Nitric Oxide and Regulation of Arterial Elasticity: Right Idea, Wrong Vascular Bed?
To the Editor:
We were disappointed with the reply to our recent letter about the involvement of nitric oxide (NO) in the regulation of arterial stiffness.1 Although we enjoyed the well-written and robust reply to the points we raised, we feel obliged to point out a number of factual inaccuracies that may lead to misinterpretation of the debate and to refocus the issue on several points they seem to misunderstand.
Although Kinlay et al agree with our contention that pulse wave velocity in the brachial artery changes little with age, they suggest that this is irrelevant to their recent findings that NO regulates several indices of brachial artery elasticity (including pulse wave velocity) in vivo. However, we would disagree, because the same group have previously published data demonstrating that aging progressively impairs endothelium-dependent vasodilatation in the forearm vascular bed.2 Therefore, if, as they maintain, NO is important in regulating arterial elasticity in the arm, surely brachial artery elasticity should decrease with age. Indeed, we would be interested to know how the authors reconcile both sets of observations.
Kinlay et al also suggest that their own technique “is independent of blood flow, as it is a direct assessment of arterial distension.” However, as the authors well know, shear stress is the main physiological stimulus to endothelial nitric oxide production in vivo. Therefore, any drug that reduces blood flow will reduce shear stress and, thus, nitric oxide production in the large arteries. This means that changes in blood flow could influence large artery stiffness indirectly by altering local nitric oxide release. Thus, it seems to us that it is important to control adequately for any changes in flow during such experiments.
Worryingly, they appear to have misread, rather than misinterpreted, our comment on the use of pulse wave analysis (rather than pulse wave velocity) as a technique to assess endothelial function noninvasively. Indeed, we clearly refer to our own recent publication describing and validating this methodology.3 Moreover, we would fully agree that assessment of pulse wave velocity is unlikely to be of value in this respect.
Arterial stiffness is an important determinant of cardiovascular risk, and both our paper and that of Kinlay support a role for nitric oxide in regulating arterial stiffness, in contrast to 2 previous reports.4,5 Nevertheless, methodological issues are important and, far from putting our concerns to bed, their reply has given us sleepless nights.
Wilkinson IB, Webb DJ, Cockcroft JR. Nitric oxide and the regulation of arterial elasticity: right idea, wrong vascular bed? Hypertension. 2002; 39: e26–e27.
Gerhard M, Roddy MA, Creager SJ, Creager MA. Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension. 1996; 27: 849–853.
Wilkinson IB, Hall IR, MacCallum H, Mackenzie IS, McEniery CM, van der Arend BJ, Shu Y-E, MacKay LS, Webb DJ, Cockcroft JR. Pulse wave analysis: clinical evaluation of a non-invasive, widely applicable method for assessing endothelial function. Arterioscler Thromb. 2001; 22: 147–152.
Leeson CMP, Whincup PH, Cook DG, Mullen MJ, Donald AE, Seymour CA, Deanfield JE. Cholesterol and arterial distensibility in the first decade of life: a population-based study. Circulation. 2000; 101: 1533–1538.
Joannides R, Richard V, Haefeli WE, Benoist A, Linder L, Lusher TF, Thuillez C. Role of nitric oxide in the regulation of the mechanical properties of peripheral conduit arteries in humans. Hypertension. 1997; 30: 1465–1470.
We were surprised to see another letter from Wilkinson et al1 after our response to their original letter concerning our recent publication on the role of nitric oxide in regulating arterial elasticity. Their study in sheep2 confirms our earlier results in humans3—so why the debate?
We are asked to reconcile the observations that endothelium-dependent vasodilation in the arm decreases with age, whereas some studies have not shown a change in brachial pulse-wave velocity with age. Indeed, pulse wave velocity in the brachial artery has been shown to increase with age, indicative of worsening arterial compliance.4 Thus, our recent observation that nitric oxide contributes to compliance and our prior observation that brachial endothelium-dependent vasodilation worsens with age are entirely consistent with each other.
They are also concerned that the drugs used in our experiment would have affected resistance vessel tone and, therefore, blood flow and shear stress. They argue that our measurements were not controlled for changes in flow by the infusions. As stated before,5 we did control for the flow effect of the infusion by comparing our drug infusions with a control infusion at the same infusion rate. However, they imply that the reduction in blood flow with L-NMMA would have reduced shear stress on the conduit brachial artery and decreased nitric oxide production. Although their speculation is plausible, it does not really matter how nitric oxide in the conduit artery was inhibited. Whether LNMMA inhibited nitric oxide by direct effects on the conduit artery or indirect effects from decreased blood flow, our conclusion that inhibition of nitric oxide impairs conduit arterial elasticity remains solid because our measurement of elasticity was not flow-dependent. In contrast, their technique (ie, pulse wave velocity)2 could well be affected by flow.
Finally, we could be forgiven for not commenting on their use of pulse wave analysis as a measure of endothelial function. When our original paper was published, their study on the use of pulse wave analysis for this purpose had not been published, and it was cited as “in press” in their letter that we were asked to review. Although their published letter subsequently referenced this paper, they incorrectly cited their published date as 2001 instead of 2002.1 As the paper was still unpublished, we feel that this is a most petty criticism because we had no way of evaluating their claims.
From our point of view, it seems that we all agree with the principle that nitric oxide regulates elasticity. Thus, it is surprising that Wilkinson et al continue to amass questions to create a “debate.”
Wilkinson IB, Webb DJ, Cockcroft JR. Nitric oxide and the regulation of arterial elasticity: right idea, wrong vascular bed? Hypertension. 2002; 39: e26–27.
Wilkinson IB, Qasem A, McEniery CM, Webb DJ, Avolio AP, Cockcroft JR. Nitric oxide regulates local arterial distensibility in vivo. Circulation. 2002; 105: 213–217.
Kinlay S, Creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP, Ganz P. Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo. Hypertension. 2001; 38: 1049–1053.
Avolio AP, Chen SG, Wang RP, Zhang CL, Li MF, O’Rourke MF. Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community. Circulation. 1983; 68: 50–58.
Kinlay S, Ganz P, Creager MA. Response. Hypertension. 2002; 39: e26–27.