Rebuttal from David C. Poole.

Abstract

Direct observation of the muscle microcirculation at rest reveals moving red blood cells (RBCs) in most capillaries, and this is consonant with dye injections in conscious animals and rest and exercise measurements of muscle [hemoglobin] in humans (Fraser et al. 2012; Poole, 2014; Poole et al. 2011, 2013; Richardson et al. 2003). There is substantial heterogeneity of RBC flux and haematocrit among capillaries and across time within capillaries. Thus, the notion of a given capillary, or unit of its surface area, representing a quantum unit of exchange either for RBC-borne O2 or for plasma substrates is absurd. The presence of the endothelial surface layer (glycocalyx) means that RBCs and plasma move at very different rates. This phenomenon renders the notion of ‘blood volume’ obscure because the volumetric proportion of RBCs versus plasma varies widely and is dependent upon flow rate. My learned colleagues (Barrett et al. 2014) find evidence for insulin-induced capillary recruitment in skin (Meijer et al. 2012). Whilst suggesting that, for some undisclosed reason, thin muscles are not representative of thicker muscles, they suppose that skin capillaries behave synonymously to those in muscle, contrary to their own data (Meijer et al. 2012). Profound organ-dependent differences exist with respect to capillary structure and function (Poole, 2014; Poole et al. 2011, 2013). The support by Barrett et al. (2014) for de novo capillary recruitment is predicated upon model-based interpretation of increased contrast-enhanced ultrasound bubbles and 1-methyl xanthine metabolism with insulin (non-flow dependent) and muscle contractions (partly flow dependent). These indirect techniques have been heavily criticized (Poole, 2014, Poole et al. 2011, 2013). Moreover, their observed microvascular volume increases are accounted for in toto by modification of the endothelial surface layer (Eskens et al. 2013). In addition, the studies by Barrett and colleagues (Inyard et al. 2007; Barrett et al. 2014) are implausible because contractions in healthy muscle were not accompanied by an increased blood flow‡ The wrong view of science obscures basic mechanisms of function/ dysfunction. For instance, heart failure and diabetes (type I/II) decrease the proportion of muscle capillaries supporting flow (Poole et al. 2011, 2012, 2013). An understanding of this phenomenon helps to explain the reduced O2 diffusing capacity and impaired glucose uptake in these diseases. This pathology would be undetected if massive capillary stasis were considered normal, and the correct therapeutic targets may be missed. In closing, Barrett et al. (2014) and I agree that ‘microvascular recruitment’ is important for increased delivery of O2 and substrates to muscle. However, the nature of that recruitment is not massive initiation of RBC flux in non-flowing vessels with insulin or contractions but, rather, an expansion of capillary volume by endothelial surface layer modification and longitudinal recruitment of exchange capacity along the length of already flowing capillaries.