Sheng-Kun Yao

Endogenous and Exogenous Nitric Oxide Protect Against Intracoronary Thrombosis and Reocclusion After Thrombolysis

BACKGROUND Nitric oxide (NO), an endothelium-derived relaxing factor, plays an important role in regulating platelet activation. We evaluated the effect of NO in a canine model of intracoronary thrombosis, thrombolysis, and reocclusion. METHODS AND RESULTS Before thrombosis was induced, 34 anesthetized dogs were treated with a continuous intracoronary infusion of saline (n = 8); NG-nitro-L-arginine (L-NNA, n = 8), an inhibitor of NO synthetase; L-arginine (n = 7), the precursor for NO; or sodium nitroprusside (SNP, n = 11), an NO donor. Ten minutes after the infusion was begun, an electric current of 150 microA was applied to the endothelium of coronary arteries to induce thrombosis. Occlusive thrombi developed in all dogs in the saline group (38 +/- 4 minutes) and the L-NNA group (30 +/- 6 minutes), in 6 of 7 dogs in the L-arginine group (81 +/- 18 minutes), and in 6 of 11 dogs in the SNP group (102 +/- 21 minutes) (P < .01). The time to thrombus was prolonged by L-arginine (P < .05) and SNP (P < .01). After 3 hours of thrombus formation in coronary arteries, tissue plasminogen activator and heparin were administered intravenously. Thrombi were lysed in 4 (of 8) dogs in the saline group (71 +/- 8 minutes), in 4 (of 8) dogs in the L-NNA group (72 +/- 8 minutes), in 4 (of 6) dogs in the L-arginine group (50 +/- 14 minutes), and in 4 (of 6) dogs in the SNP group (49 +/- 11 minutes) (P > .05). After thrombolysis, coronary artery reocclusion developed in all reperfused dogs in the saline group (30 +/- 8 minutes) and in the L-NNA group (48 +/- 12 minutes), in 3 (of 4) reperfused dogs in the L-arginine group (123 +/- 26 minutes), and in 3 (of 4) reperfused dogs in the SNP group (128 +/- 19 minutes) (P < .01). The ex vivo platelet aggregation induced by collagen was inhibited after in vivo treatment with L-arginine or SNP. CONCLUSIONS Increasing NO production or giving an NO donor may inhibit platelet aggregation and delay intracoronary thrombus formation and reocclusion after thrombolysis.

Liposome-bound prostaglandin E1 often prevents cyclic flow variations in stenosed and endothelium-injured canine coronary arteries.

BACKGROUND Prostaglandin E1 is a potent vasodilator with anti-inflammatory and antiplatelet effects. We tested the hypothesis that prostaglandin E1 attenuates or prevents platelet aggregation-associated cyclic flow variations (CFVs) in severely stenosed and endothelium-injured coronary arteries. METHODS AND RESULTS We induced CFVs in 21 dogs by placing an external constrictor around the left anterior descending coronary artery at the site where the endothelium had been mechanically injured. The blood flow velocity in the artery was monitored by a pulsed Doppler flow probe. Sixty minutes after CFVs were established, liposome-bound prostaglandin E1, a stable formulation, was administered intravenously to 12 dogs at incremental doses of 0.25, 0.5, 1, and 2 micrograms/kg body wt; it abolished CFVs in 8 of the 12 dogs (67%). After CFVs were eliminated, epinephrine was infused intravenously, and at a dose of 6.6 +/- 1.6 micrograms/min, it restored CFVs in 7 of 7 dogs. Control dogs (n = 9) were treated with free prostaglandin E1, which did not abolish CFVs in any dog. CONCLUSIONS Liposome-bound but not free prostaglandin E1 effectively diminishes CFVs in severely stenosed and endothelium-injured canine coronary arteries.

Cyclic flow alterations and neointimal proliferation following experimental coronary stenosis and endothelial injury

We evaluated the hypothesis that recurrent platelet aggregation as evidenced by the frequency and severity of cyclic coronary blood flow variations is an important pathophysiologic factor in the development of neointimal proliferation. In 24 chronically instrumented dogs, variable degrees of coronary artery neointimal proliferation were observed 3 weeks after mechanical injury of the arterial endothelium and the placement of an external coronary artery constrictor. The severity of neointimal proliferation at 21 days was closely related to the frequency and severity of cyclic coronary blood flow variations during the initial 7 days after instrumentation of the animals. Pharmacological therapy with a dual thromboxane A2 synthetase inhibitor and receptor antagonist and a serotonin S2 receptor antagonist frequently was successful in abolishing cyclic blood flow variations and appeared to attenuate neointimal proliferation.