on June 2, 2005
Published online before print June 2, 2005, doi: 10.1161/01.ATV.0000172626.00296.ba
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Submitted on March 31, 2005
Accepted on May 20, 2005
Mechanisms of Inducible Nitric Oxide Synthase-Mediated Vascular Dysfunction
C. A. Gunnett ;
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.
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.
Key words: acetylcholine • adenovirus • gene transfer • sepiapterin
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