Capillary transit times vary between 0.5 and 1.5s during which the red blood cells squeeze and deform in the capillary stream transiently opening stress-gated PIEZO1 channels, creating minuscule quantal changes in RBC ion contents and volume. Ideas originally advanced four decades ago and widely assumed to be correct suggested that quantal changes generated during capillary transits add up over time to generate the documented changes in RBC density during their long circulatory lifespan, the

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... ntal hypothesis. Applying the new PIEZO1 extension of the RBC model (RCM) introduced in the previous paper we investigate here in detail the changes in homeostatic variables that may be expected during single capillary transits resulting from transient PIEZO1 channel activation. The results showed that quantal volume changes were infinitesimal in magnitude, biphasic in nature, and essentially irreversible within inter-transit periods. A sub-second transient PIEZO1 activation triggered a sharp swelling peak followed by a much slower dehydration period towards lower-than-baseline volumes. The peak response was caused by net CaCl2 and fluid gain via PIEZO1 channels driven by the steep electrochemical inward Ca2+ gradient. The ensuing dehydration followed a complex time-course with sequential, but partially overlapping contributions by KCl loss via Ca2+-activated Gardos channels, PMCA mediated calcium extrusion and chloride efflux by the Jacobs-Steward mechanism. The change in relative cell volume predicted for single capillary transits was below 10-4, an infinitesimal magnitude incompatible with a functional role in capillary flow. The biphasic response predicted by the RCM appears to conform to the quantal hypothesis, but whether its cumulative effects could account for the documented changes in density during RBC senescence required an investigation of the effects of myriad transits over the full period of circulatory lifespan, the subject of the next paper of this series.