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Acta Physiologica 2009; Volume 197, Supplement 675
Joint meeting of The Slovenian Physiological Society, The Austrian Physiological Society and The Federation of European Physiological Societies
11/12/2009-11/15/2009
Ljubljana, Slovenia
ASYMMETRIC DIMETHYLARGININE (ADMA) BY ACTIVATING THE ANGIOTENSIN II NAD(P)H OXIDASE PATHWAY ELICITS SUPEROXIDE RELEASE, WHICH INTERFERES WITH NO-MEDIATED DILATIONS
Abstract number: P237
Koller1,2,3 Akos, Marki2 Alex, Gara2 Edit, Vamos3 Zoltan, Veres1,2 Zoltan
1Dept. of Physiology, New York Med. College, Valhalla, New York USA
2Dept. of Pathophysiology, Semmelweis University, Budapest, Hungary
3Dept. of Pathophysiology and Gerontology, University of Pcs, Hungary
Increased level of asymmetric dimethylarginine (ADMA) contributes to the pathogenesis of cardiovascular diseases, but the underlying pathomechanisms have not yet been elucidated. Previously we have found that ADMA induced superoxide production, in isolated microvessels but the mechanisms remain unknown. We hypothesized that elevated level of exogenous ADMA, by activating vascular oxidases elicits increased superoxide production, which interferes with NO-mediated dilations. Isolated arterioles from rat gracilis muscle (~160 mm in diameter at 80 mmHg) were treated with indomethacin. Basal arteriolar diameter and flow-induced dilation were obtained in the presence of ADMA (10-4 mol/L). Incubation arterioles with ADMA elicited significant constrictions (from 162±4 mm to 143±4 mm) and eliminated the dilations to increases in intraluminal flow. In the presence of ADMA, superoxide dismutase (SOD) plus catalase (CAT) restored dilations to flow. Incubation of arterioles with the NAD(P)H oxidase inhibitor apocynin or the angiotensin-converting enzyme (ACE) inhibitor quinapril inhibited ADMA-induced constrictions. In addition, apocynin, quinapril or the angiotensin type 1 receptor blocker losartan restored flow-induced dilations reduced by ADMA. ADMA-induced increased production of superoxide - assessed by dihydroethidium fluorescence - was inhibited by apocynin, quinapril or losartan. ADMA or pyrogallol (known to generate superoxide) reduced arteriolar dilations to the NO donor, sodium nitroprusside (SNP), which was partially restored by SOD/CAT. Also, ADMA-induced constrictions were prevented by SOD/CAT and the NAD(P)H oxidase inhibitor apocynin, but not by the xanthine oxidase inhibitor oxypurinol.
In conclusion, we suggest that ADMA activates NAD(P)H oxidase via the renin-angiotensin system, and the produces superoxide reducing thereby the bioavailability of NO resulting in diminished NO mediated dilations. This pathophysiological mechanism may contribute to the development of cardiovascular diseases associated with elevated levels of ADMA.
(Grants by Hungarian Nat. Sci. Res. Fund-OTKA K71591, K-67984, AHA Founders Aff., 0555897T)
To cite this abstract, please use the following information:
Acta Physiologica 2009; Volume 197, Supplement 675 :P237