title: Therapeutic modulation of the nitric oxide: all ace inhibitors are not equivalent.
abstract: The properties of the angiotensin-converting enzyme (ACE) inhibitors have largely been attributed to a class effect. However, this opinion is now increasingly challenged in view of the findings from recent clinical trials, which have demonstrated differential effects of ACE inhibitors, in particular with respect to secondary cardiovascular prevention outcomes. In this experimental study, Sprague-Dawley rats were treated with five different ACE inhibitors (enalapril, perindopril, quinapril, ramipril, and trandolapril) at equihypotensive doses. All ACE inhibitors increased endothelial nitric oxide synthase (eNOS) protein expression and activity in the aorta (both P<0.0001 versus vehicle) and in cardiac myocytes (both P<0.05 versus vehicle). A highly significant effect was observed with perindopril when compared with vehicle in the modulation of eNOS protein expression and activity in aorta (22.52+/-1.09 versus 9.12+/-0.57 AU microg(-1) protein and 1.59+/-0.03 versus 0.77+/-0.02 pmol l(-1) citrulline min(-1)mg protein(-1), respectively) and in cardiac myocytes (17.64+/-0.94 versus 11.30+/-0.59 AU microg(-1) protein and 0.93+/-0.02 versus 0.62+/-0.03 pmol l(-1) citrulline min(-1)mg protein(-1), respectively). On the basis of the eNOS protein expression in the rat aorta, the other ACE inhibitors had similar, but lower effects. Indeed, the rank of potency - based both on eNOS protein expression and activity - was perindopril>trandolapril approximately quinapril approximately ramipril approximately enalapril (P<0.05 perindopril versus trandolapril and ramipril and P<0.01 perindopril versus enalapril, respectively). Levels of circulating nitrite/nitrate, the end-metabolites of nitric oxide, were also significantly affected by ACE inhibition, with the same order of potency. Our findings provide further evidence in favor of differential effects associated with ACE inhibitor therapy and suggest that the clinical benefits associated with these drugs may not solely reflect a class effect extending their benefit beyond blood pressure-lowering effect.
authors.affiliation: Cardiovascular Pathophysiology Research Center, Salvatore Maugeri Foundation, IRCCS, Gussago, Brescia, Italy. lcomini@fsm.it
authors.forename: L
authors.initials: L
authors.lastname: Comini
authors.forename: T
authors.initials: T
authors.lastname: Bachetti
authors.forename: A
authors.initials: A
authors.lastname: Cargnoni
authors.forename: D
authors.initials: D
authors.lastname: Bastianon
authors.forename: G L
authors.initials: GL
authors.lastname: Gitti
authors.forename: C
authors.initials: C
authors.lastname: Ceconi
authors.forename: R
authors.initials: R
authors.lastname: Ferrari
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004656:Enalapril / Q000494:pharmacology; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D020913:Perindopril / Q000494:pharmacology; D000077583:Quinapril; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D009566:Nitrates; D009573:Nitrites; D044005:Tetrahydroisoquinolines; C052035:trandolapril; D009569:Nitric Oxide; D004656:Enalapril; D052250:Nitric Oxide Synthase Type III; D017257:Ramipril; D000077583:Quinapril; D020913:Perindopril