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      Nitric Oxide, Peroxynitrite and cGMP in Atherosclerosis-Induced Hypertension in Rabbits: Beneficial Effects of Cicletanine

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          We studied the effect of the furopyridine derivative antihypertensive drug, cicletanine, on blood pressure, vascular nitric oxide (NO) and cyclic guanosine 3′:5′-monophosphate (cGMP) content in the aorta and the renal and carotid arteries, aortic superoxide production, and serum nitrotyrosine level in hypertensive/atherosclerotic rabbits. The effect of cicletanine was compared to that of furosemide. Rabbits were fed a normal or a cholesterol-enriched (1.5%) diet over 8 weeks. On the 8th week, the rabbits were treated per os with 2 × 50 mg/kg daily doses of cicletanine, furosemide, or vehicle for 5 days (n = 5–6 in each groups). The cholesterol diet increased mean arterial blood pressure (MABP) from 86 ± 1 to 94 ± 2 mm Hg (p < 0.05). Cicletanine decreased MABP in atherosclerotic rabbits to 85 ± 1 mm Hg (p < 0.05), but it did not affect MABP in normal animals. Furosemide was without effect in both groups. In normal animals, NO content (assessed by electron spin resonance after in vivo spin trapping) in the aorta and the renal and carotid arteries was increased by cicletanine, and the drug increased cGMP in the renal artery as measured by radioimmunoassay. The cholesterol-enriched diet decreased both vascular NO and cGMP and increased aortic superoxide production assessed by lucigenin-enhanced chemiluminescence and serum nitrotyrosine determined by ELISA. In atherosclerotic animals, cicletanine increased NO and cGMP content in the aorta and the renal and carotid arteries and decreased aortic superoxide production and serum nitrotyrosine. Furosemide did not influence these parameters. We conclude that cicletanine lowers blood pressure in hypertensive/atherosclerotic rabbits. The antihypertensive effect of the drug in atherosclerosis may be based on its beneficial effects on the vascular NO-cGMP system and on the formation of reactive oxygen species.

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          Most cited references 10

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          Endothelial function in health and disease: new insights into the genesis of cardiovascular disease.

          The vascular endothelium secretes factors that not only modulate blood vessel tone, but also participate in the development and progression of atherosclerosis through their effects on platelet adhesion and aggregation, thrombogenicity, and cell proliferation. Altered activities of these substances in patients with risk factors for cardiovascular disease (e.g., hypercholesterolemia, hypertension, diabetes, aging, postmenopausal status, smoking, and infections) appear to underlie the atherosclerotic process. There is increasing evidence from both preclinical studies and clinical trials that nitric oxide (NO) plays a pivotal role in the pathophysiology of arteriosclerosis. This review describes the role of NO in human health and disease and summarizes strategies currently being used to measure and improve endothelial dysfunction.
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            Tyrosine modification by reactive nitrogen species: a closer look.

            Peroxynitrite (ONOO-) is a powerful oxidant and cytotoxic species formed by the rapid reaction between nitrogen monoxide (nitric oxide, .NO) and superoxide (O2.-). At neutral pH ONOO- is partly protonated and this protonated form, peroxynitrous acid (ONOOH), decomposes rapidly to nitrate, forming (an) intermediate(s) with reactivity similar to .OH and .NO2. Peroxynitrite can hydroxylate and nitrate aromatic rings, and aromatic nitration of phenols such as tyrosine by ONOOH is proposed to proceed via a radical mechanism, with intermediate formation of .NO2. Modification of tyrosine by .NO2 also involves nitration via a radical mechanism. Aromatic nitration of phenols by ONOO- has been shown to be enhanced by superoxide dismutase or Fe(3+)-EDTA, which were proposed to catalyze heterolytic cleavage of ONOOH to form a nitrating species similar to the nitronium ion (NO2+). We investigated possible mechanisms of tyrosine modification by various reactive nitrogen species, including ONOO-, 3-morpholinosydnonimine (SIN-1), and .NO2. Reaction of tyrosine with ONOO- leads to formation of 3-nitrotyrosine and dityrosine, indicating intermediate formation of tyrosyl radicals. The pH dependence of formation of both 3-nitrotyrosine and dityrosine by ONOO- suggests that intermediate formation of ONOOH is required. Qualitatively similar results were obtained when ONOOH was generated continuously by H2O2 and NaNO2 at mildly acidic pH or with SIN-1, a compound which at neutral pH releases both .NO and O2.-, presumably producing ONOO-. However, relatively low yields of nitrotyrosine were obtained with SIN-1, possibly because of competing reactions of tyrosyl radicals with .NO or O2.-. Possible involvement of .NO2 in tyrosine modification by ONOO- was studied using hydroxyl radical scavengers, which can increase the radical yield during decomposition of ONOOH and thereby enhance generation of .NO2. Hydroxyl radical scavengers did not affect tyrosine modification by .NO2 directly and slightly inhibited tyrosine modification by authentic ONOO-. However, when ONOO- was produced at a slower rate, either by SIN-1 or by H2O2/NaNO2 at acidic pH, hydroxyl radical scavengers were found to significantly enhance tyrosine nitration. Our results suggest that ONOO- or ONOO(-)-generating systems induce nitration of tyrosine (or tyrosine residues in proteins) via intermediate formation of tyrosyl radicals and .NO2.
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              Generation of peroxynitrite contributes to ischemia-reperfusion injury in isolated rat hearts.

              The acute release of radicals upon reperfusion following myocardial ischemia may include both nitric oxide (NO) and superoxide anion (O2-.). The generation of peroxynitrite (ONOO-) from these radicals may contribute to ischemia-reperfusion injury. Our objective was to measure the generation of ONOO- during reperfusion of isolated hearts subjected to ischemia and to determine the effects of inhibition of NO synthase with NG-monomethyl-L-arginine (L-NMMA), or supplementation of NO with S-nitroso-N-acetyl-D,L-penicillamine (SNAP), on ONOO- generation and on the recovery of mechanical function. Isolated rat hearts were perfused at constant pressure with Krebs' buffer containing L-tyrosine, which reacts with ONOO- to form dityrosine, a fluorescent product. Dityrosine was detected in the coronary effluent of hearts infused with synthetic ONOO-. In hearts subjected to 20 min of global, no-flow ischemia there was a marked rise in endogenous ONOO- formation which peaked at 30 s of reperfusion. Formation of ONOO- was dependent upon synthesis of both NO and O2-., as dityrosine release was abolished by L-NMMA or superoxide dismutase, respectively. L-NMMA caused a concentration-dependent improvement in the recovery of mechanical function during reperfusion. Infusion of SNAP also abolished dityrosine release at reperfusion and improved the recovery of post-ischemic function. Our results show for the first time that reperfusion of the ischemic heart causes the acute production of ONOO-. Inhibiting the biosynthesis of ONOO- with L-NMMA or antagonizing its oxidant actions with SNAP are possible strategies to protect the heart from ischemia-reperfusion injury.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                February 2001
                08 February 2001
                : 38
                : 1
                : 39-46
                aDepartment of Pharmacology, University of Debrecen, Debrecen, bCardiovascular Research Group, Department of Biochemistry, University of Szeged, cDepartment of Biophysics, Biological Research Center, Szeged, Hungary, and dIPSEN-Beaufour, Paris, France
                51028 J Vasc Res 2001;38:39–46
                © 2001 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 1, References: 51, Pages: 8
                Research Paper


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