The angiotensin-converting enzyme inhibitor (ACE-I) enalapril has been shown to lower elevated levels of circulating adhesion molecules (cAM) in critically ill patients. To delineate the mechanisms of this possibly beneficial effect of enalapril, we studied the acute effects of enalapril in a well-defined model of endotoxin-triggered, cytokine-mediated cAM up-regulation. In a randomized, controlled trial, 30 healthy male volunteers received 2 ng/kg lipopolysaccharide (LPS) after pretreatment with placebo or 20 mg/day enalapril for 5 days or with a single dose of 20 mg of enalapril 2 h before LPS infusion. LPS infusion increased TNF levels 300-fold above normal, circulating (c) E-selectin levels by 425% (CI, 359%–492%), and P-selectin, VCAM-1, ICAM-1, and von Willebrand factor levels by 47%–74%. LPS infusion also enhanced ICAM-1 and CD11b expression 2- to 3-fold on monocytes. However, no differences were seen between treatment groups (P > 0.05), despite 95% inhibition of ACE activity by enalapril. Inhibition of ACE activity by enalapril does not influence plasma indices of endothelial activation after endotoxin infusion in healthy individuals. Our results do not support the concept of a beneficial clinical effect of enalaprilat in septicemia.
*Department of Clinical Pharmacology and †Division of Angiology, and ‡Clinical Institute of Medical and Chemical Laboratory Diagnostics, Vienna University, Vienna, Austria; and §Department of Medicine, Thrombosis and Vascular Biology Unit, University of Birmingham, Birmingham, United Kingdom
Received 16 Sep 2002;
first review completed 15 Oct 2002; accepted in final form 6 Nov 2002
Address reprint requests to Dr. Bernd Jilma, Department of Clinical Pharmacology, Division of Hematology and Immunology, Vienna University, Waehringer Guertel 18-20, A-1090 Wien, Austria.
This study was supported by the Austrian Nationalbank (grant no. 8917).