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POINT-COUNTERPOINT
1Departments of Kinesiology, Anatomy and Physiology
Kansas State University
e-mail: poole{at}vet.k-state.edu
2School of Sport and Exercise Science
University of Birmingham
3University of Birmingham Medical School
The notion that a substantial proportion of capillaries do not contain moving red blood cells (RBCs) in muscle at rest but are "recruited," i.e., begin flowing with RBCs during contractions, is one basis for our present understanding of blood-muscle exchange during exercise (20, 28). This concept emanates, in part, from August Krogh, who showed that many capillaries in resting muscle did not contain India ink after high pressure perfusion (19). Despite Krogh himself recognizing that India ink particles clumped together, more likely to prevent complete perfusion of the capillary bed at rest than during exercise, these experiments, and Krogh's O2 diffusion model based on them, are still cited by researchers invoking capillary recruitment (e.g., Refs. 22). Today capillary recruitment during exercise is accepted by many to explain important physiological phenomena, including: 1) greater blood-muscle delivery and extraction of O2, free fatty acids, and glucose and 2) reduced capillary-to-mitochondrial diffusion distances. It makes great sense that, if there were a reserve of capillaries at rest, during exercise when the muscle demands for O2 may increase up to 100-fold, all—or at least most—capillaries would contribute to meet that demand.
Why, therefore, choose to oppose the concept of capillary recruitment during exercise? In Britain, the motto of The Royal Society is "Nullius in Verba" (Take nobody's word for it, see it for yourself). However, the majority of research papers invoking capillary recruitment have not visualized the capillary bed (e.g., Refs. 3, 7, 25). In his letter to the editor of The American Journal of Physiology, the eminent microcirculation expert, Professor Eugene Renkin (26) criticized Dr. Bentzer for entitling his paper "Capillary filtration coefficient is independent of number of perfused capillaries in skeletal muscle"(4) on the basis that "... its title is misleading. No direct measurements of [RBC-flowing] capillary number were made. ..." The same criticism could be leveled at almost all papers that include the words capillary recruitment in their titles. Evidence that most capillaries already sustain flow in resting muscle would preclude the possibility that recruitment of previously nonperfused capillaries occurs to any great extent during contractions.
Direct evidence for RBC flow in most capillaries in resting muscle.
In resting muscle, intravital light microscopy shows that over 80% of capillaries support RBC flow, e.g., in rat spinotrapezius (14, 17, 24), diaphragm (15), and extensor digitorum longus (1), hamster cremaster and sartorius (8), cat sartorius (6), rabbit tenuissimus (30). However, animals in these experiments were anesthetized to facilitate muscle exteriorization and viewing of the capillary beds. To address this, Bailey and colleagues (2) employed minimally invasive techniques to measure blood flow (radioactive microspheres) and microvascular oxygen partial pressure in muscle in situ and neither criterion was altered by exteriorization. Moreover, the dynamic matching of increased O2 delivery and 
O2 during contractions in situ was preserved in the exteriorized muscle. It is difficult to conceive how anesthesia might affect arteriolar smooth muscle function at rest (to produce a falsely high %RBC-perfused capillaries) and yet muscles increase their blood flow and O2 at a ratio of 
6:1 (11), which is precisely that seen in intact voluntary exercising animals and humans (23).
Another valid concern about intravital microscopy is that there are non-RBC containing capillaries at rest that cannot be seen because of their translucency. However, neither observation of contracting (17) nor vasodilated (16) muscles revealed a significant number of such vessels (see also Refs. 8, 14). The technical requirements necessary to observe capillaries within living muscle restrict the procedure to a limited selection of animal muscles so that one question to ask is: How representative of other muscles in the animals' body and in humans are these? In anesthetized and conscious animals, Snyder et al. (29) used systemic indicator injections and demonstrated that essentially all capillaries in each muscle examined (vastus lateralis, diaphragm, soleus) were perfused within 3–7 s.
Indirect evidence for RBC flow in most capillaries in resting human muscle. Noninvasive near-infrared spectroscopy (NIRS) measures muscle hemoglobin concentration ([Hb]). If there were significant recruitment of previously non-RBC containing capillaries during exercise, say from 20 to 90%, [Hb] would be expected to increase several-fold. However, the rest-to-exercise [Hb] increase is less than onefold (e.g., 10) and can be accounted for by increased capillary hematocrit (18). Thus, as in animal muscles, there is little room for substantial capillary recruitment in human muscle.
Against the evidence for capillary recruitment during exercise. The literature that purports to demonstrate capillary recruitment deserves to be evaluated on its own merits, but the following must be considered as possible explanations for reports of many non-RBC flowing capillaries in resting muscle. 1) Capillaries are fragile structures, subject to damage by blunt trauma, surgery, and/or manipulations such as stretching (24). 2) PO2 within resting muscle is normally very low and raising this will cause arteriolar constriction and capillary flow stoppage (22). 3) Anesthetized preparations are often hypovolemic and hypotensive, which provokes reflex vasoconstriction.
In addition, misinterpretation of histological techniques has supported the notion of capillary recruitment. The conclusion that a RBC in the muscle capillary cross-section indicates RBC flow, whereas its absence supports no flow is erroneous (e.g., Ref. 13). In resting animal muscle observed in vivo, RBC movement in flowing capillaries varies over time, appearing either continuous or stop-start (9). Muscle contractions result in more continuously flowing vessels with higher RBC velocities (5). Hargreaves et al. (12) used thioflavine S (a plasma marker) to show that, since all capillaries were perfused, during contractions the increase in muscle blood flow (microspheres) could be accounted for by the increased velocity rather than capillary recruitment. Reduced flow heterogeneity and hence augmented capillary hematocrit from rest to exercise decreases the length of inter-RBC plasma gaps and increases the probability that an RBC will appear in cross section.
Is the concept that most capillaries support RBC flow in resting muscle mathematically possible?
In a typical 70-kg human with 31.5 kg of muscle (45% body mass), resting muscle blood flow is estimated as 1 l/min (or 5.4 x 1012 RBCs/min; Refs. 20, 28). Accepting a mean value for capillary density and length of 300/mm2 and 1,000 µm, respectively, if 80% of the 8.9 x 109 capillaries support RBC flow at rest, as in the rat (14, 17, 24), this would be 12 RBCs per capillary per second—very close to the 15–20 RBCs per capillary/s actually measured in rat muscle (17). Whereas such calculations are certainly not proof that most skeletal muscle capillaries have RBC flow in humans at rest, they support that it is feasible.
Why is it crucial that we question the dogma of capillary recruitment? If most capillaries support RBC flow at rest and are not recruited at exercise onset, increased substrate delivery must occur within already flowing capillaries. Accordingly, is the recruitment of more surface area along the length of already flowing capillaries, rather than de novo flow in previously stagnant capillaries, key to increased blood-myocyte exchange? Diabetes (21), heart failure (27), and chronic ischemia (5) decrease the proportion of RBC-perfused capillaries in resting muscle. If we do not recognize that most capillaries may support RBC flow at rest in healthy muscle, our ability to appreciate the mechanisms for impaired blood-muscle exchange, which may be pathognomonic to these and other diseases, is crippled.
Nullius in verba!
The online version of this article contains supplemental data showing intravital microscopy recordings demonstrating RBC flow in almost all capillaries in healthy resting spinotrapezius muscle (first video, Refs. 24, 27) and diaphragm (third video, Ref. 15). The second video demonstrates the effects of chronic heart failure (CHF; left coronary artery ligation, Ref. 27) on capillary perfusion in spinotrapezius muscle. Note, in the CHF condition, the presence of stopped RBCs in central capillaries and other capillaries that have intermittent RBC flow and/or very low/sporadic RBC flux. Adherence to the misconception that many capillaries do not flow in healthy resting muscle (i.e., capillary recruitment notion) would confound identification of the effects of this disease on capillary hemodynamics and therefore O2 delivery and substrate exchange.
GRANTS
This work was supported, in part, by grants from National Heart, Lung, and Blood Institute, HLBI-17731 and -50306, and grants-in-aid from the American Heart Association, Heartland Affiliate.
ACKNOWLEDGMENTS
We thank Professors Timothy I. Musch and George A. Brooks for facilitating presentation of the capillary recruitment debate at the American College of Sports Medicine's Integrative Physiology of Exercise meeting in Indianapolis in September 2006.
REFERENCES
This article has been cited by other articles:
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  G. F. Clough and S. Egginton Vasomotion and insulin-mediated capillary recruitment \#8211; part of the explanation? J. Physiol., July 15, 2009; 587(14): 3407 - 3408. [Full Text] [PDF]
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 G. F. Clough, M. Turzyniecka, L. Walter, A. J. Krentz, S. H. Wild, A. J. Chipperfield, J. Gamble, and C. D. Byrne Muscle Microvascular Dysfunction in Central Obesity Is Related to Muscle Insulin Insensitivity but Is Not Reversed by High-Dose Statin Treatment Diabetes, May 1, 2009; 58(5): 1185 - 1191. [Abstract] [Full Text] [PDF]
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 M. G. Clark Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscle Am J Physiol Endocrinol Metab, October 1, 2008; 295(4): E732 - E750. [Abstract] [Full Text] [PDF]
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 Rebuttal from Drs. Clark, Rattigan, Barrett, and Vincent J Appl Physiol, March 1, 2008; 104(3): 893 - 893. [Full Text] [PDF]
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D. Poole, M. Brown, and O. Hudlicka Last Word on Point:Counterpoint: There is/is not capillary recruitment in active skeletal muscle during exercise J Appl Physiol, March 1, 2008; 104(3): 901 - 901. [Full Text] [PDF]
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J. Van Teeffelen, H. Vink, B. T. Ameredes, A. M. Jones, S. Egginton, L. F. Ferreira, G. W. Schmid-Schoenbein, W. L. Murfee, S. S. Segal, K. Tyml, et al. J Appl Physiol, March 1, 2008; 104(3): 895 - 899. [Full Text] [PDF]
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