Differential effects of short-term ACE- and AT1-receptor inhibition on postischemic injury and leukocyte adherence in vivo and in vitro

There is recent evidence that angiotensin-converting enzyme (ACE) inhibitio n reduces postischemic injury and angiotensin II receptor inhibition may ha ve similar effects. We therefore further characterized the role of ACE- vs. AT1-receptor inhibition on cell injury and temporal association of leukocy te endothelial interaction in response to ischemia-reperfusion. A combined in vivo and in vitro study comparing the ACE inhibitor enalapril and the AT 1-receptor antagonist losartan was performed. The extent and temporal corre lation of cellular damage (propidium-iodide staining), microvascular perfus ion failure and leukocyte-endothelial interaction (leukocyte adherence) wer e investigated by means of intravital microscopy, after the application of hemodynamically ineffective doses of enalapril and losartan (5 mg/kg). A ha mster dorsal skinfold model with a 4-h tourniquet ischemia was used. In vit ro, the effect of enalapril and losartan on polymorphonuclear cell (PMN) ad herence, as well as adhesion molecule expression (ICAM-1, VCAM-1), on hypox ia- or IL-1 beta-stimulated endothelial cells (HUVEC) was assessed using a PMN-adhesion assay and flow cytometry, respectively. Ischemia-reperfusion r esponses revealed a biphasic pattern, comprised of an early phase (30 min) of acute cellular damage and microvascular perfusion failure, followed by a late increase (240 min) in leukocyte adherence in vivo. Enalapril signific antly reduced early cellular damage, microvascular perfusion failure, and l eukocyte adherence in response to ischemia-reperfusion. Conversely AT1 rece ptor inhibition with losartan proved to be ineffective at attenuating posti schemic microcirculatory disorders (leukocyte-endothelial interactions, mic rovascular perfusion failure) and aggravated cellular injury. In vitro, ena lapril reduced PMN adherence and ICAM-1 and VCAM-1 expression, while losart an was ineffective in the same respect. Following ischemia-reperfusion inju ry; ACE- versus AT1-receptor inhibition induce differential effects concern ing the extent and temporal association of cell injury and leukocyte-endoth elial interaction. The use of enalapril combines the beneficial effects of preventing cell and vascular injury immediately after reperfusion, with a d elayed inhibition of the inflammatory response. Since the AT1-receptor inhi bitor losartan did not mimic effects obtained with ACE inhibition, it is co nceivable that the responses in ischemia-reperfusion are mediated by a non- angiotensin II-AT1 receptor-dependent mechanism.