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J Appl Physiol 99: 1237-a-1238-a, 2005; doi:10.1152/japplphysiol.00672.2005
8750-7587/05 $8.00
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POINT-COUNTERPOINT

REBUTTAL FROM DRS. TSCHAKOVSKY AND PYKE

We have taken the sage advice of our erudite colleague Dr. Green to heart...namely indulging in a bottle of robust Australian Shiraz. We, first off, thank him for his suggestion as it has helped us to identify within this debate a classic blunder. Equating FMD with NO-mediated endothelial function repeats the folly of the simple tourist who sees one black sheep and concludes that black is the color of all the sheep in England. The first well-characterized FMD response in humans (2) was found to be NO dependent (4, 11) and this has lead to the assumption that all FMD must share this mechanism. Recent publications do not support this position (12) and it is time to... "shear" erroneous assumptions from our concept of FMD.

The argument by Dr. Green could be partially correct if the statement to be defended qualified the type of FMD as 1) brachial or radial artery specific (4, 11), 2) specific to 5 min of distal occlusion reactive hyperemia without ischemic handgrip exercise (1, 12), and 3) in healthy subjects (11). This is critical because primarily NO-mediated FMD has been confirmed only under this specific combination of conditions (4, 11). Furthermore, it has been demonstrated that slight deviations from these conditions resulting in small stimulus profile alterations can dramatically alter the NO dependence of the FMD response (12). Readers! Pay attention to the following statement in the very guidelines that Dr. Green cites to support a consensus on FMD assessment of endothelial NO function: "Studies have variably used either upper arm or forearm cuff occlusions and there is no consensus as to which technique provides more accurate or precise information... The change in diameter is similar after 5 and 10 min of occlusion; therefore the more easily tolerated 5-min occlusion is typically used" (3). These statements by experts in the field do not acknowledge the critical importance of the stimulus creation technique in determining the NO dependence of the FMD response.

Finally, we reiterate that, even when the methodological constraints that allow for an NO-dependent FMD response are followed, other factors may influence the magnitude of vasodilation. Specifically, the elevated sympathetic activation, common in pathologies also associated with endothelial dysfunction, may blunt the FMD response (10). In these groups, FMD in response to even 5 min of distal occlusion reactive hyperemia is a reflection of combined NO bioavailability and sympathetic activation.

Finally, it has been clearly demonstrated that some FMD responses in humans are not NO mediated (12). Under these circumstances, to state that FMD as a whole reflects NO-mediated endothelial function is to ignore this or to imply that all other mechanisms of FMD are irrelevant. This is inappropriate on two counts. First, FMD is an important vasoregulatory mechanism in both the coronary and peripheral vasculature systems (6, 9) and thus all mechanisms of FMD should be studied. Second, it has not been clearly established that all coronary FMD is NO dependent (13). In atherosclerotic coronary arteries dilation in response to increases in blood flow (regardless of the mechanism responsible) can help to attenuate myocardial ischemia (5, 7, 8). Therefore from a clinical perspective, all mechanisms of FMD in this vascular bed require focused research.

In conclusion, at present FMD can only be said to reflect NO-mediated endothelial function if it is in response to a very narrowly defined stimulus in only the radial or brachial arteries. To imply that FMD in response to other stimulus profiles in other areas of the vasculature is NO dependent might be akin to, dare we say, embracing the only black sheep in the family.

REFERENCES

  1. Betik AC, Luckham VB, and Hughson RL. Flow-mediated dilation in human brachial artery after different circulatory occlusion conditions. Am J Physiol Heart Circ Physiol 286: H442–H448, 2004.[Abstract/Free Full Text]
  2. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, and Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340: 1111–1115, 1992.[CrossRef][Web of Science][Medline]
  3. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, and Vogel R. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 39: 257–265, 2002.[Abstract/Free Full Text]
  4. Doshi SN, Naka KK, Payne N, Jones CJ, 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]
  5. Duffy SJ, Castle SF, Harper RW, and Meredith IT. Contribution of vasodilator prostanoids and nitric oxide to resting flow, metabolic vasodilation, and flow-mediated dilation in human coronary circulation. Circulation 100: 1951–1957, 1999.[Abstract/Free Full Text]
  6. Gaenzer H, Neumayr G, Marschang P, Sturm W, Kirchmair R, and Patsch JR. Flow-mediated vasodilation of the femoral and brachial artery induced by exercise in healthy nonsmoking and smoking men. J Am Coll Cardiol 38: 1313–1319, 2001.[Abstract/Free Full Text]
  7. Gielen S and Hambrecht R. Effects of exercise training on vascular function and myocardial perfusion. Cardiol Clin 19: 357–368, 2001.[CrossRef][Medline]
  8. Gielen S, Schuler G, and Hambrecht R. Exercise training in coronary artery disease and coronary vasomotion. Circulation 103: E1–E6, 2001.
  9. Gordon JB, Ganz P, Nabel EG, Fish RD, Zebede J, Mudge GH, Alexander RW, and Selwyn AP. Atherosclerosis influences the vasomotor response of epicardial coronary arteries to exercise. J Clin Invest 83: 1946–1952, 1989.[Web of Science][Medline]
  10. Hijmering ML, Stroes ES, Olijhoek J, Hutten BA, Blankestijn PJ, and Rabelink TJ. Sympathetic activation markedly reduces endothelium-dependent, flow-mediated vasodilation. J Am Coll Cardiol 39: 683–688, 2002.[Abstract/Free Full Text]
  11. Joannides R, Haefeli WE, Linder L, Richard V, Bakkali EH, Thuillez C, and Luscher 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]
  12. 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: relevance to endothelial dysfunction in hypercholesterolemia. Circ Res 88: 145–151, 2001.[Abstract/Free Full Text]
  13. Shiode N, Morishima N, Nakayama K, Yamagata T, Matsuura H, and Kajiyama G. Flow-mediated vasodilation of human epicardial coronary arteries: effect of inhibition of nitric oxide synthesis. J Am Coll Cardiol 27: 304–310, 1996.[Abstract]




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