title: Asymmetric dimethylarginine (ADMA) induces vascular endothelium impairment and aggravates post-ischemic ventricular dysfunction in rats.
abstract: Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) inhibitor recognized as an independent risk factor for endothelial dysfunction and coronary heart diseases. This study investigated whether ADMA (10 mg/kg day for 14 days) affected endothelial function and aggravated post-ischemic ventricular dysfunction in the perfused rat heart. Systolic blood pressure and heart rate, plasma levels of ADMA and nitrite/nitrate were measured in vehicle- and ADMA-treated rats. Perfused hearts were submitted to global ischemia-reperfusion and vascular endothelial dysfunction was examined with angiotensin II in coronary vessels and aortic rings. Endothelial NO synthase (eNOS) and angiotensin-converting enzyme (ACE) mRNA expression in aortic and cardiac tissues were measured. ADMA-treated rats had higher systolic blood pressure (1.3-fold, P<0.01) and slower heart rate (16%, P<0.05) than controls. Plasma ADMA rose (1.9-fold, P<0.01) and nitrite/nitrate concentration decreased 59% (P<0.001). Ventricular contraction (stiffness) increased significantly, with worsening of post-ischemic ventricular dysfunction. In preparations from ADMA-treated rats the coronary vasculature's response to angiotensin II was almost doubled (P<0.01) and the maximal vasorelaxant effect of acetylcholine in aortic rings was significantly lower than in preparations from vehicle-treated rats. In cardiac and aortic tissues eNOS mRNA and ACE mRNA levels were similar in controls and ADMA-treated rats. The increased plasma levels of ADMA presumably cause endothelial dysfunction because of a deficiency in NO production, which also appears involved in the aggravation of myocardial ischemia-reperfusion injury.
authors.affiliation: Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Via Vanvitelli 32, Italy. vito.colonna@unimi.it
authors.forename: Vito
authors.initials: V
authors.lastname: De Gennaro Colonna
authors.forename: Sara
authors.initials: S
authors.lastname: Bonomo
authors.forename: Paolo
authors.initials: P
authors.lastname: Ferrario
authors.forename: Mauro
authors.initials: M
authors.lastname: Bianchi
authors.forename: Marco
authors.initials: M
authors.lastname: Berti
authors.forename: Marco
authors.initials: M
authors.lastname: Guazzi
authors.forename: Barbara
authors.initials: B
authors.lastname: Manfredi
authors.forename: Eugenio E
authors.initials: EE
authors.lastname: Muller
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Berti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rossoni
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000503:physiopathology*; D009566:Nitrates / Q000032:analysis; D009573:Nitrites / Q000032:analysis; D010477:Perfusion; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D018754:Ventricular Dysfunction / Q000503:physiopathology*
chemical_list: D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; C018524:N,N-dimethylarginine; D001120:Arginine; D000109:Acetylcholine