examine the efficacy of new antiplatelet agents in relatively small numbers of patients.