Augmented contractile response to endothelin and blunted endothelium-dependent relaxation in post-ischemic reperfused...

To elucidate the pathogenesis of the post-ischemic vascular injury in reperfused coronary arteries, the left anterior descending coronary artery (LAD) was occluded for 30 min or 60 min in 26 dogs. After 120 min of reperfusion, vascular strips were prepared from LAD and the left circumflex coronary artery (LCX) as control, and suspended in organ chambers containing Krebs-Henseleit solution and vascular reactivity was evaluated pharmacologically. In a separate experiment, LCX-strips from 12 dogs were subjected ex vivo to blood cell-free simulated ischemia by the substitution of perfusate to hypoxic, low pH and high K+ for 60 min and the following 60 min of reoxygenation. Vascular responses to various agents were compared prior to and after simulated ischemia. Vascular injury was also investigated histologically with electron microscopy. As the results; significantly blunted endothelium-dependent relaxations to acetylcholine (10(-6) M) and Ca-ionophore (A-23187: 10(-6) M) in LAD-strips compared to LCX were noticed (43.7 +/- 4.8 vs 61.6 +/- 7.3%, 22.7 +/- 5.2 vs 47.9 +/- 8.4% in % relaxation, respectively). Augmented contractile response selective to endothelin was also observed in reperfused vessels (LAD) compared to control vessels (10(-9) M: 105.4 +/- 19.5 vs 42.4 +/- 12.3% of 20 mM-KCl induced contraction, p less than 0.01). Electron microscopy revealed partial detachment and blebbing of endothelial cells in reperfused coronary arteries. Similar changes were also observed in the simulated ischemia and reoxygenation study, but the augmented response to endothelin was seen only when polymorphonuclear leukocytes (PMN) activated with phorbol myristate acetate were added. Our results suggest that endothelial injury does not essentially depend on PMN, but PMN promote augmented response to endothelin. These changes indicate that enhanced spasmogeneity is present in reperfused arteries, which may contribute to post-infarction angina and prolonged myocardial dysfunction after reperfusion.