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

Abstract

There is recent evidence that angiotensin-converting enzyme (ACE) inhibition reduces postischemic injury and angiotensin II receptor inhibition may have similar effects. We therefore further characterized the role of ACE- vs. AT1-receptor inhibition on cell injury and temporal association of leukocyte endothelial interaction in response to ischemia-reperfusion. A combined in vivo and in vitro study comparing the ACE inhibitor enalapril and the AT1-receptor antagonist losartan was performed. The extent and temporal correlation of cellular damage (propidium-iodide staining), microvascular perfusion failure and leukocyte-endothelial interaction (leukocyte adherence) were investigated by means of intravital microscopy, after the application of hemodynamically ineffective doses of enalapril and losartan (5 mg/kg). A hamster dorsal skinfold model with a 4-h tourniquet ischemia was used. In vitro, the effect of enalapril and losartan on polymorphonuclear cell (PMN) adherence, as well as adhesion molecule expression (ICAM-1, VCAM-1), on hypoxia- or IL-1beta-stimulated endothelial cells (HUVEC) was assessed using a PMN-adhesion assay and flow cytometry, respectively. Ischemia-reperfusion responses 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 significantly reduced early cellular damage, microvascular perfusion failure, and leukocyte adherence in response to ischemia-reperfusion. Conversely, AT1 receptor inhibition with losartan proved to be ineffective at attenuating postischemic microcirculatory disorders (leukocyte-endothelial interactions, microvascular perfusion failure) and aggravated cellular injury. In vitro, enalapril reduced PMN adherence and ICAM-1 and VCAM-1 expression, while losartan was ineffective in the same respect. Following ischemia-reperfusion injury, ACE- versus AT1-receptor inhibition induce differential effects concerning the extent and temporal association of cell injury and leukocyte-endothelial interaction. The use of enalapril combines the beneficial effects of preventing cell and vascular injury immediately after reperfusion, with a delayed inhibition of the inflammatory response. Since the AT1-receptor inhibitor losartan did not mimic effects obtained with ACE inhibition, it is conceivable that the responses in ischemia-reperfusion are mediated by a non-angiotensin II-AT1 receptor-dependent mechanism.

• Authors: M Guba, M Steinbauer, M Büchner, D Frölich, S Farkas, K W Jauch, M Anthuber
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 13 Issue 3 Pg. 190-6 (Mar 2000) ISSN: 1073-2322 [Print] United States
• PMID: 10718375 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin Receptor Antagonists
• Angiotensin-Converting Enzyme Inhibitors
• Interleukin-1
• Receptor, Angiotensin, Type 1
• Receptor, Angiotensin, Type 2
• Receptors, Angiotensin
• Enalapril
• Peptidyl-Dipeptidase A
• Losartan

Topics

• Angiotensin Receptor Antagonists
• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Capillaries (drug effects)
• Cell Adhesion
• Cell Death (drug effects)
• Cell Hypoxia
• Cell Line (drug effects)
• Cricetinae
• Enalapril (pharmacology)
• Endothelium, Vascular (cytology, drug effects)
• Hemodynamics
• Hemorheology
• Humans
• Interleukin-1 (pharmacology)
• Leukocytes (cytology, metabolism)
• Losartan (pharmacology)
• Mesocricetus
• Neutrophils (cytology, drug effects)
• Peptidyl-Dipeptidase A (metabolism)
• Receptor, Angiotensin, Type 1
• Receptor, Angiotensin, Type 2
• Receptors, Angiotensin (metabolism)
• Reperfusion Injury (drug therapy, metabolism)