This Article Full Text Full Text (PDF) All Versions of this Article: 25/8/1617    most recent 01.ATV.0000172626.00296.bav1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gunnett, C.A. Articles by Heistad, D.D. Search for Related Content PubMed PubMed Citation Articles by Gunnett, C.A. Articles by Heistad, D.D. Pubmed/NCBI databases Medline Plus Health Information Carotid Artery Disease Vasculitis

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1617.)
© 2005 American Heart Association, Inc.

Vascular Biology

Mechanisms of Inducible Nitric Oxide Synthase–Mediated Vascular Dysfunction

C.A. Gunnett; D.D. Lund; A.K. McDowell; F.M. Faraci; D.D. Heistad

From the Departments of Internal Medicine (C.A.G., D.D.L., F.M.F., D.D.H.) and Pharmacology (A.K.M., F.M.F., D.D.H.), University of Iowa Carver College of Medicine and VA Medical Center, Iowa City, Iowa.

Correspondence to Donald D. Heistad, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242. E-mail donald-heistad{at}uiowa.edu

Objective— Inducible nitric oxide synthase (iNOS) is expressed in arteries during inflammation and may contribute to vascular dysfunction. Effects of gene transfer of iNOS to carotid arteries were examined in vitro in the absence of systemic inflammation to allow examination of mechanisms by which iNOS impairs contraction and relaxation.

Methods and Results— After gene transfer of iNOS with an adenovirus (AdiNOS), constrictor responses to phenylephrine (PE) and U46619 were impaired. After AdiNOS, inhibition of soluble guanylate cyclase (sGC) with 1H-[1,2,4]oxadiazolo-[4,3,2]quinoxalin-1-one (ODQ) reduced the EC₅₀ for PE from 4.33±0.78 µmol/L to 1.15±0.43 µmol/L (mean±SEM). These results imply that iNOS impairs contraction by activation of the NO/cGMP pathway. Relaxation to acetylcholine (ACh) also was impaired after AdiNOS. Sepiapterin (300 µmol/L), the precursor for tetrahydrobiopterin (BH₄), improved relaxation to Ach. Because BH₄ is an essential cofactor for production of NO by both iNOS and endothelial nitric oxide synthase (eNOS), these results suggest that iNOS may reduce production of NO by eNOS by limiting availability of BH₄. Next, we examined effects of expression of iNOS in endothelium and adventitia. Selective expression of iNOS in endothelium, but not adventitia, impaired contraction to phenylephrine and relaxation to acetylcholine.

Conclusions— We conclude that: (1) iNOS may impair contraction in part by activation of sGC; (2) iNOS impairs relaxation, at least in part, by limiting availability of BH₄; and (3) expression of iNOS in endothelium may be a more important mediator of vascular dysfunction than expression of iNOS in adventitia.

Inducible nitric oxide synthase (iNOS) is expressed in arteries during inflammation and may impair vascular contraction of rabbit carotid artery by activation of soluble guanylate cyclase. iNOS also impairs vascular relaxation by limiting availability of BH_4. Furthermore, expression of iNOS in endothelium impairs vascular function more than expression of iNOS in adventitia.

Key Words: acetylcholine • adenovirus • gene transfer • sepiapterin

This article has been cited by other articles:

				H. Soliman, G. P. Craig, P. Nagareddy, V. G. Yuen, G. Lin, U. Kumar, J. H. McNeill, and K. M. MacLeod Role of inducible nitric oxide synthase in induction of RhoA expression in hearts from diabetic rats Cardiovasc Res, July 15, 2008; 79(2): 322 - 330. [Abstract] [Full Text] [PDF]

				J. H. Lee, S. Xia, and L. Ragolia Upregulation of AT2 receptor and iNOS impairs angiotensin II-induced contraction without endothelium influence in young normotensive diabetic rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2008; 295(1): R144 - R154. [Abstract] [Full Text] [PDF]

				T. Machida, Y. Hamaya, S. Izumi, Y. Hamaya, K. Iizuka, Y. Igarashi, M. Minami, R. Levi, and M. Hirafuji Sphingosine 1-Phosphate Inhibits Nitric Oxide Production Induced by Interleukin-1{beta} in Rat Vascular Smooth Muscle Cells J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 200 - 209. [Abstract] [Full Text] [PDF]

				Y. Zhang, T. Tazzeo, V. Chu, and L. J. Janssen Membrane potassium currents in human radial artery and their regulation by nitric oxide donor Cardiovasc Res, July 15, 2006; 71(2): 383 - 392. [Abstract] [Full Text] [PDF]