J Appl Physiol 99: 1237, 2005;
doi:10.1152/japplphysiol.00634.2005
8750-7587/05 $8.00
POINT-COUNTERPOINT
REBUTTAL FROM DR. GREEN
At the risk of being controversial, I will begin by stating that I agree with much of the Tschakovsky and Pyke statement. When the FMD technique was introduced in humans there was indeed no direct evidence it was NO dependent. However, one should not assume that the vision of a cart dragging a horse necessarily infers the horse is lame. Further studies not only proved the FMD approach NO dependent (3, 7–9), but also that the L-NMMA effect was definitively not due to attenuation of reactive hyperemia (8, 9) (e.g., Fig. 2A of Ref. 9).
Although FMD can technically be defined as the response to any shear stress stimulus, the widely adopted approach involves quantification of radial or brachial vasodilator response to an 
5-min ischemic stimulus where the cuff is distal to the probe (2, 3). The papers reviewed previously (3, 7–9) indicate that, under these circumstances, FMD is NO mediated and Tschakovsky and Pyke do not directly contradict this. Rather they make the case that stimulus-response specificity exists in FMD responses, where FMD is more broadly defined (e.g., different ischemic periods). I agree. Ultimately, however, the point is that we have a noninvasive technique, which, if performed appropriately, provides a valid index of NO function in vivo.
The example of coronary FMD being different to that in the periphery misses the point. Although coronary lesions are focal in nature, atherosclerosis is a systemic disease (5) that can be interrogated via peripheral NO bioassay (1). This is why FMD predicts cardiovascular events (10) and why it may reflect the compound effect of risk factors, including elevated sympathetic nervous system tone, on arterial health. Furthermore, shear stress-mediated upregulation of NO synthase expression and phosphorylation occurs in vivo (5).
Finally, the Hijmering paper provides an important reminder that controls need to be instituted before comparing FMD responses, especially between groups. However, this study did not infuse L-NMMA and in no way invalidates others that indicate that FMD is NO dependent (3, 7–9), including those that have isolated improvement in endothelial function to enhanced NO bioavailability (4, 6).
Tschakovsky and Pyke are to be lauded for bringing the issue of stimulus-response specificity to the forefront of the FMD debate. Their conclusion, that "FMD in response to many shear stress profiles is not sensitive to NO blockade"... is qualified ("...many..."), but true. However, the point remains that when the appropriate FMD approach is adopted, it provides a valid index of NO bioactivity in vivo.
REFERENCES
- Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, Leiberman EH, Ganz P, Creager MA, and Yeung AC. Close relationship of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 26: 1235–1241, 1995.[Abstract]
- Corretti MC, Anderson TJ, Benjamin EJ, Celermajer DS, Charbonneau F, Creager MA, Deanfield J, Drexer H, Gerhard-Herman M, Herrington D, Vallance P, and Vogel R. Guidelines for the ultrasound assessment of flow-mediated vasodilation of the brachial artery. J Am Coll Cardiol 39: 257–265, 2002.[Abstract/Free Full Text]
- Doshi SN, Naka KK, Payne N, Jones CJH, Ashton M, Lewis MJ, and Goodfellow J. Flow-mediated dilatation following wrist and upper arm occlusion in humans: the contribution of nitric oxide. Clin Sci (Lond) 101: 629–635, 2001.[Medline]
- Goto C, Higashi Y, Kimura M, Noma K, Hara K, Nakagawa K, Kawamura M, Chayama K, Yoshizumi M, and Nara I. Effect of different intensities of exercise on endothelium-dependent vasodilation in humans. Role of endothelium-dependent nitric oxide and oxidative stress. Circulation 108: 530–535, 2003.[Abstract/Free Full Text]
- Hambrecht R, Adams V, Erbs S, Linke a Krankel N, Shu Y, Baither Y, Geilen S, Thiele H, Gummert JF, Mohr FW, and Schuler G. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation 107: 3152–3158, 2003.[Abstract/Free Full Text]
- Hornig B, Maier V, and Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation 93: 210–214, 1996.[Abstract/Free Full Text]
- Joannides R, Haefeli WE, Linder L, Richard V, Bakkali E, Thuillez C, and Lüscher TF. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation 91: 1314–1319, 1995.[Abstract/Free Full Text]
- Lieberman EH, Gerhard MD, Uehata A, Selwyn AP, Ganz P, Yeung AC, and Creager MA. Flow-induced vasodilation of the human brachial artery is impaired in patients &cjs0060; 40 years of age with coronary artery disease. Am J Cardiol 78: 1210–1214, 1996.[CrossRef][ISI][Medline]
- Mullen MJ, Kharbanda RK, Cross J, Donald AE, Taylor M, Vallance P, Deanfield JE, and MacAllister RJ. Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo. Circ Res 88: 145–151, 2001.[Abstract/Free Full Text]
- Widlansky ME, Gocke N, Keaney JF, and Vita JA. The clinical implications of endothelial dysfunction. JACC 42: 1149–1160, 2003.[Abstract/Free Full Text]
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