Rupture of atherosclerotic lesions, resulting in localized thrombi and marked falls in distal blood flow, is a pivotal event in unstable coronary syndromes. We tested the hypothesis that after lesion rupture, vasoconstrictor mechanisms are major contributors to a marked rise in distal microvascular resistance, which is responsible for much of the interruption in blood flow. Cholesterol-fed rabbits underwent endothelial denudation of their left iliac arteries to induce angiographically severe, fatty, American Heart Association type IV-like atherosclerotic lesions. After lesion disruption with a stiff wire, we measured distal blood flow and pressure, capillary patency in the distal vascular bed, and the response to the vasodilators adenosine, nitroprusside, and glyceryl trinitrate. Morphology of the lesions and of the associated thrombi was also examined to assess lumen restriction at the site of rupture. Disruption of atherosclerotic lesions reduced mean flow from 5.04+/-1.21 to 1.23+/-0.37 mL/min (P<0.005), and calculated distal vascular resistance rose rapidly, from 17.5+/-2.9 to 37.9+/-6.4 mm Hg. min/mL (P<0.005). Lesion rupture did not significantly affect capillary patency in the distal muscle vascular bed, and although nonocclusive thrombi were present at the site of nearly all ruptured lesions, embolized thrombi were rare in capillaries (<1%). The early rise in distal microvascular resistance could be normalized with intra-arterially administered adenosine or the NO donor nitroprusside, but not glyceryl trinitrate, an organonitrate possessing large muscular artery-selective vasodilator characteristics. Thus, rupture of atherosclerotic lesions induces rapid and marked increases in distal vascular resistance, which is the consequence of severe microvascular vasoconstriction. Therapeutic targeting of the microvasculature should improve reperfusion in acute coronary syndromes.