title: Comparison of zofenopril and lisinopril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE-inhibitors in experimental heart failure.
abstract: We evaluated the role of SH-groups in improvement of endothelial dysfunction with ACE-inhibitors in experimental heart failure. To this end, we compared the vasoprotective effect of chronic treatment with zofenopril (plus SH-group) versus lisinopril (no SH-group), or N-acetylcysteine (only SH-group) in myocardial infarcted (MI) heart failure rats. After 11 weeks of treatment, aortas were obtained and studied as ring preparations for endothelium-dependent and -independent dilatation in continuous presence of indomethacin to avoid interference of vasoactive prostanoids, and the selective presence of the NOS-inhibitor L-NMMA to determine NO-contribution. Total dilatation after receptor-dependent stimulation with acetylcholine (ACh) was attenuated (-49%, P<0.05) in untreated MI (n=11), compared to control rats with no-MI (n=8). This was in part due to impaired NO-contribution in MI (-50%, P<0.05 versus no-MI). At the same time the capacity for generation of biologically active NO after receptor-independent stimulation with A23187 remained intact. Chronic treatment with n-acetylcysteine (n=8) selectively restored NO-contribution in total dilatation to ACh. In contrast, both ACE-inhibitors fully normalized total dilatation to ACh, including the part mediated by NO (no significant differences between zofenopril (n=10) and lisinopril (n=8)). Zofenopril, but not lisinopril, additionally potentiated the effect of endogenous NO after A23187-induced release from the endothelium (+100%) as well as that of exogenous NO provided by nitroglycerin (+22%) and sodium nitrite (+36%) (for all P<0.05 versus no-MI). We conclude that ACE-inhibition with a SH-group has a potential advantage in improvement of endothelial dysfunction through increased activity of NO after release from the endothelium into the vessel wall. Furthermore, this is the first study demonstrating the selective normalizing effect of N-actylcysteine on NO-contribution to ACh-induced dilatation in experimental heart failure.
authors.affiliation: Department of Clinical Pharmacology, University of Groningen, A. Deusinglaan l, 9713 AV Groningen, The Netherlands. H.Buikema@med.rug.nl
authors.forename: H
authors.initials: H
authors.lastname: Buikema
authors.forename: S H
authors.initials: SH
authors.lastname: Monnink
authors.forename: R A
authors.initials: RA
authors.lastname: Tio
authors.forename: H J
authors.initials: HJ
authors.lastname: Crijns
authors.forename: D
authors.initials: D
authors.lastname: de Zeeuw
authors.forename: W H
authors.initials: WH
authors.lastname: van Gilst
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D002216:Captopril / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006331:Heart Diseases / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D066298:In Vitro Techniques; D017706:Lisinopril / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000150:complications; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D005996:Nitroglycerin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012977:Sodium Nitrite / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D013438:Sulfhydryl Compounds; D014665:Vasodilator Agents; D019323:omega-N-Methylarginine; C044958:zofenopril; D000001:Calcimycin; D002216:Captopril; D017706:Lisinopril; D005996:Nitroglycerin; D012977:Sodium Nitrite; D000109:Acetylcholine; D000111:Acetylcysteine