Epicardial and Endocardial Coronary Microvascular Responses: Effects of Ischemia–Reperfusion

Summary: To examine whether endocardial microvascular function is preferentially impaired by ischemia and reperfusion, we studied endothelium-dependent responses of epicardial and endocardial coronary microvessels (130–220 μm) from control pigs and from pigs subjected to 1-h regional myocardial ischemia (circumflex occlusion) followed by 1-h reperfusion (n = 8) in vitro using videomicroscopy. In control animals (n = 8), no significant transmural differences were apparent in microvascular responses to the endothelium-dependent agents bradykinin or the calcium ionophore A23187, to the endothelium-independent agent sodium nitroprusside (SNP), or to adenosine. Serotonin caused a slight but statistically insignificant greater relaxation of endocardial than of epicardial microvessels. After ischemia–reperfusion, relaxations to all endothelium-dependent agents (serotonin, bradykinin, A23187) and to adenosine were significantly reduced (p < 0.05 for all agents) as compared with the respective control responses. There were no significant differences between epicardial and endocardial responses in the ischemia-reperfusion group for any of the vasoactive agents. Endothelium-independent responses to SNP were not affected by ischemia–reperfusion, indicating no alteration in the ability of vascular smooth muscle to relax through guanylate cyclase-mediated mechanisms. Control epicardial microvascular responses were examined after endothelial denudation and after pretreatment with NG-monomethyl-l-arginine (l-NMMA), indomethacin, or glibenclamide. Control vessels denuded of endothelium demonstrated impaired responses to serotonin, bradykinin, A32187, and adenosine (p < 0.05 for all agents). Pretreatment of microvessels with l-NMMA reduced endothelium-dependent relaxations (p < 0.05), but did not alter responses to adenosine significantly. Indomethacin reduced relaxations to bradykinin, A23187, and adenosine (p < 0.05), and glibenclamide impaired adenosine responses (p < 0.05). Although the subendocardium is believed to be preferentially susceptible to ischemia, the microvascular dysfunction induced by ischemia–reperfusion is similar at epicardial and endocardial transmural levels. The diminished vasodilatory responses are probably related in large part to endothelial dysfunction with reduced production or release of nitric oxide (NO). Ischemia/reperfusion may also impair microvascular relaxation by altering production or release of prostaglandin substances from the endothelium or by damaging ATP-sensitive potassium channels on vascular smooth muscle.