Vascular endothelial dysfunction contributes to myocardial depression in ischemia-reperfusion in the rat.

Endocardial and vascular myocardial capillary endothelium has been shown to modulate the contractile characteristics of myocardium by altering myofibrillar affinity for calcium. Although the release of endothelial-derived substances that modify myocardial contractility has been shown to be altered in certain physiologic and pathologic situations, until now no study has evaluated whether the direct modulatory effects of endothelium on its subjacent myocardium were altered in pathologic situations and contributed to loss of contractile function. This study was designed to evaluate whether the direct contractile modulatory effects of endocardial and (or) vascular endothelium were altered and whether these alterations contributed to contractile dysfunction in a model of ischemia-reperfusion. Sixty-two perfused rat hearts as Langendorff preparations were randomized to no intervention, intracoronary Triton X100 injection (to render vascular endothelium dysfunctional), ischemia (30 min)-reperfusion (20 min), and ischemia-reperfusion followed by intracoronary Triton X100 injection. Coronary endothelial-dependent vascular reactivity and vascular smooth muscle reactivity were assessed by serotonin and sodium nitroprusside, respectively. Myocardial damage was assessed by coronary effluent creatine phosphokinase and by morphologic studies. Papillary muscles were then excised and contractile characteristics evaluated at varying extracellular calcium concentration prior to and after endocardial endothelial removal with Triton X100. All three interventions eliminated all coronary vascular response to serotonin but did not modify response to nitroprusside. Creatine phosphokinase values rose only in hearts with ischemia-reperfusion, and only minor morphologic changes occurred, mostly in hearts with ischemia-reperfusion. Papillary muscles from hearts with intracoronary Triton X100 injection had lower contractile indices compared with normal controls (total tension 4.0 vs. 4.6 g/mm2, p < 0.01) and an abbreviation of contraction duration. Increasing extracellular calcium concentration from to 0.7 to 3.25 mM eliminated these differences. Similar but more marked decreases in contractile indices and twitch duration were noted in the two ischemia-reperfusion groups, but consistent with some myocardial damage being present, increasing extracellular calcium concentration to 3.25 or 7 mM did not fully eliminate these differences. In both ischemia-reperfusion groups and the intracoronary Triton X100 group, the relative increase in total tension with increasing extracellular calcium concentrations was similar (35 to 38%) and greater than that of the control group (25%), consistent with dysfunction of vascular endothelium contributing to myocardial dysfunction in the three intervention groups. Endocardial endothelial removal had a similar effect in all four groups, suggesting that dysfunction of endocardial endothelium does not play a role in this model. We conclude that vascular but not endocardial endothelial dysfunction contributes to the myocardial dysfunction that occurs during ischemia-reperfusion injury.