Alterations in endocardial vascular resistance after reperfusion in a low flow, high demand model of ischemia: effects of dipyridamole and WEB-2086, a platelet-activating factor antagonist

Abstract

To determine if alterations in regional coronary vascular resistance could occur in the type of myocardial ischemia present in severe angina pectoris, regional perfusion and function were studied in 35 conscious sedated dogs. A stenosis producing severe hypokinesia of the perfused segment was created for 2 h on the left anterior descending coronary artery and 10 episodes of 1 min of high demand ischemia (atrial pacing at a rate sufficient to induce dyskinesia in the hypoperfused segment) were superimposed before reperfusion.The dogs were randomized into three treatment groups: control (n=13), dipyridamole (n=10) or WEB-2086 (n=12), an antagonist of the effects of the endogenous platelet-activating factor. During stenosis, residual endocardial blood flow in the ischemic but nonnecrotic area averaged 0.72 ± 0.14, 0.38 ± 0.13 and 0.68 ± 0.17 ml/min per g in the control, WEB-2086 and dipyridamole groups, respectively. Twenty-four hours after reperfusion, endocardial blood flow in the ischemic area was significantly lower in control dogs (1.04 ± 0.15 ml/min per g) than in dogs treated with WEB-2086 (1.44 ± 0.28 ml/min per g; p < 0.03) or dipyridamole (3.00 ± 0.83 ml/min per g; p < 0.01).Accordingly, in control dogs, endocardial coronary vascular resistance in the ischemic area was increased after reperfusion from 85 ± 11 to 124 ± 27 mm Hg/(ml/min per g) (p < 0.05) after 24 h. In contrast, coronary vascular resistance in the ischemic ana remained unchanged in dogs receiving WEB-2086 (77 ± 8 to 79 ± 9 mm Hg/(ml/min per g); p = NS) and it decreased significantly in dogs receiving dipyridamole (72 ± 8 to 44 ± 8 mm Hg/(ml/min per g); p < 0.01). Regional function after 24 h remained depressed in all three groups.These data indicate that low flow, high demand ischemia induces alterations in the subendocardial microvasculature. Such alterations in regional coronary vascular resistance might play a role in several forms of ischemic heart disease such as in severe angina, bat they appear susceptible to improvement by therapeutic interventions that influence granulocyte and platelet activation.