3-nitrotyrosine and Angina--Unstable

Nitrates are the most frequently prescribed and utilized drugs worldwide. The elderly are a major population receiving nitrate therapy. Both nitrates and aging can increase in vivo reactive oxygen species (ROS) and reactive nitrogen species (RNS). To date, the effects of aging upon nitrate-induced ROS/RNS alteration are unknown. The present study tested the effects of aging upon nitrate-induced ROS/RNS alteration in vivo. 32 adults and 43 elderly unstable angina (UA) patients were subjected to 48 hours of isosorbide dinitrate intravenous injection (50  μg/minutes) in this clinical study. Blood samples were obtained at baseline and conclusion. Outcome measures of oxidative stress included plasma malondialdehyde (MDA), myeloperoxidase (MPO), and reduced glutathione (GSH). Plasma concentrations of NOx and nitrotyrosine served as markers of RNS. Because of the significant differences in basic clinical characters between adults and the elderly, we designed an additional experiment determining ROS/RNS stress in rat cardiac tissue. Additionally, rat thoracic aortic NOS activity served as a marker indicating endothelial function. Our study demonstrated that nitrate therapy significantly increased in vivo ROS/RNS stress in the elderly compared to adult patients, confirmed by animal data. Decreased NOS activity was observed in old rats. Taken together, the present study's data suggests a synergism between nitrate treatment and the aging process.

Topics: Adult; Aged; Aging; Angina, Unstable; Animals; Aorta, Thoracic; Female; Glutathione; Humans; Isosorbide Dinitrate; Male; Malondialdehyde; Middle Aged; Nitric Oxide Synthase; Peroxidase; Rats; Rats, Sprague-Dawley; Reactive Nitrogen Species; Reactive Oxygen Species; Tyrosine

Inadequate angiogenic response to ischemia in diabetic myocardium could result in poor collateral formation. Because hypoxia-inducible factor (HIF)-1alpha is a transcriptional activator of vascular endothelial growth factor (VEGF) and is critical for initiating angiogenic responses to hypoxia, we investigated the expression of HIF-1alpha and VEGF in specimens of human heart tissue to elucidate the molecular responses to myocardial ischemia in diabetic patients during unstable angina. Moreover, accumulation of a marker of protein nitration nitrotyrosine, as well as the superoxide anion (O(2)(-)) levels and inducible nitric oxide synthase (iNOS), were evaluated. Ventricular biopsy specimens from 15 type 2 diabetic and 14 nondiabetic patients presenting with unstable angina (ischemic group) and from 20 patients (11 type 2 diabetic and 9 nondiabetic patients) who underwent coronary bypass surgery without angina within the preceding 10 days (control group) were collected during coronary bypass surgery. Nondiabetic patients had higher HIF-1alpha and VEGF expressions compared with diabetic patients (P < 0.001). As compared with nondiabetic specimens, diabetic specimens showed higher levels of both iNOS mRNA and protein levels (P < 0.001) associated with the highest tissue levels of nitrotyrosine and O(2)(-) (P < 0.001). Diabetes is associated with increased myocardial tissue levels of iNOS, O(2)(-), and nitrotyrosine and reduced expression of myocardial angiogenesis factors during ischemia.

Topics: Acute Disease; Angina, Unstable; Collateral Circulation; Coronary Artery Bypass; Diabetes Mellitus, Type 2; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; RNA, Messenger; Superoxides; Transcription Factors; Tyrosine; Vascular Endothelial Growth Factor A; Ventricular Function

Macrophages in atherosclerotic plaque may express the inducible isoform of NO synthase (iNOS), which produces large amounts of NO. On one hand, the production of NO can be protective by its vasodilatory, antiaggregant and antiproliferative effects. On the other hand, the formation of peroxynitrite from NO may favour vasospasm and thrombogenesis. In this study, we investigated whether iNOS is present in human coronary atherosclerotic plaque, and we correlated these data with the clinical instability of the patients.. Fragments were retrieved by coronary atherectomy from 24 patients with unstable angina and 12 patients with stable angina. The presence of macrophages, and the production of TNF alpha, iNOS and nitrotyrosine were detected by immunocytochemistry.. Macrophage clusters were found in 67% of stable patients and 87% of patients with unstable angina (NS). TNF alpha was expressed in about 50% of cases in both groups. iNOS was not expressed in fragments from stable patients but was found in macrophages from 58% of unstable patients (P < 0.001). The expression of iNOS was associated with the presence of nitrotyrosine residues, a marker of peroxynitrite formation. Expression of iNOS was correlated both with complaints of angina at rest (P < 0.05) and with the presence of thrombus at morphological examination (P < 0.001).. The expression of iNOS may be induced in human coronary atherosclerotic plaque and is associated with different factors of instability.

Topics: Adult; Aged; Angina Pectoris; Angina, Unstable; Coronary Artery Disease; Coronary Vessels; Female; Humans; Immunohistochemistry; Macrophages; Male; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Tumor Necrosis Factor-alpha; Tyrosine