Inducible nitric oxide synthase inhibits oxygen consumption in collateral-dependent myocardium

Abstract

RJ. Inducible nitric oxide synthase inhibits oxygen consumption in collateral-dependent myocardium. Am J Physiol Heart Circ Physiol 306: H356 -H362, 2014. First published December 6, 2013 doi:10.1152/ajpheart.00308.2013.-Following coronary artery occlusion growth of collateral vessels can provide an effective blood supply to the dependent myocardium. The ischemia, which results in growth of collateral vessels, recruits an inflammatory response with expression of cytokines and growth factors, upregulation of endothelial nitric oxide (NO) synthase (eNOS) in vascular endothelial cells, and expression of inducible nitric oxide synthase (iNOS) in both vessels and cardiac myocytes. Because NO is a potent collateral vessel dilator, this study examined whether NO derived from iNOS or constitutive NOS regulates myocardial blood flow (MBF) in the collateral region. Nonselective NOS inhibition with N G -nitro-L-arginine (LNA) caused vasoconstriction with a significant decrease in MBF to the collateral region during exercise. In contrast, the highly selective iNOS inhibitor 1400W caused a 21 Ϯ 5% increase of MBF in the collateral region. This increase in MBF following selective iNOS blockade was proportionate to an increase in myocardial O2 consumption (MV O2). The results suggest that NO produced by iNOS inhibits MV O2 in the collateralized region, so that the increase in MBF following iNOS blockade was the result of metabolic vasodilation secondary to an increase in MV O2. Thus the coordinated expression of iNOS to restrain MV O2 and eNOS to maintain collateral vasodilation act to optimize the O2 supplydemand relationship and protect the collateralized myocardium from ischemia. collateral vessel; coronary artery NITRIC OXIDE (NO) produced by constitutively expressed endothelial NO synthase (eNOS) is known to mediate the vasodilator responses to endothelium-dependent agonists such as acetylcholine and bradykinin, and is responsible for the flowmediated coronary artery dilation that occurs in response to increased endothelial shear stress (27). In addition to effects on coronary vascular smooth muscle, NO within the cardiac myocytes can compete with oxygen at cytochrome c oxidase in the mitochondrial respiratory chain to inhibit oxygen consumption (MV O 2 ) (3, 6).Coronary artery occlusion results in growth of native interarterial anastomotic channels to develop an effective collateral circulation that provides an alternative blood supply to the dependent myocardium. Developed collateral vessels have an organized smooth muscle media and are responsive to both vasodilator and vasoconstrictor influences (1, 9, 18). The ischemia, which results in growth of collateral vessels, recruits an inflammatory response with expression of cytokines in the vessel wall and a dramatic release of growth factors such as VEGF into the myocardial interstitial fluid (33). VEGF has been shown to upregulate eNOS expression in vascular endothelial cells but can also induce iNOS expression (4, 26, 30). Vascular NO effects are increased in collatera...

Exercise Promotes Collateral Artery Growth Mediated by Monocytic Nitric Oxide

“…It should be noted that the effect of NO on vascular growth 20 and myocardial blood flow 21 has been discussed controversially in the literature. Uncoupling of the eNOS enzyme can also aggravate oxidative stress.…”

Repetitive ischemia increases myocardial dimethylarginine dimethylaminohydrolase 1 expression

“…Because ADMA inhibits NOS activity, this increase in DDAH1 expression may help preserve NO-dependent collateral vessel development and dilation 1,3 under conditions in which protein arginine methylation is increased. In support of the concept that increased DDAH1 expression increases eNOS activity and NO formation, a prior study from our lab found that inhibition of NOS activity with L-N G -Nitroarginine ( l -NNA) produced a greater decrease of blood flow in the collateral zone as compared to the remote zone or to normal hearts, 20 suggesting that vasodilation in the collateral zone is particularly dependent on NOS activity. In a previous study examining flow heterogeneity in normal canine hearts, Laussmann et al 29 reported that DDAH1 levels are high and ADMA levels are low in areas of low flow, compared to high flow regions.…”

“…We previously reported that iNOS expression and iNOS activity were increased in the collateral zone after 3 weeks of occlusions, and the coordinated expression of iNOS and eNOS acted to maintain collateral vasodilation to optimize the O 2 supply-demand relationship and protect the collateralized myocardium from ischemia. 20 Therefore, iNOS expression is important for both collateral vessel development and collateral vasodilation.…”